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Purpose: To investigate whether genetic variations in cytokine genes involved in the pathogenesis of peri-implantitis are associated with the occurrence of peri-implantitis, an issue that remains controversial and may vary according to the population evaluated. Materials and Methods: A cross-sectional analytical study was carried out on 102 Caucasian Portuguese individuals who were divided into two groups: (1) 43 individuals with peri-implantitis and (2) 59 individuals with good peri-implant health. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for IL-1A and IL-1B and PCR for IL-1RN. Results: The IL-1A-889 C/T polymorphism presented with a higher prevalence of the less common allele (T allele) in patients with peri-implantitis (27.9%) than in healthy patients (16.9%), but without statistical significance (P = .060). For the IL-1B+3954 C/T and IL-1RN (variable number of tandem repeats [VNTR]) polymorphisms, analysis revealed that the allele and genotype frequencies did not differ significantly between groups. There was a significant association between a history of periodontitis and peri-implantitis (P = .020). Conclusions: The evaluated genetic polymorphisms had no influence on the occurrence of peri-implantitis in the study population. Further research into genetic variations in different populations is needed to elucidate the role of genetic factors in the onset and progression of peri-implant disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: IL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP). METHODS: Pregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation. RESULTS: IUI induced a robust expression of IL6 mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP. The major sources of IL6 mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, ADAM17 (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and IL6R mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced IL6 mRNAs in the AMC and variably decreased elements of IL6 trans-signaling. DISCUSSION: These data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.

Background: Sciatica and low back pain are prevalent clinical types of neuropathic pain that significantly impair patients' quality of life. Conventional therapies often lack effectiveness, making these conditions challenging to treat. Electroacupuncture (EA) is an effective physiotherapy for pain relief. Prior research has demonstrated a relationship between the frequency of neuropathic pain and the analgesic impact of EA stimulation. This work aimed to assess the analgesic effects of EA in a rat model of chronic compression of the dorsal root ganglion (CCD) and to understand the underlying processes. Methods: We established a rat CCD model to simulate sciatica and low back pain. EA was applied to rats with CCD at various frequencies (2 Hz, 100 Hz, and 2/100 Hz). The paw withdrawal threshold (PWT) was measured to assess analgesic effects. Additionally, protein levels of the purinergic receptor P2X3 (P2X3) and the expression of nociceptive neuronal markers were analyzed using immunohistochemistry and western blot (WB) techniques. The study also measured levels of proinflammatory cytokines TNF-α and IL-1β in the dorsal root ganglion (DRG). The involvement of P2X3 receptors was further investigated using the P2X3 agonist, α,β-methylene ATP (α,β-meATP). Results: CCD rats developed pronounced mechanical allodynia. EA stimulation at all tested frequencies produced analgesic effects, with 2/100 Hz showing superior efficacy compared to 2 Hz and 100 Hz. The expression of P2X3 was increased in ipsilateral DRG of CCD model rats. P2X3 were co-labeled with isolectin B4 (IB4) and transient receptor potential vanilloid (TRPV1), indicating their role in nociception. 2/100 Hz EA treatment significantly reduced mechanical allodynia and inhibited the overexpression of P2X3, TRPV1, substance P (SP), and calcitonin gene-related peptide (CGRP) in the ipsilateral DRG of CCD model rats. Additionally, EA reduced the levels of proinflammatory cytokines TNF-α and IL-1β in the ipsilateral DRG, indicating an anti-inflammatory effect. The P2X3 agonist α,β-me ATP attenuated the analgesic effect of 2/100 Hz EA in CCD rats. The WB and immunofluorescence results consistently demonstrated P2X3 inhibition contributed to the analgesic effects of 2/100 Hz EA on CCD-induced neuropathic pain. Conclusions: Our findings suggest that 2/100 Hz EA alleviates neuropathic pain in rats by inhibiting the upregulation of P2X3 receptors in the ipsilateral DRG. This study backs up EA as a viable treatment option for sciatica and low back pain in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Menstrual irregularities significantly distress women living with HIV (WLHIV), impacting their reproductive health and quality of life. Although the underlying mechanism remains inconclusive, studies have outlined possible contributory factors. This narrative review explores the burden of menstrual irregularities and associated hormonal dysregulation among women living with HIV in Nigeria. It synthesises data from studies to present an overview of the prevalence, patterns, potential etiology, and impacts of menstrual irregularities among WLHIV. Main body: A literature search across electronic databases such as PubMed, Google Scholar, and Web of Science was conducted, and information was extracted and synthesized to delineate the burden of menstrual irregularities in WLHIV. Eligibility criteria included original studies assessing the prevalence, aetiology, and impact of menstrual abnormalities among WLHIV in Nigeria. A narrative data synthesis approach utilized common themes and key concept extraction, including identifying patterns in the literature to present specific trends such as prevalence, patterns, etiology, and determinants. Menstrual irregularities were found to be prevalent among Nigerian WLHIV, varying from 29 to 76% across different regions, exceeding reports of similar studies in developed nations. Similarly, menstrual disorders including amenorrhea, oligomenorrhea, and polymenorrhea, were attributed to factors like HIV acquisition, antiretroviral therapy, low body mass index, and hormonal imbalances. Low CD4 count and high viral load with associated complications have been identified as major contributing factors. Distortion of the hypogonadal-pituitary-ovarian axis by viral-induced pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-gamma (IFN-γ) may disrupt the hormonal balance necessary for regular menstrual cycles. Fluctuating levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), estradiol, and prolactin have been reported among WLHIV. Although adherence to antiretroviral therapy has offered immense relief, its direct therapeutic effects on menstrual irregularities are inconclusive.. Conclusions: This study highlights the burden of menstrual disorders among WLHIV. It underscores the interplay between clinical, therapeutic, and client-associated factors as determinants of these abnormalities. Exploring associated complications like secondary infertility, reduced bone mineral density, and resultant osteoporosis, mirrors the significant impact of menstrual and hormonal irregularities on the reproductive health and quality of life of WLHIV. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disorder, characterized by recurrent fever and serositis. It primarily affects individuals of Mediterranean descent, including Arabs, Armenians, Turks, and Jews. The Mediterranean fever (MEFV) gene, responsible for FMF, was discovered in 1997. Biallelic pathogenic variants lead to excessive activation of the pyrin inflammasome, resulting in inflammation. Clinical manifestations include recurrent fever, abdominal pain, and joint involvement, with attacks typically lasting 12-72 hours. Diagnosis relies on clinical criteria and is supported by genetic testing. Colchicine is the primary treatment to reduce attack frequency and prevent the complications like renal amyloidosis. Despite advancements in understanding FMF, including its genetic basis and treatment options, challenges remain in distinguishing it from other autoinflammatory diseases. Co-existing conditions such as juvenile idiopathic arthritis and inflammatory bowel disease are common among FMF patients. Ongoing research should aim to clarify the development of the disease, enhance diagnostic accuracy, and address its clinical presentation and genetic variability, with a focus on identifying new genetic mutations and epigenetic factors that contribute to its pathogenesis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is used by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation after TBI that could contribute to more severe TBI-related secondary injury. STUDY DESIGN: Thirty-six female pigs were used to test TBI vs Sham TBI, hypoxia vs normoxia, and hypobaria vs ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 ft were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO2 while at altitude. Serum cytokines, ubiquitin C-terminal hydrolase L1, and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein and phosphorylated tau. RESULTS: Serum interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly elevated after TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared with ground level/normoxia. No difference in TBI biomarkers after TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue glial fibrillary acidic protein or phosphorylated tau when comparing the most different conditions of Sham TBI + ground or normoxia with the TBI + hypobaria/hypoxia group was noted. CONCLUSIONS: The hypobaric environment of AE induces systemic inflammation after TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE after TBI. [ABSTRACT FROM AUTHOR]

Group B Streptococcus (GBS) is one of the most common bacteria responsible for placental and neonatal infection and inflammation resulting in lifelong neurobehavioral impairments. In particular, GBS-induced chorioamnionitis is known in preclinical models to upregulate inflammatory pathways, primarily through the activation of the interleukin-1 (IL-1) pathway, leading to brain injury and subsequent neurodevelopmental issues. Previous studies from our laboratory using Lewis rat pups have shown that male offspring exposed in utero to GBS chorioamnionitis develop brain injuries leading to neurobehavioral impairments such as autistic traits. In the present study, we aimed to explore whether blocking the IL-1 pathway could prevent or mitigate these neurodevelopmental impairments in adulthood. Using our established preclinical model, we administered IL-1 receptor antagonist (IL-1Ra) to dams with GBS-induced chorioamnionitis. Here, we show that IL-1Ra administration to dams reversed autistic and cerebral palsy traits in male adult offspring exposed in utero to GBS. Hence, IL-1 blockade could serve as a therapeutic intervention against pathogen-induced neurodevelopmental disorders. This research supports the need for future human randomized controlled trials to assess IL-1 blockade administered during pregnancy or in newborns as a strategy to reduce the long-term neurobehavioral consequences of prenatal infections, such as autism, cerebral palsy, learning disabilities, and other neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

In this study, we uncovered the novel mechanism of IL-1α-mediated downregulated in adenoma (DRA) (SLC26A3) downregulation in the context of Brachyspira spp.-induced malabsorptive diarrhea. Experimentally infected pigs with Brachyspira spp. had significantly reduced DRA expression in the colon accompanied by IL-1α upregulation. This response was recapitulated in vitro by exposing Caco-2 cells to either Brachyspira lysate or IL-1α. Both p38 and MAPK-activated protein kinase 2 (MAPKAPK-2 also referred as MK-2) showed an increased phosphorylation after exposure to either. SB203580 application, a p38 inhibitor blocked the MK-2 phosphorylation and attenuated the DRA and IL-1α response to both lysate and IL-1α. Exposure to IL-1 receptor antagonist (IL-1RA) produced a similar response. In addition, exposure of cells to either of these blockers without IL-1α or lysate results in increased DRA and decreased IL-1α expression, revealing that DRA needs IL-1α signaling for basal physiological expression. Dual inhibition with both blockers completely inhibited the effect from IL-1α while significantly attenuating the response from Brachyspira lysate, suggesting a minor contribution from another pathway. Together this demonstrates that Brachyspira activates p38 MAPK signaling driving IL-1α expression, which activates IL-1R1 causing DRA downregulation while also driving upregulation of IL-1α through p38 in a positive feedback mechanism. In conclusion, we elucidated a major pathway involved in DRA downregulation and its role in Brachyspira-induced diarrhea. In addition, these observations will aid in our understanding of other inflammatory and infectious diarrhea conditions. NEW & NOTEWORTHY: The diarrheal disease caused by the two infectious spirochete spp. B. hyodysenteriae and B. hampsonii reduced the expression of DRA (SLC26A3), a major Cl−/HCO–3 exchanger involved in Cl− absorption. This is attributed to the upregulation of IL-1α driven by p38 MAPK. This work also describes a potential new mechanism in inflammatory diseases while showing the importance of IL-1α in maintaining DRA levels. [ABSTRACT FROM AUTHOR]

Suppression of Tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor/ Toll-like receptor superfamily, and its specific ligand is Interleukin-33 (IL-33). IL-33/ ST2 signaling has been implicated in numerous inflammatory and allergic diseases, as well as in promoting malignant behavior of tumor cells and angiogenesis. However, the precise role of ST2 in gastric cancer angiogenesis remains incompletely elucidated. We observed a significant correlation between high expression of ST2 in gastric cancer tissues and poor prognosis, along with various clinicopathological features. In vitro experiments demonstrated that the IL-33/ ST2 axis activates the PI3K/AKT/NF-κB signaling pathway through TRAF6, thereby promoting VEGFA-mediated tumor angiogenesis; meanwhile sST2 acts as a decoy receptor to regulate the IL-33/ST2L axis. Consistent findings were also observed in subcutaneous xenograft tumor models in nude mice. Furthermore, we investigated the molecular mechanism by which IL-33 promotes ST2L expression in GC cells via upregulation of transcription factors YY1 and GATA2 through intracellular signaling pathways. [ABSTRACT FROM AUTHOR]

Objective: In nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the strongest predictor of adverse outcomes. We sought to investigate the relationship between liver fibrosis and cardiac remodeling in participants from the general population using magnetic resonance imaging (MRI), as well as explore potential mechanistic pathways by analyzing circulating cardiovascular biomarkers. Methods: In this cross-sectional study, we prospectively included participants with type 2 diabetes and individually matched controls from the SCAPIS (Swedish CArdioPulmonary bioImage Study) cohort in Linköping, Sweden. Between November 2017 and July 2018, participants underwent MRI at 1.5 Tesla for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography), left ventricular (LV) structure and function, as well as myocardial native T1 mapping. We analyzed 278 circulating cardiovascular biomarkers using a Bayesian statistical approach. Results: In total, 92 participants were enrolled (mean age 59.5 ± 4.6 years, 32 women). The mean liver stiffness was 2.1 ± 0.4 kPa. 53 participants displayed hepatic steatosis. LV concentricity increased across quartiles of liver stiffness. Neither liver fat nor liver stiffness displayed any relationships to myocardial tissue characteristics (native T1). In a regression analysis, liver stiffness was related to increased LV concentricity. This association was independent of diabetes and liver fat (Beta = 0.26, p = 0.0053), but was attenuated (Beta = 0.17, p = 0.077) when also adjusting for circulating levels of interleukin-1 receptor type 2. Conclusion: MRI reveals that liver fibrosis is associated to structural LV remodeling, in terms of increased concentricity, in participants from the general population. This relationship could involve the interleukin-1 signaling. Clinical relevance statement: Liver fibrosis may be considered a cardiovascular risk factor in patients without cirrhosis. Further research on the mechanisms that link liver fibrosis to left ventricular concentricity may reveal potential therapeutic targets in patients with non-alcoholic fatty liver disease (NAFLD). Key Points: Previously, studies on liver fibrosis and cardiac remodeling have focused on advanced stages of liver fibrosis. Liver fibrosis is associated with left ventricular (LV) concentricity and may relate to interleukin-1 receptor type 2. Interleukin-1 signaling is a potential mechanistic interlink between early liver fibrosis and LV remodeling. [ABSTRACT FROM AUTHOR]

People with depression have increased levels of pro-inflammatory cytokines compared to healthy subjects. Physical exercise can alleviate depressive symptoms and has anti-inflammatory properties. The aim of this study was to identify the effects of exercise on inflammatory biomarkers in people with depression. Clinical trials evaluating the acute and chronic effects of exercise on inflammatory biomarkers in adults with clinical depression were included. The search was conducted on the following databases: PubMed, Embase, Web of Science, PsycINFO, and SPORTDiscus. The risk of bias was assessed with the "Risk of bias in randomized trials" (RoB2) tool. Random effects meta-analyses estimated the acute and chronic effects of exercise for each marker separately. Heterogeneity was estimated with the l2 test. A total of 10 studies (497 participants) were included. No significant acute effects interleukins (IL)-6, IL-10, and IL-8 levels were found. Chronically, exercise increased the levels of TNF-α (Standardized Mean Difference = 0.296; 0.03–0.562, p = 0.029). No chronic effects were found for IL-6 and IL-1B. Overall, 90% of the studies had a moderate or high risk of bias. Exercise seems to promote a small increase in TNF-α, but literature is scarce and with a high risk of bias. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the rare manifestation of retinal vasculitis in Familial Mediterranean fever (FMF) and its correlation with specific gene mutations, particularly the MEFV gene, with a focus on the severity of phenotypes and systemic vasculitis. Methods: A case report of a 45-year-old Armenian patient with FMF history and dual mutations (M680I and M694V) was analyzed. Clinical assessments, including ocular examinations, were conducted at various stages of the disease. Treatment modalities, including prednisone, Anakinra, and Canakinumab, were administered and their effectiveness was assessed. Results: The patient presented with bilateral ocular pain and decreased vision, exhibiting acute anterior uveitis, perivascular hemorrhages resembling Roth spots, and subsequent features of persistent vascular sheathing and cotton-wool spots. Dual mutations, especially M694V, were associated with a severe phenotype and systemic vasculitis. Treatment with prednisone induced remission, and IL-1 pathway inhibition with Anakinra and Canakinumab successfully managed relapses. Conclusion: This case underscores the rarity of retinal vasculitis in FMF, particularly involving arteries, and highlights the correlation between specific gene mutations (M680I, M694V) and disease severity. The successful management with IL-1 pathway inhibitors suggests a potential therapeutic approach. Increased clinical awareness, further research, and reporting are crucial for optimizing the understanding and treatment of FMF-related ocular manifestations. [ABSTRACT FROM AUTHOR]

Objectives: Juvenile scleroderma is a heterogeneous group of diseases associated with sclerotic skin lesions, grouped as juvenile systemic sclerosis and juvenile localized scleroderma. This study aims to measure the cytokine and chemokine levels involved in interferon (IFN) signalling in patients with juvenile scleroderma and determine their correlation with disease severity. Methods: Twenty-nine juvenile localized scleroderma, five juvenile systemic sclerosis, and nine healthy controls were included in the study. Cytokines and chemokines involved in IFN gene signalling (IL-1, IL-6, IL-8, IP-10, MCP1, TNF-α, CXCL-11, IFN-α, IFN-β, IFN-γ) and IFN-stimulated genes (ISGs), including IFI27, IFI44, ISIG15, IFIT1, OAS1, RSAD2, were measured by ELISA and RT-PCR method, respectively. Results: A significant increase in IFN-α, IFN-β, IFN-γ, TNF-α, IL-1, IL-6 IL-8, IP-10, and MCP1 levels was observed in patients with juvenile systemic sclerosis compared with the healthy control group. Furthermore, IFN-α and IP-10 were elevated in both juvenile localized scleroderma and juvenile systemic sclerosis compared to the healthy control group. IFN-γ and IFN-α positively correlated with LoSAI and LoSDI levels, respectively. According to PGA-A analysis, IFN-β, IFN-γ, TNF-α, IL-8, IP10, MCP1, and CXCL11 were significantly higher in active disease than in the inactive state in both groups. Conclusion: The results suggest that IFN signalling may be impaired in patients with juvenile scleroderma. Significant changes were observed in cytokines and genes related to IFN signalling, which may have a crucial role in monitoring disease activity. In addition, we have gained important insights into the possibility of using IFN-α and IFN-γ as biomarkers for monitoring juvenile scleroderma activity and damage. [ABSTRACT FROM AUTHOR]

• cDAMPs are endogenous molecules released by necrotic CNS-resident cells after injury. • cDAMPs such as IL-1α, IL-33, nucleotides (e.g. ATP), and HMGB1 are key actors of neuroinflammation. • cDAMPs can initiate both proinflammatory mechanisms (e.g. IL-1α, ATP, HMGB1) and anti-inflammatory reprogramming (e.g. IL-33). • Interfering with the HMGB1/RAGE axis is a promising therapy for treating spinal cord and brain injuries, and stroke. Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways. [ABSTRACT FROM AUTHOR]

Objective: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer. Methods: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo. Results: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G0/G1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05). Conclusion: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a neoplasm related to inflammation; the expression of cytokines, such as CCL3, CCL4, CCL20, IL-1a, IL-1b, IL-6, IL-8, and IL-10, among others, is presumed to be associated with NPC occurrence and development. Therefore, the circulating levels of these cytokines may be potential biomarkers for assessing tumor aggressiveness, exploring cellular interactions, and monitoring tumor therapeutic responses. Numerous scholars have comprehensively explored the putative mechanisms through which these inflammatory factors affect NPC progression and therapeutic responses. Moreover, investigations have focused on elucidating the correlation between the systemic levels of these cytokines and the incidence and prognosis of NPC. This comprehensive review aims to delineate the advancements in research concerning the relationship between inflammatory factors and NPC while considering their prospective roles as novel prognostic and predictive biomarkers in the context of NPC. [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]

Pre‐clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti‐oncogenic effects of exercise were associated with the exercise‐mediated release of myokines such as interleukin (IL)‐15. However, no study has quantified the acute IL‐15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high‐intensity interval exercise (HIIE) [4×4 min at 85–95% heart rate (HR) peak, 3 min at 50–70% HR peak] before and after 7 months of three times weekly high‐intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL‐15, IL‐6, IL‐10, IL‐1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL‐15 concentrations (pre‐intervention: 113%; P = 0.013, post‐intervention: 102%; P = 0.005). Post‐exercise IL‐15 concentrations were associated with all other post‐exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre‐ or post‐HIIE IL‐15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL‐15 and other myokines including IL‐6, IL‐10 and IL‐1ra which may be clinically relevant in the anti‐oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. Key points: Exercise has been demonstrated to reduce the risk of cancer recurrence.Pre‐clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise‐induced myokines (IL‐6 and IL‐15).High‐intensity interval exercise significantly increased myokines associated with the anti‐oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response.Given IL‐15 has been implicated in the anti‐oncogenic effect of exercise and is being explored as an immunotherapy agent, high‐intensity interval exercise may improve outcomes for people living beyond cancer through IL‐15‐mediated pathways.Interventions that increase lean mass may also enhance this response. [ABSTRACT FROM AUTHOR]

Inflammation is a key response to a variety of stimuli, and inflammatory molecules such as cytokines play a central role in the pathogenesis of many diseases, including bone and joint diseases. Proinflammatory cytokines are mainly produced by immune cells, which mediate inflammation and innate immune responses. Inflammasomes are newly recognized as important players in innate immunity. The most typical one is the NOD-like receptor protein 3 (NLRP3) inflammasome. NLRP3 detects exogenous pathogenic invasion and endogenous cell damage and responds by forming the NLRP3 inflammasome. The three main components of the NLRP3 inflammasome are NLRP3 (capturing danger signals and recruits downstream molecules), caspase-1 (inducing the maturation of cytokines IL-18 and IL-18 to mediate the release and focal death of cytokines) and apoptosis-related spot-like protein containing caspase recruitment domain (ASC, which connects NLRP3 and caspase-1). In addition, proinflammatory cytokines accelerate bone absorption and cartilage destruction, leading to bone and joint tissue destruction. Therefore, proinflammatory cytokines are involved in regulating the pathogenesis of bone and joint diseases. This paper reviewed the research progress on the activation and function of NLRP3 inflammatory corpuscles in bone and joint diseases in recent years. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the protective effects of low fluid shear stress (FSS ≤ 2 dyn/cm²) against interleukin-1β (IL-1β)-induced chondrocyte apoptosis and explored the underlying molecular mechanisms. Methods: Chondrocytes were cultured under four conditions: control, IL-1β stimulation, low FSS, and combined low FSS + IL-1β stimulation. Apoptosis was assessed using Hoechst staining and flow cytometry. Western blotting determined the expression of caspase-3 (CASP3), caspase-8 (CASP8), and NF-κB p65. Quantitative real-time PCR measured miR-143-3p expression. The roles of miR-143-3p and the extracellular signal-regulated kinase 5 (ERK5)/Krüppel-like factor 4 (KLF4) signaling pathway were further investigated using miR-143-3p mimics and inhibitors, an ERK5 inhibitor, and a KLF4 overexpression vector. Results: IL-1β induced significant chondrocyte apoptosis, which was markedly inhibited by low FSS. Mechanistically, low FSS suppressed miR-143-3p expression, thereby enhancing ERK5 signaling. This activated ERK5 subsequently upregulated KLF4 expression, further mitigating IL-1β-induced damage. Importantly, miR-143-3p overexpression under low FSS conditions exacerbated IL-1β-induced apoptosis, while miR-143-3p inhibition attenuated it. Consistent with this, ERK5 inhibition augmented IL-1β-induced apoptosis, whereas KLF4 overexpression suppressed it. Conclusion: Low FSS protects chondrocytes from IL-1β-induced apoptosis by suppressing miR-143-3p and activating the ERK5/KLF4 signaling pathway. This study reveals a novel mechanism by which mechanical stimulation protects cartilage. [ABSTRACT FROM AUTHOR]

Chronic noncommunicable diseases (NCDs) are responsible for approximately 74% of deaths globally. Medicinal plants have traditionally been used to treat NCDs, including diabetes, cancer, and rheumatic diseases, and are a source of anti-inflammatory compounds. This study aimed to evaluate the anti-inflammatory effects of Rhus trilobata (Rt) extracts and fractions in lipopolysaccharide (LPS)-induced inflammation models in vitro and in vivo. The aqueous extract (RtAE) and five fractions (F2 to F6) were obtained via C18 solid-phase separation and tested in murine LPS-induced J774.1 macrophages. Key inflammatory markers, such as IL-1β, IL-6, TNF-α, and COX-2 gene expression were measured using RT-qPCR, and PGE2 production was assessed via HPLC-DAD. The in vivo effects were tested in an LPS-induced paw edema model in Wistar rats. Results showed that RtAE at 15 μg/mL significantly decreased IL-1β and IL-6 gene expression in vitro. Fraction F6 further reduced IL-1β, TNF-α, and IL-6 gene expression, COX-2 expression, and PGE2 production. In vivo, F6 significantly reduced LPS-induced paw edema, inflammatory infiltration, and IL-1β and COX-2 protein expression. Chemical characterization of F6 by UPLC/MS-QTOF revealed at least eight compounds with anti-inflammatory activity. These findings support the anti-inflammatory potential of RtAE and F6, reinforcing the medicinal use of Rt. [ABSTRACT FROM AUTHOR]

Background: Linarine is a natural chemical component widely found in Buddleja officinalis Maxim., Chrysanthemum indicum L., Mentha canadensis L., and other medicinal plants. Modern pharmacological studies have shown that linarine with good anti-inflammatory and antioxidant activities can inhibit the proliferation and induce apoptosis of many kinds of tumor cells. Moreover, linarine showed protective effect on the liver, kidneys, and other organs. Methods: Inflammation model of human corneal epithelial cell (HCEC) was constructed using NaCl induction, and cytotoxicity was detected by the CCK8 assay. The levels of inflammatory factors tumor necrosis factor-a (TNF-a) and interleukin 1b (IL-1b) were measured using Enzyme-linked immunoassay (ELISA). Chronic painful stimulation (tail clamping) in combination with Benzalkonium Chloride Solution drops in a desiccator established a mouse model of dry eye disease (DED). The following parameters were recorded: body mass, anal temperature, tear secretion, tear film rupture time, and corneal fluorescein staining. The levels of inflammatory factors mitogen activated protein kinase (MAPK), nuclear factor kappa-B (NF-kB), c-Jun N-terminal kinase (JNK), IL-1b, Interleukin 18(IL-18), A2A, A3, P2X4, P2X7, P2Y1 were measured by using immunofluorescence (IF) staining. Results: Linarine can inhibit the secreation of TNF-a, and IL-1b in HCECs. Linarine prolonged tear film rupture time, promoted tear secretion, repaired corneal damage, and reduced the levels of inflammatory factors of MAPK, NF-kB, JNK, IL-1b, IL-18, and modulated the levels of the purinergic receptor. Conclusions: Linarine is effective in treating dry eye in mice by inhibiting purinergic receptors-mediated inflammatory response. [ABSTRACT FROM AUTHOR]

Growing research has suggested an association between chronic inflammation and Intervertebral disc degeneration (IVDD), but whether there is a causal effect remains unknown. This study adopted two-sample Mendelian randomization (MR) approach to explore the etiological role of chronic inflammation in IVDD risk. Here, summary statistics for C-reactive protein (CRP), interleukin (IL)-1 α , IL-1 β , IL-6 expression and IVDD were obtained from genome-wide association studies (GWAS) of European ancestry. MR analyses were conducted by using inverse variance weighted (IVW), Wald Ratio, weighted median, and MR-Egger method. Sensitivity analyses were conducted to assess the robustness of the results. The MR analyses suggested a lack of causal association of CRP, IL-6 , and IL-1 α levels on IVDD (CRP-IVDD: odds ratio [OR] = 0.97, 95% confidence interval [CI] 0.86–1.09, P = 0.583; IL-6-IVDD: OR = 1.04, 95% CI 0.86–1.27, P = 0.679; IL-1 α -IVDD: OR = 1.09, 95%CI 1.00–1.18, P = 0.058). However, there was a sign of a connection between genetically elevated IL-1 β levels and a decreased IVDD incidence (OR = 0.87, 95%CI 0.77–0.99, P = 0.03). Our findings suggest a connection between IL-1 β levels and the risk of IVDD. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, the specific underlying mechanisms warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: Cancer-related fatigue (CRF) is a prevalent adverse effect experienced by cancer patients while receiving and after treatment, impacting as many as 90% of individuals. Although CRF is common, the genetic processes responsible for it and their influence on individual vulnerability are not well understood and are still being investigated. Objective: The primary objective of this scoping review is to identify and assess genes linked to the vulnerability and severity of CRF. This will help us better understand the genetic factors involved and assist in developing targeted nursing treatments in clinical settings. Methods: This review followed the PRISMA guidelines. A comprehensive search was performed in databases, such as PubMed, EMBASE, Web of Science, Cochrane Library, SinoMed, CNKI, and VIP, encompassing genetic association studies on CRF published up to February 25, 2024. The JBI Critical Appraisal Tools were used to assess the quality of observational studies. Results: This evaluation encompassed a comprehensive analysis of 14 studies that involved 3,254 patients. The results indicate strong connections between CRF and various inflammatory cytokines (IL-4, IL-6, IL-8, IL-10, IL-1b), tumor necrosis factor-alpha (TNF-a), catechol-O-methyltransferase (COMT), and circadian rhythm genes (CLOCK, PER). Conclusion: This scoping review emphasizes the significant genetic factor in CRF, with multiple genes showing distinct effects on cancer fatigue symptoms. Identifying these genes enhances our comprehension of CRF and unveils novel avenues for cancer treatment approaches. Future research should prioritize conducting cohort studies to monitor alterations in gene expression pre- and post-treatment, hence improving individualized medicinal strategies in oncology. [ABSTRACT FROM AUTHOR]

The ST6GAL1 sialyltransferase is overexpressed in multiple cancers, including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an a2-6-linked sialic acid to N-glycosylated membrane receptors, which consequently modulates receptor structure and function. While many studies have investigated the effects of ST6GAL1 on cell phenotype, there is a dearth of knowledge regarding mechanisms that regulate ST6GAL1 expression. In the current study, we evaluated the regulation of ST6GAL1 by two pro-inflammatory cytokines, IL-1β and IL-6, which are abundant within the PDAC tumor microenvironment. Cytokine activity was monitored using the Suit-2 PDAC cell line and two Suit-2-derived metastatic subclones, S2-013 and S2-LM7AA. For all three cell models, treatment with IL-1β or IL-6 increased the expression of ST6GAL1 protein and mRNA. Specifically, IL-1β and IL-6 induced expression of the ST6GAL1 YZ mRNA isoform, which is driven by the P3 promoter. The ST6GAL1 H and X isoforms were not detected. Promoter reporter assays confirmed that IL-1α and IL-6 activated transcription from the P3 promoter. We then examined downstream signaling mechanisms. IL-1b is known to signal through the NFkB transcription factor, whereas IL-6 signals through the STAT3 transcription factor. CUT&RUN experiments revealed that IL-1β promoted the binding of NFkB to the ST6GAL1 P3 promoter, and IL-6 induced the binding of STAT3 to the P3 promoter. Finally, we determined that inhibitors of NFkB and STAT3 blocked the upregulation of ST6GAL1 stimulated by IL-1β and IL-6, respectively. Together, these results highlight a novel molecular pathway by which cytokines within the tumor microenvironment stimulate the upregulation of ST6GAL1 in PDAC cells. [ABSTRACT FROM AUTHOR]

Background: Over the past decades, it has become increasingly evident that sleep disturbance contributes to inflammation‐mediated disease, including depression, mainly through activation of the innate immune system and to an increased risk of infections. Methods: A comprehensive literature search was performed in PubMed to identify relevant research findings in the field of immunity, inflammation and infections, with a focus on translational research findings from the past 5 years. Results: Physiological sleep is characterized by a dynamic interplay between the immune system and sleep architecture, marked by increased innate immunity and T helper 1 (Th1) ‐mediated inflammation in the early phase, transitioning to a T helper 2 (Th2) response dominating in late sleep. Chronic sleep disturbances are associated with enhanced inflammation and an elevated risk of infections, while other inflammatory diseases may also be affected. Conversely, inflammation in response to infection can also disrupt sleep patterns and architecture. This narrative review summarizes current data on the complex relationships between sleep, immunity, inflammation and infections, while highlighting translational aspects. The bidirectional nature of these interactions are addressed within specific conditions such as sleep apnea, HIV, and other infections. Furthermore, technical developments with the potential to accelerate our understanding of these interactions are identified, including advances in wearable devices, artificial intelligence, and omics technology. By integrating these tools, novel biomarkers and therapeutic targets for sleep‐related immune dysregulation may be identified. Conclusion: The review underscores the importance of understanding and addressing immune imbalance related to sleep disturbances to improve disease outcomes. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that synovial inflammation plays a pivotal role in knee osteoarthritis. Although biomechanical findings have shown that medial open-wedge proximal tibial osteotomy (OWPTO) decreases medial compartment loading by correcting knee alignment, the relationship between knee alignment and synovial inflammation in the biological microenvironment has not yet been elucidated. Purposes: To investigate the relationship between preoperative and postoperative knee alignment and synovial gene expression and to determine the cutoff point of postoperative knee alignment at which gene expression of synovial inflammation improves. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 36 patients with osteoarthritis who underwent OWPTO between June 2018 and May 2020 were enrolled. Synovial tissue was collected from affected knees during initial OWPTO and plate removal surgeries, and gene expression associated with the pathogenesis of osteoarthritis in the synovial tissue was investigated using real-time polymerase chain reaction. The correlation between weightbearing line ratio (WBLR) and synovial gene expression was determined. Receiver operating characteristic curve analysis was used to determine the cutoff values of WBLR for improving gene expression. The participants were divided into 2 groups, according to the cutoff values of their WBLR, and compared according to Knee injury and Osteoarthritis Outcome Score (KOOS) and synovial gene expression. Results: Postoperative WBLR was correlated with gene expression of interleukin 1β (IL1B) (ρ = −0.43; P =.008) and of interleukin 6 (IL6) (ρ = −0.41; P =.01). The cutoff value to predict improvement of IL6 was postoperative WBLR of 52%, with an area under the curve of 0.74 (P =.03). Patients with WBLR of <52% showed higher postoperative inflammatory gene (IL1B [ P =.04] and IL6 [ P =.03]) and inferior postoperative KOOS values compared with those with WBLR of >52%. Conclusion: The novel cutoff alignment for biological improvement after OWPTO in patients with medial compartment osteoarthritis was determined to be WBLR of 52%, and WBLR of <52% was associated with higher residual intra-articular inflammation and poor clinical outcomes. After accounting for surgical errors, the surgeon should set the target surgical alignment so that the postoperative WBLR does not fall below 52%. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a critical medical condition that results in significant neurological deficits and tissue damage, affecting millions worldwide. Currently, there is a significant lack of reliable tools for assessing and predicting IS outcomes. The inflammatory response following IS may exacerbate tissue injury or provide neuroprotection. This review sought to summarize current knowledge on the IL-1 family's involvement in IS, which includes pro-inflammatory molecules, such as IL-1α, IL-1β, IL-18, and IL-36, as well as anti-inflammatory molecules, like IL-1Ra, IL-33, IL-36A, IL-37, and IL-38. The balance between these opposing inflammatory processes may serve as a biomarker for determining patient outcomes and recovery paths. Treatments targeting these cytokines or their receptors show promise, but more comprehensive research is essential to clarify their precise roles in IS development and progression. [ABSTRACT FROM AUTHOR]

Objectives We investigated the potential of serum proteins for distinguishing clinical and molecular subtypes in patients with GCA. Methods Proximity extension assays were used to analyse 1463 proteins in serum samples from patients with new-onset GCA (n  = 16) and patients who have achieved remission (n  = 13). Unsupervised and supervised cluster analyses were performed. Results Unsupervised cluster analysis identified three distinct clusters based on the protein signature. Compared with cluster 2, patients of cluster 1 had fewer PMR symptoms, increased levels of macrophage migration inhibitory factor (MIF) and pronounced NF-κB, STAT5 and IL-1 signalling. The changes in serum proteins upon remission differed between cluster 1 and 2. Patients with cranial GCA were characterized by altered endothelial and Th17 signalling, whereas patients not responding to treatment within the GUSTO-trial showed increased Th1 and diminished B cell signalling. Patients with anterior ischaemic optic neuropathy displayed higher levels of CHI3L1 (YKL40) and MMP12, and reduced levels of TIMP3. Conclusion Protein profiling identified patient clusters in GCA with distinct proteomic features and therefore likely different pathophysiology. These unique proteomic footprints might lead to more targeted treatments in future. [ABSTRACT FROM AUTHOR]

Severe acute pancreatitis (SAP) is an inflammatory disease with varying severity, ranging from mild local inflammation to severe systemic disease, with a high incidence rate and mortality. Current drug treatments are not ideal. Therefore, safer and more effective therapeutic drugs are urgently needed. 7α,14β-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione DGA, a diterpenoid compound derivatized from glaucocalyxin A, exhibits anti-inflammatory activity. In this study, we demonstrated the therapeutic potential of DGA against SAP and elucidated the underlying mechanisms. Treatment with DGA markedly (1) inhibited death of RAW264.7 and J774a.1 cells induced by Nigericin and lipopolysaccharide, (2) alleviated edema, acinar cell vacuolation, necrosis, and inflammatory cell infiltration of pancreatic tissue in mice, and (3) inhibited the activity of serum lipase and the secretion of inflammatory factor IL-1β. DGA significantly reduced the protein expression of IL-1β and NLRP3 and inhibited the phosphorylation of NF-κB. However, DGA exhibited no inhibitory effect on the expression of caspase-1, gasdermin D (GSDMD), NF-κB, TNF-α, or apoptosis-associated speck-like protein (ASC) and on the cleavage of caspase-1 or GSDMD. Molecular docking simulation confirmed that DGA can bind to TLR4 and IL-1 receptor. In conclusion, DGA may effectively alleviate the symptoms of SAP in mice and macrophages by inhibiting the binding of TLR4 and IL-1 receptor to their ligands; therefore, DGA is a promising drug candidate for the treatment of patients with SAP. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive and irreversible neurological condition that occurs with age and poses a significant global public health concern, is distinguished by the degeneration of neurons and synapses in various regions of the brain. While the exact processes behind the neurodegeneration in AD are not completely known, it is now acknowledged that inflammation may have a significant impact on the beginning and advancement of AD neurodegeneration. The severity of many neurological illnesses can be influenced by the equilibrium between pro-inflammatory and anti-inflammatory mediators. The IL-1 family of cytokines is linked to innate immune responses, which are present in both acute inflammation and chronic inflammatory diseases. Research on the role of the IL-1 family in chronic neurological disease has been concentrated on AD. In this context, there is indirect evidence suggesting its involvement in the development of the disease. This review aims to provide a summary of the contribution of every IL-1 family member in AD pathogenesis, current immunotherapies in AD disease, and present treatment possibilities for either targeting or boosting these cytokines. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine particular single-nucleotide polymorphisms (IL-1A-889 C/T — rs1800587, IL-1B +3953 C/T — rs 1143634) of interleukins 1A and 1B in the development and prognosis of medication-related osteonecrosis of the jaw. DentiGen Parodontitis Tests were applied for collecting samples. This test is suitable for sampling oral mucosa cells in order to detect interleukins 1A and 1B single nucleotide polymorphisms (IL-1A−889, IL-1B+3953). Genetic samples were evaluated in the Istenhegyi Genediagnostic Center using the DNA-hybridization method. Genetic samples were collected in the patient group and the control group. The role of gene polymorphisms in the development of the disease was investigated by comparing the genetic results for the patient and control groups. The investigation of gene polymorphisms in disease prognosis is based on stage improvement, recovery, and relapses following treatment. In total, 91 patients with MRONJ and 59 healthy controls were included in the study. 51 patients in the patient group and 37 controls had unfavorable allelic variants. No association (Mp = 1.42, SDp = 0.496, Mc = 1.35, SDc = 0.482, p = 0.52) was found between unfavorable polymorphisms and the development of the MRONJ. In the patient group, surgical therapy was required in 79 cases. Stage improvement was detected in 78 cases, recovery in 67 cases, and relapse in 33 cases. No stage improvement was found in one case, recovery in nine cases, or relapse in 34 cases. Of the 79 patients requiring surgical therapy, 49 had unfavorable allelic variants. No connection was found between the polymorphisms examined and stage improvement (Mp = 1.37, SDp = 0.486, Mnp = 2, SDnp = –, p = 0.800) or recovery (Mp = 1.39, SDp = 0.491, Mnp = 1.44, SDnp = 0.527, p = 0.990). However, a significant association (Mp = 1.21, SDp = 0.415, Mnp = 1.58, SDnp = 0.502, p < 0.001) was found between relapses and the presence of unfavorable allelic variants. Within the possible limitations of this study, it can be assumed that the analysis of certain single-nucleotide polymorphisms of interleukin-1 may have the potential to help define the risk stratification of MRONJ after surgical therapy. [ABSTRACT FROM AUTHOR]

[Objective] Shimac® is a cosmetic product that is applied to the surface of the teeth to form a tr ansparent film. Applying it to the teeth inhibits the growth of Streptococcus mutans, the bacteria that is responsible for tooth decay. It also suppresses the production of inflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). For these reasons, this product is attracting attention as a new type of oral care product aimed at preverrting tooth decay and periodontal disea se. This study evaluated the medicinal effects of Shimac® on six inflammatory cytokines and its po tential for preventing periodontai disease・ [Methods] Approximately 20 mL of peripheral blood was collected from six healthy subjects and subsequently separated into PBMCs. The resulting PBMCs wer e cultured for 4 days with various concentrations of Shimac® and concanavalin. After culturing, ce 11 supernatants were collected and IL-10, IL-6, IL-8, IL-10, TNF-a, and IL-12p70 inflammatory cy tokines were quantified using the BD® Cytometric Bead Array (CBA) assay. [ResuIts] The addition of Shimac® suppressed PBMC proliferation in healthy subjects in a concentration-dependent manner・ In the group without Shimac®, IL-1B, IL-6, IL-8, and TNF-a concentrations in the PBMC culture super natant were 370. 3 ± (422. 6) pg/mL, 18797. 7 ± (7412.1) pg/mL, 20208.1 ± (4408. 6) pg/mL, and 1570. 9 土 (1300.1) pg/mL respectively・ In contrast, in the group with 1% Shimac® added, concentrations we re 2.7 ± (2. 6) pg/mL (p < 0.01), 1.7 ± (0. 8) pg/mL (p < 0.05), 14.6 ± (10.9) pg/mL (p < 0.01), an d 1. 3 ± (1. 1) pg/mL (p < 0. 01) respectively, showing signifiesnt reduction in multiple inflammato ry cytokines. [Discussion] Unlike pharmaceuticals, cosinetics are not legally permitted to display medicinal efficacy under laws such as those for pharmaceuticals and medical devices. However, Shim ac® significantly reduced inflammatory cytokines IL~10, IL-6, IL~8, and TNF-ck, suggesting that it may suppress inflammatory symptoms associated 科ith periodontal disease. [ABSTRACT FROM AUTHOR]

Background Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish. Methods We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM) or antidepressants sertraline (1 mM) or venlafaxine (1 mM). Results Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b– and IL-6–induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b–induced production of IL-2 and IL-13 by R-ketamine and of IL-1b–induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6–induced production of IL-13, whereas S-ketamine inhibited IL-6–induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b–induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6–induced kynurenine pathway activation. Conclusions Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from depression. [ABSTRACT FROM AUTHOR]

Simple Summary: The intestinal tract is one of the most important barriers in an organism. Cyclophosphamide can lead to the destruction of the structural integrity of the intestinal barrier, causing immunosuppression, oxidative stress, and microbiota disorders. Conversely, cow placenta extract can improve the immunity and antioxidant power of the organism, etc. Therefore, it is important to investigate the protective effects of cow placenta extract on the intestinal barrier, intestinal immune function, and intestinal microbiota caused by cyclophosphamide to provide a new approach for its clinical application in the treatment of intestinal injury caused by immunosuppression. Immunosuppression undermines intestinal barrier integrity. Cow placenta extract (CPE) primarily consists of active peptides with immunomodulatory and antioxidant effects. This study aimed to examine the preventive effect of CPE against intestinal damage induced by cyclophosphamide (Cy) in immunosuppressed mice. Thirty-six mice were randomly allocated into three groups: control group (C), model group (M), and treatment group (CPE). The mice in the CPE group were provided with 1500 mg/kg/day of CPE via gavage. In the last 3 days, mice in the groups M and CPE received intraperitoneal injections of 80 mg/kg/day of Cy. The results showed that CPE improved intestinal barrier function by decreasing serum d-Lactate (D-LA) levels and diamine oxidase (DAO) activity, while elevating the relative expression of Occludin, zonula occludens-1 (ZO-1), and mucin-2 (MUC-2) mRNA. Additionally, CPE improved the immune organ index and elevated the levels of secretory immunoglobulin A (sIgA), superoxide dismutase (SOD), interleukin-1beta (IL-1β), interleukin-4 (IL-4), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) in the intestine, thereby enhancing intestinal mucosal immune function. Furthermore, CPE improved the diversity of intestinal microbiota and increased the abundance of Candidatus_Saccharimonas, Psychrobacter, and Enterorhabdus, which promoted the proper functioning of the intestines. These findings suggest that CPE effectively ameliorates Cy-induced intestinal damage by enhancing the intestinal barrier, improving immune function, and restoring intestinal microbiota. [ABSTRACT FROM AUTHOR]

Purpose: This study performed a bidirectional Mendelian randomization (MR) analysis to elucidate the causal relationships of C-reactive protein and 41 inflammatory regulators with melanoma, including data from UK Biobank, Cardiovascular Risk in Young Finns Study, and Cohorts for Inflammation Work Group. Methods: We selected the inverse variance weighting (IVW) to merge the estimated causal effects of multiple SNPs into a weighted average. To evaluate the heterogeneities of IVW, the Cochran Q statistic, and I2 index were used. What's more, several sensitivity analyses were employed, including IVW, MR-Egger, weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO). Results: With SNPs reaching P < 5 × 10−8, the analyses findings revealed that IL-16 had a significant positively association with genetically risk of melanoma (ORIVW: 1.05; 95% CI: 1.03–1.07; P < 0.001), and high levels of MCP1 (ORIVW: 1.13; 95% CI: 1.03–1.23; P = 0.01) were suggestively associated with melanoma susceptibility. What's more, TNF-β (ORIVW: 1.07; 95% CI: 1.01–1.13; P = 0.02) and IL-8 (ORIVW: 1.08, 95% CI: 1.01–1.16; P = 0.03) were demonstrated a positive association with the risk of melanoma under a less stringent cut-off (P < 5 × 10−6). Conversely, we found a facilitative effect of melanoma susceptibility on IP-10 and inhibitory effects on IL-6, IL-1b, and GRO-α. Conclusion: The genetic evidence that we have uncovered indicates a potential association between the levels of specific inflammatory markers (IL-16, IL-8, MCP-1, and TNF-β) and the risk of melanoma. Further research is imperative to translate these findings into clinical applications. [ABSTRACT FROM AUTHOR]

Host genetic variation has been recognized as a key predictor of diverse clinical sequelae among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. Insights into the link between the Interleukin-6 receptor (IL-6R) and Interleukin-1 beta (IL-1β) genetic variation and severe coronavirus disease 2019 (COVID-19) are crucial for developing new predictors and therapeutic targets. We aimed to investigate the association of IL-6R rs12083537, IL-1β rs16944, and IL-1β rs1143634 SNPs with the severity of COVID-19. Our study was conducted on 300 COVID-19-negative individuals (control group) and 299 COVID-19-positive cases, classified into mild, moderate, and severe subgroups. Analyses of IL-1β (rs16944, rs1143634) and IL-6R (rs12083537) SNPs' genotypes were performed using qPCR genotyping assays. The IL-1β (rs16944) CC genotype and IL-6R (rs12083537) GG genotype were substantially related to COVID-19 severity, which was also associated with comorbidities and some laboratory parameters (p < 0.001). The IL-1β (rs1143634) TT genotype was found to be protective. Likewise, the IL-1β (rs16944) CC genotype was associated with increased mortality. IL-1β rs16944 and IL-6R rs12083537 SNPs are promising potential predictors of SARS-CoV-2 disease severity. Meanwhile, the rs1143634 SNP T allele was protective against severity and mortality risk. [ABSTRACT FROM AUTHOR]

Objective: Cryopyrin-associated periodic syndrome (CAPS) is characterized by excessive IL-1β release resulting in systemic and organ inflammation. As an anti-IL-1 agent, canakinumab has been approved with all CAPS phenotypes in USA and European countries. However, the use of canakinumab in CAPS in Chinese patients was rarely reported. In this study, we aimed to assess the effectiveness and safety of canakinumab in Chinese patients with CAPS. Methods: Patients with CAPS treated with canakinumab were included. Clinical data were collected retrospectively from medical records. Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels. Data was analyzed at canakinumab initiation, at months 1, 3, 6, 9, and 12, or the last follow-up. Results: A total of 10 CAPS patients were included. 40% of patients were males, the median age at disease onset was 2.5 (2.5, 6) days and the median duration of follow-up while on canakinumab was 22.5 (8.5, 27.5) months. 80% (8/10) of CAPS patients presented with moderate-severe disease activity before the canakinumab treatment. 30% (3/10) of patients required canakinumab dose increase to control disease activity. After treatments, 60% (6/10) of CAPS patients achieved complete remission without relapse and the rest showed minimal disease activity. Clinical symptoms such as fever and rash were improved significantly in most patients (80%). Although abnormal imaging in brain MRI remained in over half of those patients, neurological manifestations were all relieved. 60% (6/10) of patients received prednisone before starting canakinumab therapy and five of them discontinued prednisone later. The most common adverse event was infection (40%). No serious adverse events occurred during the treatment of canakinumab. Conclusions: Canakinumab may be effective and tolerable for Chinese CAPS patients, helping to reduce the dosage of corticosteroids. However, additional trials on large samples are required to further evaluate its efficacy and safety in China. [ABSTRACT FROM AUTHOR]

Ornithonyssus sylviarum (O. sylviarum) is an obligatory, blood-sucking ectoparasite widely distributed among poultry and other mammals, causing significant economic losses. This study represented the first report of molecular genotypic identification of O. sylviarum from pigeons, Columba livia domestica, in Egypt. PCR and sequencing of the 28S rRNA gene were conducted. The resulting mite sequences were subjected to BLAST analysis, revealing 90–100% similarity to O. sylviarum in all tested samples. The sequences were deposited in GenBank under the accession numbers PP049086 and PP033720. A phylogenetic tree was constructed to compare the obtained species with related species worldwide. Additionally, infected pigeons showed increased expression of IL-1, IL-10, IFN-γ, and TGF-β3 genes and elevated serum levels of stress biomarkers. The increased level of these cytokines indicates there was a disturbance in the immune status of the infected host with parasite compared with control healthy ones. This increases the susceptibility to infection with other pathogens. [ABSTRACT FROM AUTHOR]

Introduction: Chronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS. Methods: This is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels ≥ 1.7 nmol/L, and C-reactive protein (CRP) ≥ 1.0 mg/L. Patients received 100 mg/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography--tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021). Results: Median [interquartile range (IQR)] androstenedione increased by 0.5 [--0.1, 1.6] nmol/L (p = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol/L [p = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (p < 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment. Discussion: Our findings suggest that anakinra suppresses IL-1-mediated chronic lowgrade inflammation in PCOS and might attenuate biochemical hyperandrogenemia. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards Mtb. These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasome platforms activate caspases, leading to the maturation of the proinflammatory cytokines interleukin (IL)-1 and 18 and the cleavage of gasdermin D (GSDMD), a poreforming protein responsible for cytokine release and pyroptotic cell death. Recent in vitro and in vivo findings have highlighted the importance of inflammasome signaling and subsequent necrotic cell death in Mtb-infected innate immune cells. However, we are just beginning to understand how inflammasomes contribute to disease or to a protective immune response in tuberculosis (TB). A detailed molecular understanding of inflammasomeassociated pathomechanisms may foster the development of novel hostdirected therapeutics or vaccines with improved activity. In this mini-review, we discuss the regulatory and molecular aspects of inflammasome activation and the associated immunological consequences for Mtb pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the correlation between homocysteine (Hcy), 25-hydroxyvitamin D [25-(OH)-D], high mobility group protein B1 (HMGB1) and oxidative stress indexes and inflammatory cytokines in serum and aqueous humor of patients with age-related cataract (ARC). Methods: 135 ARC patients admitted to The Sixth People's Hospital of Chengdu from January 2021 to January 2023 were selected as ARC group and 60 patients with ocular trauma in the same period were selected as control group. The levels of Hcy, 25(OH)-D, HMGB1, oxidative stress indexes [superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GSH-PX)] and inflammatory cytokines [tumor necrosis factor-a (TNF-a), interleukin (IL) -1B, IL-6, IL-8] in serum and aqueous humor were detected. The correlation between serum and aqueous humor Hcy, 25(OH)-D, HMGB1 and oxidative stress and inflammatory cytokine levels in ARC patients were analyzed by Pearson correlation analysis. Results: The levels of Hcy, HMGB1, MDA, TNF-a, IL-1B, IL-6 and IL-8 in serum and aqueous humor in ARC group were higher than those in control group, while the levels of 25-(OH)-D, SOD, CAT and GSH-PX were lower than those in control group(P<0.05). Pearson correlation analysis showed that, Hey and HMGB1 in serum and aqueous humor of ARC patients were negatively correlated with SOD, CAT and GSH-PX, and positively correlated with MDA, TNF-α, IL-1B, IL-6 and IL-8 (P<0.05). 25-(OH)-D was positively correlated with SOD, CAT and GSH-PX, and negatively correlated with MDA, TNF-α, IL-1B, IL-6 and IL-8 (P<0.05). Conclusions: The levels of Hey and HMGB1 in serum and aqueous humor of ARC patients increase, and the level of 25(OH)-D decrease, which is significantly correlate with oxidative stress and inflammatory cytokines. Hcy, HMGB1, 25-(OH)-D may be involve in the development of ARC through oxidative stress and inflammatory response. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression and clinical significance of serum nucleotide-binding oligomerization do- main-like receptor protein 3 (NLRP3) inflammasome and its downstream inflammatory factors in patients with allergic rhinitis (AR). Methods: 206 AR patients (AR group) admitted to our hospital from April 2021 to September 2023 were selected, and patients were di- vided into mild group (107 cases) and moderate to severe group (99 cases) according to the severity of the disease, another 168 healthy volunteers (control group) who underwent physical examination in our hospital during the same period were selected. The levels of serum NLRP3 inflammasome, interleukin (IL)-1ẞ and IL-18 were detected in two groups. The symptoms of AR patients were evaluated by al- lergic rhinitis rating scale (SFAR). The correlation between serum NLRP3 inflammasome, IL-1B, IL-18 and SFAR score in AR patients was analyzed by Pearson method. The value of NLRP3 inflammasome, IL-1ẞ and IL-18 in the diagnosis of AR and the prediction of moderate to severe AR were analyzed by receiver operating characteristic (ROC) curve. Results: The levels of serum NLRP3 inflamma- some, IL-1ẞ and IL-18 in AR group were higher than those in control group(P<0.05). The levels of serum NLRP3 inflammasome, IL-1B, IL-18 and SFAR score in moderate and severe group were higher than those in mild group (P<0.05). The levels of serum NLRP3 inflam- masome, IL-1ẞ and IL-18 in AR patients were positively correlated with SFAR score(P<0.05). The area under the curve (AUC) of NLRP3 inflammasome, IL-1B, and IL-18 in the diagnosis of AR was 0.796, 0.821, and 0.800 respectively, the AUC of the combined diagnosis of the three indicators was 0.930, which was higher than that of each indicator alone. The AUC of NLRP3 inflammasome, IL-1ẞ and IL-18 in predicting moderate to severe AR was 0.793, 0.770 and 0.736 respectively, the AUC of the combined prediction of the three indicators was 0.893, which was higher than that of each indicator alone. Conclusion: The serum levels of NLRP3 inflammasome, IL-1ẞ and IL-18 in AR patients are significantly increase, which are relate to the aggravation of AR. The combine detection of NLRP3 inflammasome and its downstream inflammatory factors has a high value in the diagnosis of AR and the prediction of moderate to severe AR. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression and clinical significance of serum Klotho, fibroblast growth factor 23 (FGF23) and insulin-like growth factor-1 (IGF-1) in patients with chronic periodontitis (CP). Methods: 108 patients with CP (CP group) who admitted to our hospital from January 2022 to June 2023 were selected, and 92 patients with oral health who underwent ultrasonic tooth cleaning in our hospital during the same period were selected (control group), CP patients were divided into mild group (55 cases) and moderate to severe group (53 cases) according to the severity of CP. The levels of serum Klotho, FGF23, IGF-1, inflammatory factors interleukin (IL) -6, IL-1ẞ and tumor necrosis factor-a (TNF-a) in CP group and control group were detected, and the periodontal clinical indicators of probing depth (PD), attachment loss (CAL) and bleeding index (BI) in CP group were examined. The correlation between serum Klotho, FGF23, IGF-1 and periodontal clinical indicators and inflammatory factors were analyzed by Pearson method. The value of serum Klotho, FGF23 and IGF-1 in the diagnosis of CP were analyzed by receiver operating characteristic (ROC) curve. Results: The levels of serum FGF23, IL-6, IL-1ẞ and TNF-a in CP group were higher than those in control group (P < 0.05) and the levels of serum Klotho and IGF-1 were lower than those in control group (P < 0.05) The levels of serum FGF23, IL-6, IL-1B, TNF-α, PD, CAL and BI in moderate to severe group were higher than those in mild group (P < 0.05) and the levels of serum Klotho and IGF-1 were lower than those in mild group (P < 0.05) The level of serum FGF23 of CP patients was positively correlated with IL-6, IL-1B, TNF-α, PD, CAL and BI (P < 0.05) and the serum Klotho and IGF-1 levels were negatively correlated with IL-6, IL-1B, TNF-α, PD, CAL and BI (P < 0.05) The area under the curve of serum Klotho, FGF23 and IGF-1 in the diagnosis of CP was 0.819, 0.816 and 0.861, respectively, the area under the curve of the combined diagnosis of the three indexes was 0.978, which was higher than that of the single diagnosis of each index. Conclusion: The increase of serum FGF23 level, and the decrease of Klotho and IGF-1 levels in CP patients are related to the occurrence of periodontal inflammation and tissue destruction, the combined detection of serum Klotho, FGF23 and IGF-1 has high value in the diagnosis of CP. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway—IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodsResultsConclusionsTo extend cross-sectional data on cytokine ratios (CRs) in dry eye disease (DED) signs by investigating longitudinal change in pro- to anti-inflammatory CRs and associations with change in DED signs and symptoms.Secondary analysis of fifty-four subjects [mean age 57.3 (SD 13.2) years, 85.2% female; 68.5% white] with ≥ 4 uL pooled tear volumes at months 0, 6, and 12. Pro-inflammatory (IL-1b, IL-6, IL-8, IL-17A, IFN-g, and TNF-a) to anti-inflammatory (IL-6, IL-10) cytokine ratios (CR) were calculated. DED signs (corneal and conjunctival staining scores, tear break-up time, Schirmer test, Meibomian gland plugging, tear osmolarity, composite sign severity score) and symptoms [Ocular Surface Disease Index (OSDI)] were measured. Changes over time in DED signs, symptoms, and CRs were evaluated using longitudinal models. Correlations between changes in CR and changes in DED signs and symptoms were evaluated using Spearman correlation coefficients (rho).DED signs which improved over time (p < 0.001) included corneal and conjunctival staining score, tear break-up time, tear osmolarity, and composite sign severity score. Using IL-10 as anti-inflammatory, changes in corneal and conjunctival staining and composite severity score significantly correlated with changes in pro- to anti-inflammatory CRs from month 0 to 6 (|rho|: 0.29-0.45, p: 0.003-0.04) but not between month 0 to 12 (|rho|: 0.01 to 0.24, all p > 0.08). DED symptoms decreased across one year (p < = 0.001) for all OSDI measures; these changes did not correlate with changes in CRs (|rho|: 0.00 to 0.29, all p > 0.04).Improvement in some DED signs across one year correlated weakly with decreases in pro- to anti-inflammatory CRs, in alignment with the understanding of DED as inflammatory. CRs may provide greater insight than absolute tear cytokine concentrations as possible DED biomarkers. Additional studies that provide standardized clinical information and tear collection and analysis are needed to validate CRs in DED. [ABSTRACT FROM AUTHOR]

Introduction: Bruton's tyrosine kinase (BTK) and interleukin (IL)-2 Inducible Tcell Kinase (ITK) inhibitors have anti-inflammatory properties. We investigated the therapeutic effect of ibrutinib, an orally bioavailable BTK/ITK inhibitor, in a mouse model of Graves' orbitopathy (GO). Methods: Genetic immunization was performed through intramuscular administration of the recombinant plasmid, pCMV6-hTSHR cDNA, to 8-weekold female BALB/c mice. Serum levels of T3, T4, and thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs) were quantified using enzymelinked immunosorbent assay. Histopathological changes in orbital tissues were examined using immunohistochemistry (IHC) staining for TSHR and various inflammatory markers. Following successful genetic immunization, ibrutinib was orally administered daily for 2 weeks in the GO model mice. After treatment, the mRNA and protein expression levels of BTK, ITK, IL-1b, and IL-6 in orbital tissues were evaluated using real-time PCR and Western blotting. Results: In total, 20 mice were sacrificed to confirm successful genetic immunization. The GO mouse group exhibited significantly increased serum T3, T4, and TRAb levels. IHC revealed increased expression of TSHR, IL-1b, IL-6, transforming growth factor-b1, interferon-g, CD40, CD4, BTK, and ITK in the GO mouse model. The orbital inflammation was significantly attenuated in ibrutinibtreated mice. The mRNA and protein expression levels of BTK, ITK, IL-1b, and IL-6 in orbital tissue were lower in ibrutinib-treated GO mouse group compared to the phosphate-buffered saline-treated GO mouse group. Conclusion: The GO mouse model demonstrated enhanced BTK and ITK expression. Ibrutinib, a BTK/ITK inhibitor, suppressed the inflammatory cytokine production. These findings highlight the potential involvement of BTK/ITK in the inflammatory pathogenesis of GO, suggesting its role as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Limited availability and side effects of opioids have led to an increased use of non-opioid analgesia in animal disease models. However, by affecting the immune-inflammatory reactions, analgesia may disrupt the resolution of the host inflammation and modulate the survival in septic animals. This study used a clinically relevant sepsis mouse model of peritoneal contamination and infection (PCI) to investigate the antinociceptive and antiinflammatory properties of two non-opioid analgesics. Methods: Adult C57BL/6Jmicewere intraperitoneally injected with a human feces suspension and received either no analgesics (Non-A), Meloxicam, or Metamizole orally. The mice were monitored for pain and illness. Mortality was assessed at 7 days post-PCI. A separate group of mice was sacrificed 24 hours after infection. Blood, peritoneal lavage fluid (PLF), liver, and spleen were harvested for pathogen load quantification via qPCR, macrophage phenotyping, neutrophil infiltration/activation, and systemic/tissue cytokine release by flow cytometry. Results: Meloxicam but not Metamizole reduced the mortality of septic mice by 31% on day 7 compared to the Non-A group. Both analgesics effectively alleviated pain but did not affect illness severity, body weight, and temperature. Meloxicam quadrupled the bacterial burden in the blood and PLF. In high IL-6 responders, Meloxicam treatment was associated with reduced circulating IL-10 and IL-1b compared to the Non-A septic group. In low IL-6 responders, Meloxicam increased circulating MCP-1 levels and decreased PGE2 levels compared to Non-A septic mice. Notably, Meloxicam reduced spleen neutrophil infiltration by 20% compared to two other sepsis groups. Conclusion: Metamizole and Meloxicam effectively relieved pain and increased the animals' basal activity in the PCI sepsis model. Meloxicam prolonged survival yet triggered maladaptive responses due to its immunosuppressive features that decreased tissue bacterial clearance during sepsis. In contrast, Metamizole constitutes a safe and effective non-opioid alternative for analgesic control in the non-surgical PCI sepsis model. [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]

Purpose: To evaluate the impact of an interleukin-1 (IL-1) antagonist anakinra (Kineret®) on endometriosis-related quality of life (QoL), pain, and inflammatory biomarkers. Methods: This was a single-site, randomized, double-blinded, placebo-controlled, cross-over pilot clinical study of patients recruited at an academic specialty clinic. Eligible participants were females aged 18– 45 years with menstrual cycles every 24– 32 days. Subjects had moderate to severe dysmenorrhea and either a surgical diagnosis of endometriosis or an endometrioma on imaging. Subjects were randomly assigned in a double-blind fashion to receive either the study drug or placebo administered as daily injections during the first 3 periods and then the alternate intervention for the next 3 periods. Results: Fifteen subjects completed the 6 menstrual cycle study. After each period, they completed the Endometriosis Health Profile-30 (EHP-30) QoL questionnaire and an assessment of dysmenorrhea using a 0– 100 Visual Analogue Scale (VAS). All domains of the EHP-30 showed a trend towards improvement, with significant improvements in powerlessness (54.5 vs 63.3, p = 0.04) and self-image (58.1 vs 66.7, p = 0.03) on the study drug compared to placebo. The mean dysmenorrhea VAS also trended toward improvement with a score of 37.5 during active treatment and 42.6 with placebo (p = 0.26). No difference in menstrual cycle length was detected (29.3 days vs 27.7 days, p = 0.56). There were significant differences in multiple inflammatory biomarkers between the study drug and placebo, including BDNF, IL-1, and IL-6 among certain groups. Conclusion: With all EHP-30 domains and the dysmenorrhea VAS showing either a statistical improvement or trend towards improvement, there is justification for a larger study. As no impact on menstrual cycles was detected, anakinra may be a particularly impactful option for women desiring fertility. Additional evaluation is needed on the role of anakinra on inflammatory markers given significant reductions were identified in multiple biomarkers. Plain Language Summary: Endometriosis is a common gynecologic disease afflicting millions of patients. Anakinra is an IL-1 antagonist currently used for treatment of rheumatoid arthritis which has been found to improve quality of life measures for patients with endometriosis. Anakinra also reduces levels of biomarkers known to be associated with endometriosis-related inflammation. More study is needed on the role of anakinra in improving endometriosis symptoms. [ABSTRACT FROM AUTHOR]