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Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these reactive states, the cell biology underlying inflammatory reactive astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes to identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization of endolysosomal compartments, decreased autophagic flux, and increased exocytosis of certain endolysosomal cargos. Through endolysosomal proteomics, we identified and focused on one such cargo-IL-32, a disease-associated pro-inflammatory cytokine not present in rodents, whose secretion mechanism is not well understood. We found that IL-32 was partially secreted in extracellular vesicles likely to be exosomes. Furthermore, we found that IL-32 was involved in the polarization of inflammatory reactive astrocyte states and was upregulated in astrocytes in multiple sclerosis lesions. We believe that our results advance our understanding of cell biological pathways underlying inflammatory reactive astrocyte phenotypes and identify potential therapeutic targets.

BACKGROUND AND AIMS: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpars antipruritic effects and IL-31 and bile acid levels in patients with PBC. APPROACH AND RESULTS: IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS ( r = 0.54, p < 0.0001), and total ( r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p = 0.0003) and 10 mg (-52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids ( r = 0.63, p < 0.0001) in the seladelpar 10 mg group. CONCLUSIONS: Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpars antipruritic effects.

Inflammatory neuropathies, which include chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain Barré syndrome (GBS), result from autoimmune destruction of the PNS and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we used paired single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor-sequencing (scTCR-Seq) of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21-expressing CD4+ T cells that were clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells consisted of 2 transcriptionally distinct expanded cell populations, which expressed genes associated with T follicular helper (Tfh) and T peripheral helper (Tph) cell subsets. Remarkably, TCR clonotypes were shared between these 2 IL-21-expressing cell populations, suggesting a common lineage differentiation pathway. Finally, we demonstrated that IL-21 receptor-KO (IL-21R-KO) mice were protected from neuropathy development and had decreased immune infiltration into peripheral nerves. IL-21 signaling upregulated CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.

The mouse pathogen Citrobacter rodentium is utilized as a model organism for studying infections caused by the human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and to elucidate mechanisms of mucosal immunity. In response to C. rodentium infection, innate lymphoid cells and T cells secrete interleukin (IL)-22, a cytokine that promotes mucosal barrier function. IL-22 plays a pivotal role in enabling mice to survive and recover from C. rodentium infection, although the exact mechanisms involved remain incompletely understood. Here, we investigated whether particular components of the host response downstream of IL-22 contribute to the cytokine's protective effects during C. rodentium infection. In line with previous research, mice lacking the IL-22 gene (Il22-/- mice) were highly susceptible to C. rodentium infection. To elucidate the role of specific antimicrobial proteins modulated by IL-22, we infected the following knockout mice: S100A9-/- (calprotectin), Lcn2-/- (lipocalin-2), Reg3b-/- (Reg3β), Reg3g-/- (Reg3γ), and C3-/- (C3). All knockout mice tested displayed a considerable level of resistance to C. rodentium infection, and none phenocopied the lethality observed in Il22-/- mice. By investigating another arm of the IL-22 response, we observed that C. rodentium-infected Il22-/- mice exhibited an overall decrease in gene expression related to intestinal barrier integrity as well as significantly elevated colonic inflammation, gut permeability, and pathogen levels in the spleen. Taken together, these results indicate that host resistance to lethal C. rodentium infection may depend on multiple antimicrobial responses acting in concert, or that other IL-22-regulated processes, such as tissue repair and maintenance of epithelial integrity, play crucial roles in host defense to attaching and effacing pathogens.

Background: Convalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP. Methods: We measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality. Results: Of the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97). Conclusion: In patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes. Trial registration: Ethics Committee of the University Hospital of Liège CE 2020/239. Clinicaltrials.gov NCT04558476. Registered 2020-09-11, https://www.clinicaltrials.gov/study/NCT04558476. [ABSTRACT FROM AUTHOR]

Purpose: Cumulating evidence supports the close association between periodontal diseases, neuroinflammation and neurodegenerative pathologies, except for peri-implantitis (PI). Thus, this study explored the association between experimental PI and neuropathological changes in the rat brain. Materials and methods: After bilateral first molars extraction, experimental PI was induced at titanium implants placed in the maxillae by lipopolysaccharide injections and ligature placement. Following 28-weeks of disease progression, the maxillae and brains were retrieved from 6 rats. Healthy brains from 3 rats were used as control. Brains were analyzed by immunohistochemistry to detect signs of neuroinflammation (interleukin (IL)-6 and tumor necrosis factor (TNF)-α)), microglial activation (IBA-1) and astrogliosis (GFAP). To explore signs of neurodegeneration, hematoxylin/eosin and Nissl stainings were used. Also, four different antibodies against amyloid beta (Aβ 1–42) were tested. Results: Chronic PI lesions showed peri-implant bone resorption accompanied by large inflammatory infiltrates. IL-6+ and TNF-α+ cells were found within the CA1 and Dentate Gyrus regions of the hippocampus of the PI-affected group, while almost no immune-positivity was detected in the control (p < 0.05). Detection of activated GFAP+ microglia and IBA-1+ astrocytes surface were significantly higher at the CA areas, and cerebral cortex of the PI-affected group, in comparison with control (p < 0.05). Shrunk neurons with pyknotic nuclei were inconsistently found among the PI-affected group, and these were almost not detected in control. No positive Aβ reactivity was detected in any of the samples. Conclusion: Chronic experimental PI lesions led to an increased detection of IL-6 and TNF-α, GFAP+ microgliosis and IBA-1+ astrocytosis, and in some cases, neurodegeneration, in the rat brain. [ABSTRACT FROM AUTHOR]

Background: Acetaminophen (APAP)-induced hepatotoxicity is a potentially life-threatening condition. Gardenia jasminoides fruit extract (GJE), which contains geniposide (Gen) as its major active constituent, possesses anti-inflammatory and antioxidant properties and may help address the underlying pathogenesis of APAP-induced hepatotoxicity. This study aimed to evaluate the effects of GJE in a mouse model of APAP-induced hepatotoxicity. Methods: Twenty-four male ICR mice were divided into 4 groups (n = 6/group): [1] Control group, mice were given distilled water; [2] APAP group, mice received a single dose of 600 mg/kg APAP; [3] APAP + low-dose GJE group, mice received APAP followed 30 min later by 2 doses of low-dose GJE (0.44 g/kg/dose, containing Gen 100 mg/kg/dose) 8 h apart; [4] APAP + high-dose GJE group, mice received APAP followed by 2 doses of high-dose GJE (0.88 g/kg/dose, containing Gen 200 mg/kg/dose). All mice were euthanized 24 h after APAP administration. Liver tissue was used for histological examination and to measure glutathione (GSH) and malondialdehyde (MDA) levels. Serum was used to determine levels of ALT and inflammatory cytokines (tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6)). Results: Liver histopathology showed moderate to severe hepatic necroinflammation in the APAP group, whereas only mild necroinflammation was observed in both treatment groups. Serum ALT levels were significantly elevated in the APAP group compared to the control group but were significantly reduced after low- and high-dose GJE treatment. Serum TNF- α levels were significantly higher in the APAP group than in the control group and were significantly lower after high-dose GJE treatment (135.5 ± 477.2 vs. 35.5 ± 25.8 vs. 74.7 ± 47.2 vs. 41.4 ± 50.8 pg/mL, respectively). Serum IL-6 followed a similar pattern. Hepatic GSH levels were significantly lower in the APAP group compared to the control group but significantly increased after both low- and high-dose GJE treatment (19.9 ± 4.5 vs. 81.5 ± 12.4 vs. 71.4 ± 7.8 vs. 82.6 ± 6.6 nmol/mg protein, respectively). Conversely, hepatic MDA levels were significantly elevated in the APAP group compared with the control group but significantly decreased after high-dose GJE treatment (108.6 ± 201.5 vs. 40.5 ± 18.0 vs. 40.5 ± 16.8 nmol/mg protein, respectively). Conclusions: Treatment with G. jasminoides fruit extract can alleviate APAP-induced hepatotoxicity, likely through its anti-inflammatory and antioxidant properties. [ABSTRACT FROM AUTHOR]

Background: Fibromyalgia (FM) is characterized by chronic pain and a complex array of symptoms, with neuroinflammation implicated in its pathophysiology. Methods: This study aimed to explore the association between neuroinflammation, measured through interleukin levels (IL-1, IL-6, IL-8), and clinical outcomes in FM patients. Using a cross-sectional study design, blood levels of these interleukins were correlated with pain severity and disability, assessed via the Fibromyalgia Impact Questionnaire (FIQ) and pain measures. Results: Results indicated that IL-6 and IL-8 may particularly serve as biomarkers for pain severity and disability in FM patients, showing significant associations with worse clinical outcomes. Elevated IL-8 levels, for instance, correlated strongly with increased pain perception and higher disability scores. Conclusions: These findings suggest that specific interleukins are not only elevated in FM but are actively involved in the modulation of pain and disability, underscoring the role of systemic neuroinflammation in the clinical severity of FM. This study contributes to a deeper understanding of the inflammatory mechanisms in FM and underscores the potential of targeting interleukins in therapeutic strategies. [ABSTRACT FROM AUTHOR]

Interleukins play dual roles in breast cancer, acting as both promoters and inhibitors of tumorigenesis within the tumor microenvironment, shaped by their inflammatory functions. This study analyzed the subtype-specific prognostic significance of an acute inflammatory versus a chronic inflammatory interleukin signature using microarray-based gene expression analysis. Correlations between these interleukin signatures and immune cell markers (CD8, IgKC, and CD20) and immune checkpoints (PD-1) were also evaluated. This study investigated the prognostic significance of an acute inflammatory IL signature (IL-12, IL-21, and IFN-γ) and a chronic inflammatory IL signature (IL-4, IL-5, IL-10, IL-13, IL-17, and CXCL1) for metastasis-free survival (MFS) using Kaplan–Meier curves and Cox regression analyses in a cohort of 461 patients with early breast cancer. Correlations were analyzed using the Spearman–Rho correlation coefficient. Kaplan–Meier curves revealed that the prognostic significance of the acute inflammatory IL signature was specifically pronounced in the basal-like subtype (p = 0.004, Log Rank). This signature retained independent prognostic significance in multivariate Cox regression analysis (HR 0.463, 95% CI 0.290–0.741; p = 0.001). A higher expression of the acute inflammatory IL signature was associated with longer MFS. The chronic inflammatory IL signature showed a significant prognostic effect in the whole cohort, with higher expression associated with shorter MFS (p = 0.034). Strong correlations were found between the acute inflammatory IL signature and CD8 expression (ρ = 0.391; p < 0.001) and between the chronic inflammatory IL signature and PD-1 expression (ρ = 0.627; p < 0.001). This study highlights the complex interaction between acute and chronic inflammatory interleukins in breast cancer progression and prognosis. These findings provide insight into the prognostic relevance of interleukin expression patterns in breast cancer and may inform future therapeutic strategies targeting the immune–inflammatory axis. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that progresses with demyelination and neurodegeneration. To date, many studies have revealed the key role of interleukins in the pathogenesis of MS, but their impact has not been fully explained. The aim of the present study was to collect and review the results obtained so far regarding the influence of interleukins on the development and course of MS and to assess the potential for their further use. Through the platform "PubMed", terms related to interleukins and MS were searched. The following interval was set as the time criterion: 2014–2024. A total of 12,731 articles were found, and 100 papers were subsequently used. Cells that produce IL-10 have a neuroprotective effect, whereas those that synthesize IL-6 most likely exacerbate neuroinflammation. IL-12, IL-23 and IL-18 represent pro-inflammatory cytokines. It was found that treatment with an anti-IL-12p40 monoclonal antibody in a study group of MS patients showed a beneficial effect. IL-4 is a pleiotropic cytokine that plays a significant role in type 2 immune responses and inhibits MS progression. IL-13 is an anti-inflammatory cytokine through which the processes of oligodendrogenesis and remyelination occur more efficiently. The group of interleukins discussed in our paper may represent a promising starting point for further research aimed at finding new therapies and prognostic markers for MS. [ABSTRACT FROM AUTHOR]

Background: Huanglianjiedu decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) prescription with thousand years of clinical use against various malignancies, including pancreatic adenocarcinoma (PAAD). However, its potential bioactive component and molecular mechanism remains unclear. Aims: This study is to inspect the HLJDD mechanisms of action against PAAD via integrated computational and pharmacochemistry strategy, in vivo and in vitro experiments to validate associated targets and pathways. Methods: A PAAD xenograft model was established by subcutaneous injecting Panc02 cells into C57BL/6 mice. Ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) was engaged to determine constituents of HLJDD and assessed for pharmacokinetic scheme using the TCM Systems Pharmacology Platform (TCM-SP). Differentially expressed genes (DEGs) of PAAD was retrieved from the transcriptome dataset GSE43795, followed by recognizing overlapping targets the oncogenes and target genes of PAAD and HLJDD, respectively. Putative signaling pathways of HLJDD in treating PAAD were enriched using KEGG and GO analyses. The anti-PAAD effects of HLJDD was assessed in vivo and in vitro, besides, the potential mechanism was validated using immunoblotting and immunohistochemical assays. Results: HLJDD significantly suppressed the growth of transplanted PAAD tumors, constrained PAAD progression, and induced apoptosis and S-phase arrest. Seventy-five active components meeting the drug-likeness criteria and 278 target genes of HLJDD were identified. KEGG analysis indicated that the top three enriched pathways were cancer, AGE-RAGE signaling, and IL-17 signaling pathways. Disease enrichment analysis highlighted immune, pharmacological, and cancer-related diseases as the top three categories. A total of 47 potential target genes were identified. Immunoblotting revealed that HLJDD inhibited PI3K and MAPK-related signaling pathways, while immunohistochemical staining confirmed that HLJDD suppressed the expression of phosphorylated MAPK and ERK1/2. Conclusion: HLJDD inhibited PAAD in vitro and in vivo via the modulation of multiple mechanisms, including regulation of PI3K/AKT/mTOR and MAPK/ERK1/2 signaling pathways. [ABSTRACT FROM AUTHOR]

In the field of breast cancer treatment, the immunotherapy involving natural killer (NK) cells is increasingly highlighting its distinct potential and significance. Members of the interleukin (IL) family play pivotal regulatory roles in the growth, differentiation, survival, and apoptosis of NK cells, and are central to their anti-tumor activity. These cytokines enhance the ability of NK cells to recognize and eliminate tumor cells by binding to specific receptors and activating downstream signaling pathways. Furthermore, interleukins do not function in isolation; the synergistic or antagonistic interactions between different interleukins can drive NK cells toward various functional pathways, ultimately leading to diverse outcomes for breast cancer patients. This paper reviews the intricate relationship between NK cells and interleukins, particularly within the breast cancer tumor microenvironment. Additionally, we summarize the latest clinical studies and advancements in NK cell therapy for breast cancer, along with the potential applications of interleukin signaling in these therapies. In conclusion, this article underscores the critical role of NK cells and interleukin signaling in breast cancer treatment, providing valuable insights and a significant reference for future research and clinical practice. [ABSTRACT FROM AUTHOR]

Background: Some experimental data suggest that myokines may play an important role in developing cancer-associated cachexia (CAC), but their relevance in humans remains poorly explored. In our study, we tested the hypothesis that circulating myokines are associated with the pathogenesis of CAC in a model population of gastric cancer. Methods: A group of 171 treatment naïve patients with adenocarcinoma of the stomach were prospectively examined. Cachexia was defined as weight loss >5% or weight loss >2% with either BMI <20 kg/m2 or sarcopenia. A panel of 19 myokines was measured in portal and peripheral blood as well as tumour tissue and surrounding gastric mucosa. Moreover, a serum proteomic signature of cachexia was identified by a label-free quantitative proteomics with a nano LCMS/MS system and stored in a ProteomeXchange database (PXD049334). Results: One hundred (58%) patients were diagnosed with CAC. The concentrations of fatty acid-binding protein 3 (FABP3), follistatin-like 1 protein (FSTL-1), interleukin 6 (IL 6), and interleukin 8 (IL 8) were significantly higher in the peripheral blood of cachectic subjects, while leptin levels were lower. Of all the evaluated myokines, tumour tissues showed higher expression levels only for IL-15 and myostatin. However, the analysis of paired samples failed to demonstrate a decreasing concentration gradient between the portal and peripheral blood for any of the myokines, evidencing against their release by the primary tumour. Proteomic analysis identified 28 proteins upregulated and 24 downregulated in the peripheral blood of patients with cachexia. Differentially expressed proteins and 5 myokines with increased serum levels generated a significant proteinprotein interaction network. Conclusions: Our study provides clinical evidence that some myokines are involved in the pathogenesis of cachexia and are well integrated into the regulatory network of circulating blood proteins identified among cachectic patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Background: In Parkinson's disease (PD) brains, microglia are activated to release inflammatory factors to induce the production of reactive oxygen species (ROS) in neuron, and vice versa. Moreover, neuroinflammation and its synergistic interaction with oxidative stress contribute to the pathogenesis of PD. Methods: In this study, we investigated whether in-house synthetic coumarin-chalcone derivatives protect human microglia HMC3 and neuroblastoma BE(2)-M17 cells against 1-methyl-4-phenyl pyridinium (MPP+)-induced neuroinflammation and associated neuronal damage. Results: Treatment with MPP+ decreased cell viability as well as increased the release of inflammatory mediators including cytokines and nitric oxide in culture medium, and enhanced expression of microglial activation markers CD68 and MHCII in HMC3 cells. The protein levels of NLRP3, CASP1, iNOS, IL-1b, IL-6, and TNF-a were also increased in MPP+-stimulated HMC3 cells. Among the four tested compounds, LM-016, LM-021, and LM-036 at 10 µM counteracted the inflammatory action of MPP+ in HMC3 cells. In addition, LM-021 and LM-036 increased cell viability, reduced lactate dehydrogenase release, ameliorated cellular ROS production, decreased caspase-1, caspase-3 and caspase-6 activities, and promoted neurite outgrowth in MPP+-treated BE(2)-M17 cells. These protective effects were mediated by down-regulating inflammatory NLRP1, IL-1b, IL-6, and TNF-a, as well as up-regulating antioxidative NRF2, NQO1, GCLC, and PGC-1a, and neuroprotective CREB, BDNF, and BCL2. Conclusion: The study results strengthen the involvement of neuroinflammation and oxidative stress in PD pathogenicmechanisms, and indicate the potential use of LM-021 and LM-036 as dual inflammasome inhibitors in treating both NLRP1- and NLRP3-associated PD. [ABSTRACT FROM AUTHOR]

Background: While the effect of biomaterials covering the pulp tissue is considered in the success of pulpotomy treatment, the level of pulpal inflammation is still very important for treatment success. The aim of this study was to compare IL-6 and IL-8 levels, known as good indicators of pulpal inflammation, with a new biomarker, presepsin, and to evaluate the impact of biomarker levels along with the pulp capping agents used in the treatment on the one-year success of pulpotomy treatment. Methods: The study included 120 primary second molar teeth with pulpotomy indications from 75 children. To determine the pulpal inflammation status, pulpal bleeding samples were taken during treatment, and the levels of IL-6, IL-8, and presepsin were measured. During the pulpotomy treatment, MTA, NeoMTA™, and Biodentine™, and ZOE were randomly applied to groups of thirty teeth each. Patients were monitored for a period of 12 months post-treatment. Results: IL-8, IL-6, and presepsin levels were significantly higher in teeth with pathology (p < 0.001). Biomarker levels were found to be higher in the NeoMTA and Biodentine groups, but this did not result in a statistically significant difference. (p > 0.05) Following pulpotomy treatment, the most successful material groups in order were MTA, ZOE, NeoMTA™, and Biodentine™. Conclusion: Presepsin may be a usable indicator in predicting the level of inflammation. At the end of the one-year follow-up of pulpotomy treatment, more pathology was observed in the NeoMTA and Biodentine groups, where biomarker levels were higher, while no pathology was found in the MTA group, where biomarker levels were lower. Trial registration: NCT06398327/ 20,240,503. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer's disease (AD), alongside ß-amyloid deposition and the formation of neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part of the innate immune system, has been implicated in the neuropathology of both preclinical amyloid and tau transgenic models. Activation of the NLRP3 pathway involves an initial priming step, which increases the expression of Nlrp3 and interleukin (IL)-1ß, followed by the assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC, and caspase-1. This assembly leads to the proteolytic maturation of the pro-inflammatory cytokines IL-1ß and IL-18. Additionally, the NLRP3 inflammasome induces Gasdermin D (GSDMD) cleavage, forming membrane pores through which IL-1ß and IL-18 are secreted. Inhibition of NLRP3 has been shown to enhance plaque clearance by modulating microglial activation. Furthermore, blocking NLRP3 in tau transgenic mice has been found to reduce tau phosphorylation by affecting the activity of certain tau kinases and phosphatases. Methods: In this study, organotypic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1ß secretion levels in the presence and absence of NLRP3 inhibitors. The role of NLRP3 activity was investigated in fullbody Nlrp3 knockout mice crossbred with the tau transgenic P301S model. Additionally, full-body and microglia-selective Gsdmd knockout mice were crossbred with P301S mice, and tau pathology and neurodegeneration were evaluated at early and late stages of the disease using immunohistochemistry and biochemical assays. Results: Activation of the NLRP3 pathway was observed in the mouse organotypic slice culture (OSC) model following stimulation with LPS and nigericin or exposure to tau seeds. However, Nlrp3 deficiency did not mitigate tauopathy or neurodegeneration in P301S mice in vivo, showing only a minor effect on plasma neurofilament (NF-L) levels. Consistently, Gsdmd deficiency did not alter tau pathology in P301S mice. Furthermore, neither full-body nor microglia-selective Gsdmd deletion had an impact on neuronal pathology or the release of pro-inflammatory cytokines. Conclusion: The absence of key components of the NLRP3 inflammasome pathway did not yield a beneficial effect on tau pathology or neurodegeneration in the preclinical Tau-P301S mouse model of AD. Nonetheless, organotypic slice cultures could serve as a valuable ex vivo mechanistic model for evaluating NLRP3 pathway activation and pharmacological inhibitors. [ABSTRACT FROM AUTHOR]

Background: Modified furosemide responsiveness index (mFRI) is a novel biomarker for assessing diuretic response and AKI progression in patients with early AKI. However, the comparative predictive performance of mFRI and novel renal biomarkers for adverse renal outcomes remains unclear. In a single-center prospective study, we aimed to evaluate the discriminatory abilities of mFRI and other novel renal biomarkers in predicting AKI progression and prognosis in patients with initial mild and moderate AKI (KDIGO stage 1 to 2). Results: Patients with initial mild and moderate AKI within 48 h following cardiac surgery were included in this study. The mFRI, renal biomarkers (including serum or urinary neutrophil gelatinase-associated lipocalin [sNGAL or uNGAL], serum cystatin C, urinary N-acetyl-beta-D-glycosaminidase [uNAG], urinary albumin-to-creatinine ratio) and cytokines (TNF, IL-1β, IL-2R, IL-6, IL-8, and IL-10) were measured at AKI diagnosis. The mFRI was calculated for each patient, which was defined as 2-hour urine output divided by furosemide dose and body weight. Of 1013 included patients, 154 (15.2%) experienced AKI progression, with 59 (5.8%) progressing to stage 3 and 33 (3.3%) meeting the composite outcome of hospital mortality or receipt of renal replacement therapy (RRT). The mFRI showed non-inferiority or potential superiority to renal biomarkers and cytokines in predicting AKI progression (area under the curve [AUC] 0.80, 95% confidence interval [CI] 0.77–0.82), progression to stage 3 (AUC 0.87, 95% CI 0.85–0.89), and composite outcome of death and receipt of RRT (AUC 0.85, 95% CI 0.82–0.87). Furthermore, the combination of a functional biomarker (mFRI) and a urinary injury biomarker (uNAG or uNGAL) resulted in a significant improvement in the prediction of adverse renal outcomes than either individual biomarker (all P < 0.05). Moreover, incorporating these panels into clinical model significantly enhanced its predictive capacity for adverse renal outcomes, as demonstrated by the C index, integrated discrimination improvement, and net reclassification improvement (all P < 0.05). Conclusions: As a rapid, cost-effective and easily accessible biomarker, mFRI, exhibited superior or comparable predictive capabilities for AKI progression and prognosis compared to renal biomarkers in cardiac surgical patients with mild to moderate AKI. Trial registration: Clinicaltrials.gov, NCT04962412. Registered July 15, 2021, https://clinicaltrials.gov/ct2/show/NCT04962412?cond=NCT04962412&draw=2&rank=1. Highlights: The mFRI is a rapid, cost-effective and easily accessible biomarker. The mFRI exhibited superior or comparable predictive capabilities for AKI progression and prognosis compared to renal biomarkers and cytokines in cardiac surgical patients with mild to moderate AKI. Combining the functional biomarker mFRI with a urinary injury biomarker (uNAG or uNGAL) enhanced predictive accuracy for adverse renal outcomes. [ABSTRACT FROM AUTHOR]

Chronic gastritis (CG) is a common inflammatory disease of chronic inflammatory lesion of gastric mucosa and in the diagnosis of gastritis in traditional Chinese medicine (TCM), CG can be classified into Cold ZHENG (syndrome in TCM) and Hot ZHENG. However, the molecular features of Cold/Hot ZHENG in CG and the mechanism of Cold/Hot herbs in formulae for CG remained unclear. In this study, we collected a transcriptomics data including 35 patients of Cold/Hot ZHENG CG and 3 scRNA-seq CG samples. And 25 formulae for CG and 89 herbs recorded in these formulae were also collected. We conduct a comprehensive analysis based on the combination of transcriptomics datasets and machine learning algorithms, to discover biomarkers for Cold/Hot ZHENG CG. Then the target profiles of the collected formulae and Cold/Hot herbs were predicted to uncover the features and biomarkers of them against Cold/Hot ZHENG CG. These biomarkers suggest that Hot ZHENG CG might be characterized by over-inflammation and exuberant metabolism, and Cold ZHENG CG showed a trend of suppression in immune regulation and energy metabolism. Biomarkers and specific pathways of Hot herbs tend to regulate immune responses and energy metabolism, while those of Cold herbs are more likely to participate in anti-inflammatory effects. Finally, the findings were verified based on public transcriptomics datasets, as well as transcriptomics and ELISA detection, taking Jin Hong tablets as a case study. Biomarkers like leptin and IL-6 together with proportions of immune cells showed significant changes after the intervention. These findings might reflect the mechanism and build a bridge between macro and micro views of Cold/Hot ZHENG as well as Cold/Hot herbs. [ABSTRACT FROM AUTHOR]

Background: Astragali radix (AR) is one of the most widely used traditional Chinese herbal medicines. It exhibits diverse biological activities, including immunomodulatory and anti-inflammatory properties; however, some of its activities have only been demonstrated in vitro. Objective: To examine the effects of orally administered AR extract on immune cells and the intestine under physiological conditions, which bridges the gap between previously observed in vitro outcomes and in vivo results. Methods: AR extract was prepared by hot water extraction. Three separate animal experiments were conducted to isolate macrophages, splenocytes, and the small intestine epithelium. For the macrophage preparation experiment, an intraperitoneal injection of sterile thioglycolate was administered. The mice received oral AR extract at doses of 0.1, 0.5, or 2.5 g/kg for ten days. At the end of each experiment, cells or tissues were isolated. A portion of macrophages and splenocytes were analyzed for the phenotypic changes. The remaining cells were cultured and stimulated with lipopolysaccharide (LPS) or mitogen ex vivo to assess activation status, proliferation, and cytokine production. Samples of the intestine were subjected to real-time RT-PCR. Results: Peritoneal macrophages from AR-treated mice exhibited increased expression of scavenger receptors, including SRA and CD36. Stimulation of these macrophages ex vivo with LPS selectively modulated the inflammatory response, including reduced expression of the costimulatory molecules CD40 and CD86, which are important for T cell responses, without affecting TNF-α and IL-6 production. Splenocytes from AR-treated mice exhibited a dose-dependent increase in CD4 and CD8 T cells; however, stimulation with mitogen decreased T cell proliferation and reduced IFN-γ production, which is essential for macrophage activation. An analysis of the small intestinal epithelium revealed an attenuated antimicrobial response, including reduced IgA content in the lumen and decreased expression of mucin-2 and polymeric Ig receptor genes. Conclusion: The response of immune cells following oral treatment with AR extract did not replicate the previously documented in vitro findings. Immune cells and intestinal epithelium from mice administered oral AR extract exhibited a selective anti-inflammatory phenotype. The overall findings indicate that the systemic effects after oral administration of AR extract include reduced sensitivity to inflammatory insults. [ABSTRACT FROM AUTHOR]

Background: A growing interest in using Nigella sativa oil (NSO) in the prevention or treatment of several cardiovascular diseases has prompted this study. The research aims to investigate the effect of NSO on cardiac damage prevention after long-term administration in induced myocardial infarction (MI) in rats. Methods: NSO was analyzed for its fatty acids composition using gas chromatography-mass spectrometry (GC-MS) analysis and administered in rats before and after isoproterenol (45 mg/kg body weight) induced myocardial infarction. The following parameters were assessed: electrocardiograms, histopathological examination, serum biochemical aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase-myocardial band (CK-MB), serum and heart inflammation (tumor necrosis factor-alpha (TNF), interleukin 1 beta (IL-1b), and interleukin 6 (IL-6)), and tissue oxidative stress (total antioxidant capacity (TAC), total oxidative stress (TOS), nitric oxide (NO), malondialdehyde (MDA), and the total thiols (THIOL)). Results: Linoleic acid (C18:2n-6) and oleic acid (C18:1n-9) were approximately 89% of total fatty acids while palmitic acid (C16:0) was 6.10%. Administration of NSO for 28 days helped in preventing QT and QTc interval prolongation and reduced heart rate (HR), after MI induction. The histological assessment showed improvement in myofibrillary degeneration and necrosis and also better reduced inflammatory process in the groups treated with NSO. In serum, pro-inflammatory cytokines IL-1b and IL-6 were downregulated in chronic conditions (for IL-1b, NSO vs. control was 86.09vs 150.39 pg/mL, and for IL-6 NSO vs. control was 78.00 vs. 184.98 pg/ml). In the heart tissue, the downregulation was observed only for TNF in both acute and chronic conditions (acute NSO vs. control was 132.37 vs. 207.63 pg/mL, and chronic NSO vs. control was 135.83 vs. 183.29 pg/ml). The pro-oxidant parameters TOS, NO, MDA, and OSI, were reduced in the groups treated with NSO only after 14 days of treatment, suggesting that the NSO antioxidant effect is time-dependent. Conclusions: NSO administration might have a favourable impact on the regulation of oxidative stress and inflammation processes after MI induction in rats, and it is worth considering its administration as an adjuvant treatment. [ABSTRACT FROM AUTHOR]

Background: Mucosal-associated invariant T (MAIT) cells play key roles in many inflammatory diseases. However, their effects on the long-term course of oral lichen planus (OLP) and recent-onset OLP remain unclear. In this study, we aimed to investigate the function of MAIT cells in the different processes of OLP and to explore the immunological background of this disease. Methods: The frequency, phenotype, cytokine secretion, and clinical relevance of MAIT cells were investigated. MAIT cells were collected from the peripheral blood of 14 adults with recent-onset OLP (7–120 days after disease onset) and 16 adults with long-term course OLP (>2 years after diagnosis) using flow cytometry and compared with 15 healthy blood donors. Statistical analyses were performed using the GraphPad Prism software. Results: MAIT cells from adults with recent-onset OLP exhibited an activated phenotype, as indicated by an increased frequency of CD69+ (p < 0.05) and CD38+MAIT cells (p < 0.01) and elevated production of the proinflammatory cytokine IL-17 A (p < 0.01), compared with healthy adult donors. In adults with long-term OLP, MAIT cells exhibited an activated and exhausted phenotype, characterized by high expression of CD69 (p < 0.01) and PD-1 (p < 0.001) and increased production of granzyme B released (p < 0.01). Compared with recent-onset OLP patients, long-term OLP patients showed a decreased production of CD8+, and CD4−CD8− cells, but an increase in PD-1+ production (p < 0.05). Conclusions: Circulating MAIT cells exhibited activation in OLP patients across varying disease durations. Given that PD-1 expression is elevated in adults with long-term OLP, it is reasonable to infer that circulating MAIT cells in long-term OLP may exhibit a more exhausted state than those in recent-onset OLP. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is one of the most common neurological disorders worldwide. We aimed to investigate the efficacy of high-dose vitamin D3 on inflammatory biomarkers in patients with moderate to severe TBI. Methods: Thirty-five moderate to severe TBI patients were randomly assigned to intervention and control groups. Patients in the intervention group received a single intramuscular (IM) dose of 300,000 IU vitamin D. The primary endpoints were interleukin levels (IL-1β and IL-6), and the secondary endpoints were changes in neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), Glasgow Coma scale (GCS), and Glasgow Outcome Scale-Extended (GOS-E) scores compared between intervention and control arms of the study. The linear Generalized Estimating Equations were used for trend analysis and evaluating the association of independent factors to each outcome. Results: The results revealed a significant decrease in IL-1β levels (-2.71±3.02, in the intervention group: P=0.001 vs. -0.14±3.70, in the control group: P=0.876) and IL-6 (-88.05±148.45, in the intervention group: P=0.0001 vs. -35.54±175.79, in the control group: P=0.325) 3 days after the intervention. The improvement in the GCS score (P=0.001), reduction in NLR (P=0.001) and PLR (P=0.002), and improvement in the GOS-E score (P=0.039) was found to be greater in the vitamin D3 arm of the study than the control group. Conclusion: Administration of high-dose vitamin D3 in the acute phase of TBI could be effective in lowering the inflammatory markers and improving the level of consciousness and long-term performance outcomes. Trial registration number: IRCT20180522039777N2. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of the GPER in cancer is controversial due to its dual anti and protumor effects. Elevated GPER expression in cervical cancer has been associated with improved survival outcomes. In cervical cancer cell lines, the selective GPER agonist G-1 induces cell cycle arrest and apoptosis, although the precise molecular mechanisms behind these effects are not fully understood. This study explores the impact of GPER activation by G-1 on the transcriptome, cell migration, and invasion in SiHa cells, as well as in non-tumorigenic keratinocytes transduced with HPV16 E6 or E7 oncogenes. G-1 has been shown to exert antitumor effects by activating apoptotic pathways and modulating migration and invasion processes. The findings support the GPER as a promising prognostic marker and suggest that G-1 could be a valuable therapeutic tool for treating cervical cancer. Background/Objectives: Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Methods: Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Results: Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. Conclusions: GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease affecting the colon with idiopathic origin. Melinjo endosperm extract (MeE) contains polyphenolic compounds that have antioxidative and anticancer properties. We examined the effect of MeE on inflammation and mucin expression in the colons of UC of mice treated with dextran sulfate sodium (DSS). C57BL/6J male mice were assigned into four categories: control, DSS + 0% MeE, DSS + 0.1% MeE, and DSS + 0.5% MeE. The control group was provided distilled water and a standard chow diet for 4 weeks. In DSS + 0% MeE, DSS + 0.1% MeE, and DSS + 0.5% MeE groups, the mice were treated with MeE for 3 weeks followed by MeE diets and drinking water containing 3% DSS for a week. Macrophage count, the mucus area stained by Alcian blue (AB), the levels of adenosine monophosphate-activated protein kinase (AMPK), nuclear factor-κB (NFκB) p65, and silent information regulator (Sirt) 1 protein expression, as well as proinflammatory mediators and Mucin 2 mRNA expression were assessed. In the DSS + 0% MeE group, the AB-stained areas and Mucin 2 mRNA expression levels were observed to be lower than those of controls. However, the levels in the +0.5% MeE group were significantly increased. Compared with the control group, the macrophage number, the expression of IL-1β mRNA, and NFκB p65 protein in the DSS + 0% MeE group showed a significant increase. Conversely, these levels were significantly decreased in the +0.5% MeE group. The phosphorylated AMPK and Sirt1 protein levels were upregulated in the +0.5% MeE group. In conclusion, MeE may alleviate UC injury by reducing macrophage infiltration and regulating the AMPK/NFκB/Sirt1 pathway. [ABSTRACT FROM AUTHOR]

Twelve polyphenol derivatives were obtained in a protective activity-guided isolation from the Portulaca oleracea L. extract on a cell model of human umbilical vein endothelial cells (HUVECs) under diethylhexyl phthalate (DEHP) exposure. Among them, methyl (3,4,5-trimethoxybenzoyl) valylprolinate (PP-10) performed the most protective activity and inhibited DEHP exposure-induced HUVECs' apoptosis. PP-10 also inhibited the DEHP-induced inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-8) and adhesion molecule (ICAM-1 andVCAM-1) overexpression. Furthermore, DEHP-induced NLRP3 inflammasomes' and NF-κB signaling pathway activation was significantly inhibited after the PP-10 treatments. Of note, the current results suggest the potential application of Portulaca oleracea L. and PP-10 in the prevention of DEHP-induced inflammatory damages in HUVECs. [ABSTRACT FROM AUTHOR]

Sedentary behavior (SB) has been linked to risk factors of cardiometabolic disease, with inconsistent findings reported in the literature. We aimed to assess the associations of SB with multiple biomarkers of inflammation and insulin resistance in adults. Domain-specific SB, sitting time and moderate-to-vigorous physical activity (MVPA) were measured in 78 adults (mean ± SD 52.0 ± 10.8 y). Body fat percentage (BF%) was assessed using multi-frequency bioelectrical impedance. A blood draw assessed glucose, insulin, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, and adiponectin. Adiponectin-leptin ratio (ALR), homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) were calculated. Multivariable linear regression analyses, controlling for age, sex, MVPA, and BF%, were used to assess associations. After adjustment for age, sex and MVPA, total SB (7.5 ± 2.5 h/day) was positively associated with leptin, insulin, HOMA-IR, HOMA-β (Standardized Beta (β) range 0.21–0.32) and negatively associated with ALR (β = -0.24, p < 0.05 for all). Similarly, total sitting time (7.2 ± 2.9 h/day) was associated with TNF-α (β = 0.22) and ALR (β = -0.26). These associations were attenuated to non-significance after adjustment for BF%. Leisure screen time was detrimentally associated with IL-6 (β = 0.24), leptin (β = 0.21), insulin (β = 0.37), HOMA-IR (β = 0.37), and HOMA-β (β = 0.34), independent of age, sex and MVPA (p < 0.05 for all). Only the associations with insulin (β = 0.26), HOMA-IR (β = 0.26), and HOMA-β (β = 0.23) remained significant after further controlling BF% (p < 0.05). Self-reported SB is associated with biomarkers of inflammation and insulin resistance, independent of MVPA, and in some cases BF%. [ABSTRACT FROM AUTHOR]

Background: Severely ill patients with coronavirus disease 2019 (COVID‐19) show an increased risk of new‐onset atrioventricular blocks (AVBs), associated with high rates of short‐term mortality. Recent data suggest that the uncontrolled inflammatory activation observed in these patients, specifically interleukin (IL)‐6 elevation, may play an important pathogenic role by directly affecting cardiac electrophysiology. The aim of our study was to assess the acute impact of IL‐6 changes on electrocardiographic indices of atrioventricular conduction in severe COVID‐19. Methods: We investigated (1) the behavior of PR‐interval and PR‐segment in patients with severe COVID‐19 during active phase and recovery, and (2) their association with circulating IL‐6 levels over time. Results: During active disease, COVID‐19 patients showed a significant increase of PR‐interval and PR‐segment. Such atrioventricular delay was transient as these parameters rapidly normalized during recovery. PR‐indices significantly correlated with circulating IL‐6 levels over time. All these changes and correlations persisted also in the absence of laboratory signs of cardiac strain/injury or concomitant treatment with PR‐prolonging drugs, repurposed or not. Conclusions: Our study provides evidence that in patients with severe COVID‐19 and high‐grade systemic inflammation, IL‐6 elevation is associated with a significant delay of atrioventricular conduction, independent of concomitant confounding factors. While transient, such alterations may enhance the risk of severe AVB and associated short‐term mortality. Our data provide further support to current anti‐inflammatory strategies for severe COVID‐19, including IL‐6 antagonists. [ABSTRACT FROM AUTHOR]

We recently demonstrated the effectiveness of long-term treatment with rifaximin and the probiotic DSF (De Simone formulation) in improving urogenital and gastrointestinal symptoms in patients with both chronic inflammatory prostatitis (IIIa prostatitis) and diarrhea-predominant irritable bowel syndrome (IBS-D), relative to patients with IBS-D alone. Because the low-grade inflammation of the intestine and prostate may be one of the reasons for co-developing both IIIa prostatitis and IBS-D, we designed the present study to once again evaluate the efficacy of combined rifaximin and DSF treatment in patients affected by IIIa prostatitis plus IBS-D, but we also measured seminal plasma pro-inflammatory (IL-6) and anti-inflammatory (IL-10) cytokines before and after treatment. Methods: We consecutively enrolled 124 patients with IIIa prostatitis and IBS-D (diagnosed using the Rome III criteria). Patients were randomized into two groups: group A (n = 64) was treated with rifaximin (seven days per month for three months) followed by DSF, and group B (n = 60) was treated with a placebo. By the end of the intervention, 68.7% and 62.5% of patients from group A reported improved NIH-CPSI (National Institute of Health's Chronic Prostatitis Symptom Index) and IBS-SSS (Irritable Bowel Syndrome Severity Scoring System) scores, respectively, compared to only 3.3% and 5% of the placebo group. Group A patients also had significantly lower mean seminal plasma levels of IL-6 (11.3 vs. 32.4 pg/mL) and significantly higher mean levels of IL-10 (7.9 vs. 4.4 pg/mL) relative to baseline, whereas the levels of IL-6 and IL-10 did not change in the placebo group. Conclusions: The combined treatment with rifaximin and DSF appears to represent the optimal approach for addressing a syndrome such as irritable bowel syndrome (IBS-D plus), which frequently co-occurs with prostatitis (IIIa prostatitis). This approach is particularly beneficial in cases where the symptoms are not always clearly delineated, the etiology is multifactorial, and the diagnosis is multilevel. [ABSTRACT FROM AUTHOR]

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Background: Cardiovascular diseases are among the most common chronic diseases, generating high social and economic costs. Secondary immunodeficiencies occur more often than primary ones and may result from the co-occurrence of specific diseases, treatment, nutrient deficiencies and non-nutritive bio-active compounds that result from the industrial nutrient practices. Objectives: The aim of this article is to present selected secondary immunodeficiencies and their impact on the cardiovascular system. Results: The treatment of a patient with cardiovascular disease should include an assess-ment for immunodeficiencies, because the immune and cardiovascular systems are closely linked. Conclusions: Immune system dysfunctions can significantly affect the course of cardiovascular diseases and their treatment. For this reason, comprehensive care for a patient with cardiovascular disease requires taking into account potential immunodeficiencies, which can have a significant impact on the patient's health. [ABSTRACT FROM AUTHOR]

Aims Understanding the mechanisms underlying ascending aortic dilation is imperative for refined risk stratification of these patients, particularly among incidentally identified patients, most commonly presenting with tricuspid valves. The aim of this study was to explore associations between ascending aortic haemodynamics, assessed using four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR), and circulating biomarkers in aortic dilation. Methods and results Forty-seven cases with aortic dilation (diameter ≥ 40 mm) and 50 sex-and age-matched controls (diameter < 40 mm), all with tricuspid aortic valves, underwent 4D flow CMR and venous blood sampling. Associations between flow displacement, wall shear stress (WSS), and oscillatory shear index in the ascending aorta derived from 4D flow CMR, and biomarkers including interleukin-6, collagen type I α1 chain, metalloproteinases (MMPs), and inhibitors of MMPs derived from blood plasma, were investigated. Cases with dilation exhibited lower peak systolic WSS, higher flow displacement, and higher mean oscillatory shear index compared with controls without dilation. No significant differences in biomarkers were observed between the groups. Correlations between haemodynamics and biomarkers were observed, particularly between maximum time-averaged WSS and interleukin-6 (r = 0.539, P < 0.001), and maximum oscillatory shear index and collagen type I α1 chain (r = −0.575, P < 0.001 in cases). Conclusion Significant associations were discovered between 4D flow CMR derived whole-cardiac cycle WSS and circulating biomarkers representing inflammation and collagen synthesis, suggesting an intricate interplay between haemodynamics and the processes of inflammation and collagen synthesis in patients with early aortic dilation and tricuspid aortic valves. [ABSTRACT FROM AUTHOR]

Background. Systemic sclerosis (SSc) is an autoimmune disease characterized by inflammation, progressive vasculopathy, and fibrosis of skin and internal organs. The aim of the study was to evaluate extended inflammatory parameters (EIP) in patients with SSc in comparison to the control group of healthy subjects. Methods. A total of 28 patients with SSc and 29 healthy controls (HCs) were included in the study. The following EIP parameters were analyzed: neutrophil reactive intensity (NEUT‐RI), neutrophil granularity intensity (NEUT‐GI), antibody‐synthesizing lymphocytes (AS‐LYMP), and reactive lymphocytes (RE‐LYMP). Results. Patients with SSc showed significantly higher values of parameters determining neutrophil reactivity and neutrophil granularity when compared to HCs (respectively, 49.16 FI vs. 44.33 FI, p < 0.001, and 152.01 SI vs. 147.51 SI, p < 0.001). Moreover, patients with SSc had higher absolute numbers of RE‐LYMP than HCs (0.69 × 103/µl vs. 0.04 × 103/µl, p < 0.001). Importantly, significant correlations between the RE‐LYMP and either IL‐6 (R = 0.447, p < 0.001) or ESR (R = 0.532, p < 0.001) were found among patients with SSc. Conclusions. Changes in NEUT‐RI, NEUT‐GI, and RE‐LYMP levels positively correlate with inflammation in SSc and, thus, could potentially be used as an additional reliable inflammatory biomarker to assess inflammation in this disease. [ABSTRACT FROM AUTHOR]

Acute leukemia is characterized by abnormal white blood cell proliferation with rapid onset and severe complications. Natural compounds, which are alternative treatments, are widely used in cancer treatment. Piperine, an alkaloid compound from black pepper, exerts anticancer effects through the cell death signaling pathway. Autophagy and senescence signaling pathways are considered target signaling pathways for cancer treatment. In this study, we investigated the effects of piperine via autophagy and senescence signaling pathways in NB4 and MOLT-4 cells. The MTT assay results demonstrated that piperine significantly decreased the viability of NB4 and MOLT-4 cells. Piperine induced autophagy by increasing LC3, Beclin-1 and ULK1 and decreasing mTOR and NF-κB1 expression in NB4 and MOLT-4 cells. In addition, piperine increased senescence-associated beta-galactosidase fluorescence intensity by increasing p21 and IL-6 expression while decreasing CDK2 expression in NB4 and MOLT-4 cells. In conclusion, our study provides additional information about the induction of autophagy and senescence by piperine in acute leukemia. [ABSTRACT FROM AUTHOR]

Objective. The importance of early microbial dysbiosis in later development of obesity and metabolic disorders has been a subject of debate. Here we tested cause and effect in mice. Methods. Germ‐free male Swiss Webster mice were colonized in a specific‐pathogen‐free (SPF) facility at 1 week (1W) and 3 weeks (3W) of age. They were challenged with a high‐fat diet and their responses were compared with SPF mice. Gut microbiota was analyzed by 16S rRNA gene sequencing. Moreover, RNA sequencing of the liver was performed on additional 3W and SPF mice on a regular chow diet. Results. There were no significant differences in weight, food consumption, epididymal fat weight, HbA1c levels, and serum insulin and leptin, whereas the early germ‐free period resulted in mice with impaired glucose tolerance. Both the 1W and 3W group peaked 56% (p < 0.05) and 66% (p < 0.01) higher in blood glucose than the SPF control group, respectively. This was accompanied by a 45% reduction in the level of the anti‐inflammatory cytokine IL‐10 in the 1W mice (p < 0.05). There were no differences in the gut microbiota between the groups, indicating that all mice colonized fully after the germ‐free period. Marked effects on hepatic gene expression (728 differentially expressed genes with adjusted p < 0.05 and a fold change ± 1.5) suggested a potential predisposition to a higher risk of developing insulin resistance in the 3W group. Conclusions. Lack of microbes early in life had no impact on adiposity but led to insulin resistance and altered liver gene expression related to glucose metabolism in mice. The study strongly supports the notion that microbial signaling to the liver in the beginning of life can alter the host's risk of developing metabolic disorder later in life. [ABSTRACT FROM AUTHOR]

Background: Observational studies have suggested that plasma lipidome play a pivotal role in the occurrence of Parkinson's disease (PD). However, it remains unknown which lipids among plasma lipidome affect PD and how they exert their influence. Clarity is lacking regarding the causal relationship between plasma lipidome and PD, as well as whether circulating inflammatory proteins serve as mediators. Methods: Single nucleotide polymorphisms (SNPs) significantly associated with 179 plasma lipidome were selected as instrumental variables to assess their causal impact on PD. PD data, serving as the outcome, were sourced from the International Parkinson's Disease Genomics Consortium, which boasts the largest sample size to date. The inverse variance weighted (IVW), Weighted median method, MR-Egger method, Simple mode method, Weighted mode method and MR-PRESSO were employed to evaluate the influence of the 179 plasma lipidome on PD. Heterogeneity, pleiotropy tests, and reverse causality analyses were conducted accordingly. Additionally, we analyzed the causal relationship between 91 circulating inflammatory proteins and PD, exploring whether these proteins serve as mediators in the pathway from plasma lipidome to PD. Results: Among the 179 plasma lipidome, three were found to be associated with a reduced risk of PD: Phosphatidylcholine (14:0_18:2) (IVW, OR = 0.877; 95%CI, 0.787-0.978; p = 0.018), Phosphatidylcholine (16:0_16:1) levels (IVW, OR = 0.835; 95%CI, 0.717-0.973; p = 0.021), and Phosphatidylcholine (O-17:0_17:1) levels (IVW, OR = 0.854; 95%CI, 0.779-0.936; p = 0.001). Meanwhile, Sphingomyelin (d38:1) was linked to an increased risk of PD (IVW, OR = 1.095; 95%CI, 1.027-1.166; p = 0.005). Among the 91 circulating inflammatory proteins, three were associated with a lower PD risk: Fibroblast growth factor 21 levels (IVW, OR = 0.817; 95%CI, 0.674-0.990; p = 0.039), Transforming growth factor-alpha levels (IVW, OR = 0.825; 95%CI, 0.683-0.998; p = 0.048), and Tumor necrosis factor receptor superfamily member 9 levels (IVW, OR = 0.846; 95%CI, 0.744-0.963; p = 0.011). Two were associated with a higher risk of PD: Interleukin-17A levels (IVW, OR = 1.285; 95%CI, 1.051-1.571; p = 0.014) and TNF-beta levels (IVW, OR = 1.088; 95%CI, 1.010-1.171; p = 0.026). Additionally, a positive correlation was observed between Phosphatidylcholine (14:0_18:2) levels and Fibroblast growth factor 21 levels (IVW, OR = 1.125; 95%CI, 1.006-1.257; p = 0.038), suggesting that Fibroblast growth factor 21 levels may serve as a mediating factor in the pathway between Phosphatidylcholine (14.0_18.2) levels and PD. The mediation effect was estimated to be -0.024, accounting for approximately 18% of the total effect. Conclusion: Both plasma lipidome and circulating inflammatory proteins demonstrate a causal relationship with PD. Additionally, circulating inflammatory proteins may serve as mediators in the pathway from plasma lipidome to PD. These findings may contribute to the prediction and diagnosis of PD and potentially pave the way for targeted therapies in the future. [ABSTRACT FROM AUTHOR]

Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer's Disease (AD) contributes to approximately 60-70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brainresident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics. [ABSTRACT FROM AUTHOR]

Recent studies strongly suggest that gut microbiome can influence brain functions and contribute to the development of Alzheimer's disease (AD). However, reported changes in the gut microbiomes in AD patients from different countries are not similar, and more research is needed to reveal the relationships between human microbiomes and AD in diverse ethnic populations. There is also an assumption that microbiome‐associated peripheral inflammation might drive the development of sporadic AD. This cross‐sectional study is aimed at analyzing the gut microbial profile and exploring potential associations with blood cytokines and some clinical parameters among individuals diagnosed with Alzheimer's in Kazakhstan. Consistent with previous studies, we have found that the microbial landscape in AD reveals specific alterations in the gut microbiome. Specifically, the AD patient group showed a decreased Firmicutes/Bacteroidetes ratio. The differential abundance analysis highlighted a dysbiosis in the gut microbiota of AD patients, marked by a reduced presence of Bifidobacterium, particularly B. breve. In our study, AD patients' altered gut microbiota composition notably features an increased presence of Pseudomonadota like Phyllobacterium and inflammatory bacteria such as Synergistetes and the Christensenellaceae family. The metabolic profiling of the AD microbiome reveals a predominant presence of pathways related to sugar, carrier molecules, tetrapyrrole, pyrimidine biosynthesis, and nucleic acid processing. This analysis also highlighted a marked reduction in SCFA, carbohydrate, polysaccharide, polyamine, and myo‐inositol degradation pathways. The increases in the proinflammatory cytokines IL‐1a, IL‐8, IL‐17A, IL‐12p40, TNF‐β, MCP‐1, IL‐2, and IL‐12p70 and the anti‐inflammatory cytokines IL‐10 and IL‐13 were observed in AD patients. Key variables driving the separation of AD and controls include inflammatory markers (IL‐1a and IL‐8), growth factors (EGF), lipids (LDL), BMI, and gut microbes, like genus Tyzzerella and Turicibacter and species Parabacteroides distasonis and Bacteroides eggerthii. We have also demonstrated that almost all cytokines strongly correlate with serum adiponectin levels and specific microbial taxa in AD patients. Thus, our findings identify potential microbial and inflammatory signatures in an ethnically distinct cohort of AD patients. These could serve as AD biomarkers and microbiota‐based therapeutic targets for treating AD. [ABSTRACT FROM AUTHOR]

Background: Although high serum levels of interleukin (IL)-17 and its producing cells have been found in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in earlier research, it is still unclear how these findings relate to disease activity. Objectives: This study examines the link between serum levels of IL-17 and the activity of both RA and SLE. Design: This pilot case–control study included 100 patients with RA, 100 with SLE, and 100 healthy controls. Methods: The Disease Activity Score-28 (DAS28) scores assessed the activity of RA, whereas the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores assessed SLE activity. All participants' data were compared and correlated. Results: Serum levels of IL-17 were significantly higher in RA and SLE patients compared with the controls (P <.001) and showed significantly positive correlations (P <.001) with rheumatoid factor titer, anti-cyclic citrullinated peptide (anti-CCP) and DAS28 score among the RA patients. Although among SLE patients, they were significantly positively correlated (P <.001) with anti-double-stranded DNA (anti-ds DNA) levels and the SLEDAI-2K scores, the best cut-off value of IL-17 for predicting moderate and high disease activity was > 175 pg/mL among RA patients and > 95 pg/mL among SLE patients. Conclusions: There is a significant correlation between RA and SLE activity and serum levels of IL-17. This discovery emphasizes IL-17 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background/Objectives: The present study examined the effect of 12-week combined exercise training in normobaric hypoxia on arterial stiffness, inflammatory biomarkers, and red blood cell (RBC) hemorheological function in 24 obese older women (mean age: 67.96 ± 0.96 years). Methods: Subjects were randomly divided into two groups (normoxia (NMX; n = 12) and hypoxia (HPX; n = 12)). Both groups performed aerobic and resistance exercise training programs three times per week for 12 weeks, and the HPX group performed exercise programs in hypoxic environment chambers during the intervention period. Body composition was estimated using bioelectrical impedance analysis equipment. Arterial stiffness was measured using an automatic waveform analyzer. Biomarkers of inflammation and oxygen transport (tumor necrosis factor alpha, interleukin 6 (IL-6), erythropoietin (EPO), and vascular endothelial growth factor (VEGF)), and RBC hemorheological parameters (RBC deformability and aggregation) were analyzed. Results: All variables showed significantly more beneficial changes in the HPX group than in the NMX group during the intervention. The combined exercise training in normobaric hypoxia significantly reduced blood pressure (systolic blood pressure: p < 0.001, diastolic blood pressure: p < 0.001, mean arterial pressure: p < 0.001, pulse pressure: p < 0.05) and brachial–ankle pulse wave velocity (p < 0.001). IL-6 was significantly lower in the HPX group than in the NMX group post-test (p < 0.001). Also, EPO (p < 0.01) and VEGF (p < 0.01) were significantly higher in the HPX group than in the NMX group post-test. Both groups showed significantly improved RBC deformability (RBC EI_3Pa) (p < 0.001) and aggregation (RBC AI_3Pa) (p < 0.001). Conclusions: The present study suggests that combined exercise training in normobaric hypoxia can improve inflammatory biomarkers and RBC hemorheological parameters in obese older women and may help prevent cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Identifying mediators between obesity-related traits and lower respiratory tract infections (LRTIs) would inform preventive and therapeutic strategies to reduce the burden of LRITs. We aimed to recognize whether lung function and inflammatory factors mediate their associations. Methods: We conducted a two-step, two-sample Mendelian randomization (MR) analysis. Two-sample MR was performed on (1) obesity-related traits (i.e., body mass index [BMI], waist circumference [WC], and waist-to-hip ratio [WHR]) and LRTIs (i.e., acute bronchitis, acute bronchiolitis, bronchiectasis, influenza, and pneumonia), (2) obesity-related traits and potential mediators, and (3) potential mediators and LRTIs. Next, two-step MR was applied to infer whether the mediation effects exist. Results: We found that C-reactive protein (CRP), interleukin-6 (IL-6), and forced expiratory volume in the first second (FEV1) mediated 32.59% (95% CI: 17.90%, 47.27%), 7.96% (95% CI: 1.79%, 14.14%), and 4.04% (95% CI: 0.34%, 7.74%) of the effect of BMI on pneumonia, and they mediated 26.90% (95% CI: 13.98%, 39.83%), 10.23% (95% CI: 2.72%, 17.73%), and 4.67% (95% CI: 0.25%, 9.09%) of the effect of WC on pneumonia, respectively. Additionally, CRP, forced vital capacity (FVC), and FEV1 mediated 18.66% (95% CI: 8.70%, 28.62%), 8.72% (95% CI: 1.86%, 15.58%), and 8.41% (95% CI: 2.77%, 14.06%) of the effect of BMI on acute bronchitis, and they mediated 19.96% (95% CI: 7.44%, 32.48%), 12.19% (95% CI: 2.00%, 22.39%), and 12.61% (95% CI: 2.94%, 22.29%) of the effect of WC on acute bronchitis, respectively. Conclusions: Health interventions linked to reducing inflammation and maintaining normal lung function could help mitigate the risk of obesity-related LRTIs. [ABSTRACT FROM AUTHOR]

Introduction: Total knee arthroplasty (TKA) is accompanied by severe postoperative pain, which is reported to be an important cause of chronic pain. Ultrasound-guided adductor canal block (ACB) combined with infiltration between the popliteal artery and posterior capsular of the knee (IPACK) has been proven to have a better effect on relieving acute pain after TKA. However, whether it has a significant effect on the incidence of chronic pain after TKA has not been reported. This trial was designed to investigate the effect of ultrasound-guided ACB combined with IPACK on the incidence and intensity of chronic pain after TKA. Methods: In this prospective, randomized, double-blind, placebo-controlled study, 100 subjects scheduled for TKA were randomly (1:1) divided into two groups: the ropivacaine group and the placebo group. Patients in each group received ultrasound-guided ACB + IPACK procedures with 0.25% ropivacaine or equal volume normal saline. All patients received multimodal analgesia. Pain intensity was assessed using the Numerical Rating Scale (NRS). The primary outcome was the incidence of chronic pain at 3 months after TKA by telephone follow-up. In addition, pain intensity in early resting and mobilized states, chronic pain intensity, the time to first rescue analgesia; opioid consumption; CRP and IL-6 after the operation; length of postoperative hospital stay; and cost of hospitalization and postoperative complications; as well as the function of the knee in the early stage after the operation, were recorded. Results: Ninety-one participants were included in the final analysis. At 3 months, the incidence of chronic pain was 30.4% in the ropivacaine group, significantly lower than 51.1% in the placebo group. Compared with the placebo group, the ACB + IPACK with ropivacaine group had significantly lower pain scores at 4 hours, 8 hours, 16 hours, and 24 hours after the operation; increased the knee range of motion at 8 hours and 24 hours after the operation; and a significantly decreased incidence of chronic pain at 3 months after the operation. During the follow-up period, there were no nerve block-related complications in either group. Conclusion: In the context of multimodal analgesia protocols, ACB combined with IPACK before surgery decreases the incidence and intensity of chronic pain 3 months after TKA compared with placebo injection. In addition, it reduces the NRS scores, whether at rest or during mobilization, and improves knee function within 24 hours after TKA. Trial registration: This trial was registered in the China Clinical Trial Center (registration number ChiCTR2200065300) on November 1, 2022. [ABSTRACT FROM AUTHOR]

Introduction: Acute lung injury (ALI) as one kind of acute pulmonary inflammatory disorder, manifests primarily as damage to alveolar epithelial cells and microvascular endothelial cells. Activation of the complement system is a common pathological mechanism in ALI induced by diverse factors, with the complement alternative pathway assuming a pivotal role. Baicalin, a flavonoid derived from the root of Scutellaria baicalensis Georgi, exhibits noteworthy biological activities. The present study attempted the interventional effects and underlying mechanisms of baicalin in microangiopathy in ALI induced by complement alternative pathway activation. Methods: Activation of the complement alternative pathway by cobra venom factor (CVF). HMEC cells were pretreated with baicalin and then exposed to complement activation products. The expression of inflammatory mediators was detected by ELISA, and the intranuclear transcriptional activity of NF-κB was assessed by a dual fluorescent kinase reporter gene assay kit. Before establishing the ALI mouse model, baicalin or PDTC was gavaged for 7 d. CVF was injected into the tail vein to establish the ALI model. The levels of inflammatory mediators in BALF and serum were determined by ELISA. HE staining and immunohistochemistry evaluated pathological changes, complement activation product deposition, and NF-κB p65 phosphorylation in lung tissue. Results: Baicalin reduced complement alternative activation product-induced expression of HMEC cells adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokines (IL-6, TNF-α) as well as upregulation of NF-κB intranuclear transcriptional activity. Baicalin intervention reduced the number of inflammatory cells and protein content in the BALF and decreased the levels of IL-6, TNF-α, and ICAM-1 in serum and IL-6, TNF-α, ICAM-1, and P-selectin in BLAF. In addition, baicalin attenuated inflammatory cell infiltration in the lung of ALI mice and reduced the deposition of complement activation products (C5a, C5b-9) and phosphorylation of NF-κB p65 in lung tissue. Conclusion: Baicalin relieves complement alternative pathway activation-induced lung inflammation by inhibition of NF-κB pathway, delaying the progression of ALI. [ABSTRACT FROM AUTHOR]

Background and objectives: Periodontitis (PD), a chronic inflammatory disease, is a serious threat to oral health and is one of the risk factors for Alzheimer's disease (AD). A growing body of evidence suggests that the two diseases are closely related. However, current studies have not provided a comprehensive understanding of the common genes and common mechanisms between PD and AD. This study aimed to screen the crosstalk genes of PD and AD and the potential relationship between cross-talk and PANoptosis-related genes. The relationship between core genes and immune cells will be analyzed to provide new targets for clinical treatment. Materials and methods: The PD and AD datasets were downloaded from the GEO database and differential expression analysis was performed to obtain DEGs. Overlapping DEGs had cross-talk genes linking PD and OP, and PANoptosis-related genes were obtained from a literature review. Pearson coefficients were used to compute cross-talk and PANoptosis-related gene correlations in the PD and AD datasets. Cross-talk genes were obtained from the intersection of PD and AD-related genes, protein-protein interaction (PPI) networks were constructed and cross-talk genes were identified using the STRING database. The intersection of cross-talk and PANoptosis-related genes was defined as cross-talk-PANoptosis genes. Core genes were screened using ROC analysis and XGBoost. PPI subnetwork, gene-biological process, and gene-pathway networks were constructed based on the core genes. In addition, immune infiltration on the PD and AD datasets was analyzed using the CIBERSORT algorithm. Results: 366 cross-talk genes were overlapping between PD DEGs and AD DEGs. The intersection of cross-talk genes with 109 PANoptosis-related genes was defined as cross-talk-PANoptosis genes. ROC and XGBoost showed that MLKL, DCN, IL1B, and IL18 were more accurate than the other cross-talk-PANoptosis genes in predicting the disease, as well as better in overall characterization. GO and KEGG analyses showed that the four core genes were involved in immunity and inflammation in the organism. Immune infiltration analysis showed that B cells naive, Plasma cells, and T cells gamma delta were significantly differentially expressed in patients with PD and AD compared with the normal group. Finally, 10 drugs associated with core genes were retrieved from the DGIDB database. Conclusion: This study reveals the joint mechanism between PD and AD associated with PANoptosis. Analyzing the four core genes and immune cells may provide new therapeutic directions for the pathogenesis of PD combined with AD. [ABSTRACT FROM AUTHOR]

Background: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. Methods: Observational, comparative, retrospective, cross-sectional study. Interleukins 1β, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. Results: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03–86.66), p = 0.03). Interleukins 1β, 6, and 10 were not detected. Conclusion: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference. [ABSTRACT FROM AUTHOR]

Dental implant restoration shows an effective method for the rehabilitation of missing teeth. The failure rate of periodontal implants in patients with chronic periodontitis is associated with periodontal flora, inflammation, and long-term periodontal bone resorption caused by chronic periodontitis. However, the therapeutic effects of dental implant restoration on inflammation in patients with chronic periodontitis have not addressed. The purpose of this study is to evaluate the risk indicators for inflammation, bone loss and implant failure in patients with chronic periodontitis. A total of 284 patients with dental implant restoration were recruited and divided into periodontally healthy patients (n = 128) and chronic periodontitis patients (n = 156). Periodontal indices including probing depth (PD), sulcus bleeding index (SBI), plaque index (PLI), gingival bleeding (GIL) and bleeding on probing (BOP) were compared in two groups. Inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) levels at baseline, 6 and 12 months after surgery, and the implant survival rate at 12 months after surgery, as well as the risk factors associated with failure of dental implant were also assessed. Outcomes demonstrated that patients in the chronic periodontitis group had higher values of periodontal indices than those in the periodontally healthy group. All inflammatory parameters in the chronic periodontitis group were higher than those in the periodontally healthy group and negatively associated with the chronic periodontal index (CPI) in chronic periodontitis patients. Chronic periodontitis patients had higher the prevalence of mucositis and peri-implantitis than patients with healthy periodontium. Implant diameter, length and design was associated with the risk of implant failure for chronic periodontitis patients receiving dental implant. The cumulative implant failure rate and incidence of implant fractures for chronic periodontitis patients at 12 months after surgery were 12.10% and 7.23% (p < 0.05), respectively, while were lower in the heathy periodontitis patients. Location, diameter, implant design, immediate loading and bone defect were risk indicators for bone loss for dental implant patients. The risk factors associated with failure of dental implant was higher in chronic periodontitis patients than patients in the periodontally healthy group (14.25% vs. 4.92%, p < 0.05). In conclusion, data in the current study indicate that inflammation is a risk indicator bone loss, implant fracture and implant failure in patients with chronic periodontitis. [ABSTRACT FROM AUTHOR]

In this paper, we measured B cell function in elderly healthy individuals (EH) and in elderly patients with Type-2 Diabetes Mellitus (T2DM, ET2DM), which are treatment-naive, as compared to healthy young (YH) individuals. Results show a higher serum inflammatory status of elderly versus young individuals, and especially of ET2DM versus EH. This status is associated with a reduced response to the seasonal influenza vaccine and with increased frequencies of the circulating pro-inflammatory B cell subset called Double Negative (DN) B cells. B cells from ET2DM patients are not only more inflammatory but also hyper-metabolic as compared to those from EH controls. The results herein are to our knowledge the first to show that T2DM superimposed on aging further increases systemic and B cell intrinsic inflammation, as well as dysfunctional humoral immunity. Our findings confirm and extend our previously published findings showing that inflammatory B cells are metabolically supported. [ABSTRACT FROM AUTHOR]

Background: Oral cancer (OC) is a common malignancy in clinical practice. Saliva testing is a convenient and noninvasive early diagnostic technique for OC. Several salivary cytokines have been identified as potential biomarkers for OC, including IL-8, IL-6, TNF-α, IL-1β, and IL-10. Nonetheless, the optimal cytokine for OC diagnosis remains inconclusive and highly contentious. Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were comprehensively retrieved to collect all case–control studies on OC. A meta-analysis was performed to compare the levels of salivary IL-8, IL-6, IL-10, TNF-α, and IL-1β in OC patients and healthy controls. Network meta-analysis (NMA) was carried out to probe into the accuracy of these salivary cytokines in diagnosing OC. Results: This analysis included 40 studies, encompassing 1280 individuals with OC and 1254 healthy controls. Significantly higher levels of salivary IL-8, IL-6, TNF-α, IL-1β, and IL-10 were observed in patients with OC in comparison to healthy controls. The results of NMA showed that TNF-α had the highest diagnostic accuracy for OC, with a sensitivity of 79% and a specificity of 92%, followed by IL-6 (sensitivity: 75%, specificity: 86%) and IL-8 (sensitivity: 80%, specificity: 80%). Conclusion: This study suggests that IL-8, IL-6, IL-10, TNF-α, and IL-1β may be potential diagnostic biomarkers for OC. Among them, TNF-α, IL-6, and IL-8 are highly accurate in the diagnosis of OC. Nevertheless, further studies that eliminate other confounding factors are warranted, and more standardized procedures and large-scale studies are needed to support the clinical use of saliva testing. [ABSTRACT FROM AUTHOR]

Degenerative disc disease is the leading cause of lower back and leg pain, considerably impacting daily life and incurring substantial medical expenses for those affected. The development of annulus fibrosus tissue engineering offers hope for treating this condition. However, the current annulus fibrosus tissue engineering scaffolds fail to accurately mimic the natural biological environment of the annulus fibrosus, resulting in limited secretion of extracellular matrix produced by the seeded cells and poor biomechanical properties of the constructed biomimetic annulus fibrosus tissue. This inability to match the biomechanical performance of the natural annulus fibrosus hinders the successful treatment of annulus fibrosus defects. In this study, we fabricated decellularized annulus fibrosus matrix (DAFM)/chitosan hydrogel-1 (DAFM: Chitosan 6:2) and DAFM/chitosan hydrogel-2 (DAFM: Chitosan 4:4) by varying the ratio of DAFM to chitosan. Rat annulus fibrosus (AF)-derived stem cells were cultured on these hydrogel scaffolds, and the cell morphology, AF-related gene expression, and Interleukin-6 (IL-6) levels were investigated. Additionally, magnetic resonance imaging, Hematoxylin and eosin staining, and Safranine and Fast Green staining were performed to evaluate the repair effect of the DAFM/chitosan hydrogels in vivo. The gene expression results showed that the expression of Collagen type I (Col-I), Collagen type I (Col-II), and aggrecan by annulus fibrosus stem cells (AFSCs) cultured on the DAFM/chitosan-1 hydrogel was higher compared with the DAFM/chitosan-2 hydrogel. Conversely, the expression of metalloproteinase-9 (MMP-9) and IL-6 was lower on the DAFM/chitosan-1 hydrogel compared with the DAFM/chitosan-2 hydrogel. In vivo, both the DAFM/chitosan-1 and DAFM/chitosan-2 hydrogels could partially repair large defects of the annulus fibrosus in rat tail vertebrae. In conclusion, the DAFM/chitosan-1 hydrogel could be regarded as a candidate scaffold material for the repair of annulus fibrosus defects, offering the potential for improved treatment outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Microplastics (MPs) have become a global environmental problem, emerging as contaminants with potentially alarming consequences. However, long-term exposure to polystyrene microspheres (PS-MS) and its effects on diet-induced obesity are not yet fully understood. OBJECTIVES: We aimed to investigate the effect of PS-MS exposure on high-fat diet (HFD)–induced obesity and underlying mechanisms. METHODS: In the present study, C57BL/6J mice were fed a normal diet (ND) or a HFD in the absence or presence of PS-MS via oral administration for 8 wk. Antibiotic depletion of the microbiota and fecal microbiota transplantation (FMT) were performed to assess the influence of PS-MS on intestinal microbial ecology. We performed 16S rRNA sequencing to dissect microbial discrepancies and investigated the dysbiosis-associated intestinal integrity and inflammation in serum. RESULTS: Compared with HFD mice, mice fed the HFD with PS-MS exhibited higher body weight, liver weight, metabolic dysfunction-associated steatotic liver disease (MASLD) activity scores, and mass of white adipose tissue, as well as higher blood glucose and serum lipid concentrations. Furthermore, 16S rRNA sequencing of the fecal microbiota revealed that mice fed the HFD with PS-MS had greater a-diversity and greater relative abundances of Lachnospiraceae, Oscillospiraceae, Bacteroidaceae, Akkermansiaceae, Marinifilaceae, Deferribacteres, and Desulfovibrio, but lower relative abundances of Atopobiaceae, Bifidobacterium, and Parabacteroides. Mice fed the HFD with PS-MS exhibited lower expression of MUC2 mucin and higher levels of lipopolysaccharide and inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-17A] in serum. Correlation analyses revealed that differences in the microbial flora of mice exposed to PS-MS were associated with obesity. Interestingly, microbiota-depleted mice did not show the same PS-MS-associated differences in Muc2 and Tjp1 expression in the distal colon, expression of inflammatory cytokines in serum, or obesity outcomes between HFD and HFD + PS-MS. Importantly, transplantation of feces from HFD + PS-MS mice to microbiota-depleted HFD-fed mice resulted in a lower expression of mucus proteins, higher expression of inflammatory cytokines, and obesity outcomes, similar to the findings in HFD + PS-MS mice. CONCLUSIONS: Our findings provide a new gut microbiota-driven mechanism for PS-MS–induced obesity in HFD-fed mice, suggesting the need to reevaluate the adverse health effects of MPs commonly found in daily life, particularly in susceptible populations. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to examine the effect of varying ozone doses on proinflammatory cytokine levels in the synovial fluid collected from individuals with knee osteoarthritis. Patients and methods: The controlled clinical trial was conducted with 82 patients (61 females, 21 males; mean age: 63.1±10.0 years; range, 40 to 73 years) between 21 April 2023 and 20 May 2023. Synovial fluid samples were collected from the patients under ultrasound guidance and divided into three tubes, one of which was not injected with ozone, and the other two were injected with 10 and 30 gamma (γ) ozone, respectively. The total antioxidant status, total oxidant status, oxidative stress index, interleukin (IL)-1 beta (β), IL-6, and tumor necrosis factor-alpha (TNF-α) in the joint fluids were measured. Results: The oxidative stress index and IL-1 β, IL-6, and TNF-α levels in the synovial fluid were lower at 10 and 30 γ compared to 0 and 10 γ, respectively. In vitro ozone injection at 30 gamma was more effective in reducing proinflammatory cytokines in the synovial fluid than that at 10 and 0 γ. Ozone injection into the pathological joint fluid was more effective in terms of total antioxidant status at 10 and 30 γ compared to 0 and 10 γ, respectively. No significant difference in total oxidant status was observed between the groups. Conclusion: This study showed that in vitro ozone injection at 30 γ was more effective in reducing proinflammatory cytokines in the synovial fluid and in improving total antioxidant status than that at 10 and 0 γ. The results showed the potential significance of the ozone injection dosage in treating knee osteoarthritis. [ABSTRACT FROM AUTHOR]