Inflammatory Activity Research Articles

Xanthoangelol alleviates ischemic stroke injury by inhibiting the inflammatory activation of microglia

BackgroundLocal inflammation induced by microglial activation plays a significant role in the pathological process of cerebral ischemia. Angelica keiskei (Miq.) Koidz., a traditional botanical drug, can be used as a diuretic, laxative or galactagogue. Xanthoangelol (XA), an active chalcone compound from the aerial part of Angelica keiskei, has anti-inflammatory effects in the peripheral tissues. However, its effect against neuroinflammation is yet unclear. ObjectiveThe present study aims to investigate whether XA could mitigate ischemic stroke damage through attenuating neuroinflammation due to microglia activation. MethodsMiddle cerebral artery occlusion/reperfusion (MCAO/R) induced cerebral ischemia and oxygen-glucose deprivation/reperfusion (OGD/R) or lipopolysaccharide (LPS)-stimulated BV2 microglia cells were utilized to evaluate XA's protection against ischemic injury and neuroinflammation. The severity of brain injury was assessed using 2, 3, 5-triphenyltetrazolium chloride (TTC) staining and neurological assessment. The expressions of inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Reactive oxygen species (ROS) were assessed using dichlorodihydrofluorescein diacetate (DCF-DA) staining. NF-κB p65 nuclear translocation was confirmed by immunofluorescence (IF) staining. The expressions of proteins were quantified by Western blotting. ResultsXA was efficacious in reducing infarct size and improving neurological function in MCAO/R mice. In ischemic brain tissue, XA reduced microglial activation and proinflammatory cytokine expression. In lipopolysaccharide (LPS) and OGD/R-induced cell models, XA suppressed the production of ROS and decreased the secretion of inflammatory cytokines. Additionally, XA suppressed the nuclear translocation and phosphorylation of NF-κB p65 and blocked the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome. The protection of XA against MCAO/R-induced damages was not attenuated in TLR4−/− and MD2−/− mice. Mito-TEMPO treatment reversed XA's anti-inflammatory properties in OGD/R-induced BV2 cells. ConclusionXA attenuates ischemic stroke injury by suppressing microglial inflammatory responses. This efficacy is tied to its antioxidant activity and is independent of Toll-like receptor 4 (TLR4) or myeloid differentiation protein 2 (MD2).

Vitreoretinal Interface Cells Correlate In Vivo With Uveitis Activity and Decrease With Anti-Inflammatory Treatment.

To highlight the utility of en face swept-source optical coherence tomography angiography (SS-OCTA) in assessing vitreoretinal interface cells (VRICs) of patients with active uveitis and their dynamics. In this prospective, single-center study, 20 eyes from patients with active uveitis were analyzed using six 6 × 6-mm macular scans at three time points: active inflammation (baseline), clinically improving (T1), and resolved inflammation (T2). VRICs were visualized using 3-µm en face OCT slabs on the inner limiting membrane. The variation of VRIC number, density, and size over time was assessed, and VRIC measurements were compared with clinical grading. At baseline, the VRIC count was significantly higher (552.5 VRICs) than that of the healthy controls (478.2 VRICs), with a density of 15.3 cells/mm2. VRIC number decreased significantly to 394.8 (P = 0.007) at T1, with a density of 10.9 cells/mm2 (P = 0.007). VRIC size reduced from 6.8 µm to 6.3 µm at T1 (P = 0.009) and remained stable at T2 (P = 0.3). Correlation coefficients between inflammatory parameters (anterior chamber cells and National Eye Institute vitreous haze), and VRIC count indicated a positive correlation at baseline (r = 0.53), weakening at T1 (r = 0.36), and becoming negative at T2 (r = -0.24). En face SS-OCTA revealed increased VRIC number and size in active uveitis, likely due to monocyte recruitment. Post-inflammation control, VRIC number, size, and density significantly decreased, returning to normal despite residual anterior chamber cells or vitreous haze. Visualization of VRICs by in vivo OCT opens up new opportunities for therapeutic targets.

Anti- inflammatory and analgesic activity of fractions of Cedrus libani and Pinus brutia leaves ethanolic extracts

Anti- inflammatory and analgesic activity of fractions of Cedrus libani and Pinus brutia leaves ethanolic extracts

Differences in the Evaluation of Malnutrition and Body Composition Using Bioelectrical Impedance Analysis, Nutritional Ultrasound, and Dual-Energy X-ray Absorptiometry in Patients with Heart Failure.

Although malnutrition is frequently observed in patients with heart failure (HF), this diagnosis should be performed carefully since HF itself is associated with increased inflammatory activity, which affects body weight, functionality, and some nutritional parameters; thus, its isolated interpretation can erroneously identify surrogate markers of severity as markers of malnutrition. In this context, we aimed to evaluate the prevalence of malnutrition using different classification systems and perform a comprehensive nutritional evaluation to determine the reliability of different diagnostic techniques. Eighty-three patients with a recent hospital admission due to HF were evaluated. GLIM diagnosis criteria and subjective global assessment (SGA) were performed; a comprehensive anthropometric, functional, and biochemical nutritional evaluation was performed, in which bioelectrical impedance analysis (BIA), nutritional ultrasound, and dual-energy X-ray absorptiometry (DXA) were performed. Additionally, mortality and additional admissions due to HF were determined after a mean follow up of 18 months. Malnutrition according to the GLIM criteria (54%) accurately distinguished patients with impaired functionality, lower lean mass, skeletal mass index, and appendicular muscle mass (BIA), as well as lower trunk fat mass, trunk lean mass, fat-free mass (DXA), and decreased albumin and increased C-reactive protein serum levels. According to SGA, there were significant changes in body composition parameters determined by BIA, muscle ultrasound, and functional tests between well-nourished patients and patients with risk of malnutrition (53.7%) or who had malnutrition (7.1%), but not when the last two groups were compared. BIA and DXA showed strong correlations when evaluating muscle and fat mass in HF patients, but correlations with nutritional ultrasound were limited, as well as functional tests. A multivariate analysis showed that no significant association was observed between body composition and mortality, but preperitoneal fat was associated with an increased risk of new hospital admissions (OR: 0.73). GLIM criteria identified a lower percentage of patients with HF and malnutrition compared with SGA; thus, SGA could have a role in preventing malnutrition in HF patients. Nutritional evaluation with BIA and DXA in patients with HF showed reliable results of body composition parameters in HF, and both help with the diagnosis of malnutrition according to the GLIM or SGA criteria and could provide complementary information in some specific cases.

Relationship Between the Migration of Endogenous Neural Stem Cells and the Pattern of Change in Immune Cell Phenotypes in the Microenvironment After Intracerebral Hemorrhage in Rats

Intracerebral hemorrhage (ICH), the second most common type of stroke, can cause long-lasting disability in the afflicted patients. The study was conducted to examine the patterns of change in endogenous neural stem cells (eNSCs) and in the regenerative microenvironment after ICH, to observe the relationship between the migration of eNSCs and the pattern of change in the polarization state of immune cells in the microenvironment, and provide a research basis for research on clinical nerve repair. The collagenase injection method was used for modeling. The ICH model was induced in adult female Sprague-Dawley (SD) rats by injecting type VII collagenase (2 U) into the brain tissue of rats. All the experimental rats weighed 280-300 g. In order to simulate the ICU at different time points, including the acute phase (within 1 week), subacute phase (1-3 weeks), and the chronic phase (over 3 weeks), brain tissues were harvested at 3 day post injection (3 DPI), 10 DPI, 20 DPI, and 30 DPI to evaluate the modeling effect. Immunofluorescence staining of the brain tissue sections was performed with DCX antibody to observe the pattern of change in the migration of eNSCs in the brain tissue at different time points. Immunofluorescence staining of brain tissue sections was performed with CD206 antibody and CD86 antibody for respective observation of the pattern of change in pro-inflammatory (M1-type) and anti-inflammatory (M2-type) immune cells in the regenerative microenvironment of the brain tissue after ICM. Spontaneous ICH was successfully induced by injecting type Ⅶ collagenase into the brain tissue of SD rats. The volume of the hematoma formed started to gradually increase at 3 DPI and reached its maximum at 10 DPI. After that, the hematoma was gradually absorbed and was completely absorbed by 30 DPI. Analysis of the pattern of changes in eNSCs in the brain tissue showed that a small number of eNSCs were activated at 3 DPI, but very soon their number started to decrease. By 10 DPI, eNSCs gradually began to increase. A large number of eNSCs migrated to the hemorrhage site at 20 DPI. Then the number of eNSCs decreased significantly at 30 DPI (P<0.01). Analysis of the immune microenvironment of the brain tissue showed that pro-inflammatory (M1 type) immune cells increased significantly at 10 and 20 DPI (P<0.01) and decreased at 30 DPI. Anti-inflammatory (M2 type) immune cells began to increase gradually at 3 DPI, decreased significantly at 20 DPI (P<0.05), and then showed an increase at 30 DPI. After ICH in rats, eNSCs migrating toward the site of ICH first increase and then decrease. The immune microenvironment demonstrates a pattern of change in which inflammation is suppressed at first, then promoted, and finally suppressed again. Inflammation may have a stimulatory effect on the migration of eNSCs, but excessive inflammatory activation has an inhibitory effect on the differentiation and further activation of eNSCs. After ICH, the early stage of repair and protection (10 d) and the subacute phase (20 d) may provide the best opportunities for intervention.

Study on the anti–inflammatory effect of 3–(4–hydroxyphenyl) propionic acid in an in vitro LPS–stimulated acute kidney inflammation model

Acute kidney injury (AKI) is a syndrome defined by a rapid decrease in glomerular filtration that can be caused by sepsis, ischemia/reperfusion injury (IRI), or nephrotoxic drugs. Human microbiota makes significant contributions to human health by enzymatic transformation of such active substances and the release of molecules such as 3–4 hydroxyphenyl propionic acid (4–HPPA). Biological effects of 4–HPPA such as anti–inflammatory and antioxidant have been reported in many studies. The aim of the research is to reveal the anti–inflammatory activity of 4–HPPA, one of the microbiota products of flavonoids (especially naringin) found in many fruits, in an in vitro LPS (lipopolysaccharide) stimulated kidney inflammation model. HEK 293 kidney cells of human origin were used as material in the research. The trial consisted of 4 groups: control group, LPS group, 4–HPPA group and 4–HPPA+LPS group. LPS and 4–HPPA were applied to the cells at different concentrations for 24 hours. Effective concentrations of LPS and 4–HPPA were investigated by MTT viability test. Finally, IL–1β, TNF–α and NFkβ gene expression analyzes responsible for inflammatory responses were investigated by qRT–PCR method. According to the findings, after 24 hours of incubation, LPS at 2.5 ng·mL-1 and 4–HPPA at 6.25 μg·mL-1 were determined to be effective concentrations for the experiment. Again, it was observed that 4–HPPA downregulated LPS–induced IL–1β, TNF–α and NFkβ gene expressions by 7, 42 and 40%, respectively. According to the data obtained from the research, it was revealed that 4–HPPA had effective anti–inflammatory properties in the in vitro LPS–stimulated kidney inflammation model. However, it was concluded that in vivo and more advanced molecular methods are needed to fully elucidate the issue.

The Influence of Emodin Succinyl Ethyl Ester on Non-alcoholic Steatohepatitis Induced by a Diet High in Fructose, Cholesterol, and Fat in Mice.

Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis and evidence of hepatocyte injury (ballooning) and inflammation, with or without liver fibrosis. In this study, after 12 weeks of induction, the mice were treated with emodin succinyl ethyl ester (ESEE) for four weeks at doses of 10/30/90 mg/kg/d. The blood analysis of experimental endpoints showed that ESEE exhibited significant therapeutic effects on the progression of disorders of glycolipid metabolism and the induced liver injury in the model animals. Histopathological diagnosis of the liver and total triglyceride measurements revealed that ESEE had a significant therapeutic effect on the histopathological features of nonalcoholic fatty liver disease/hepatitis, such as cellular steatosis and activation of intrahepatic inflammation. Additionally, ESEE was able to improve hepatocyte fat deposition, steatosis, and the course of intrahepatic inflammatory activity. Furthermore, it showed some inhibitory effect on liver fibrosis in the model animals. In summary, this study confirms the therapeutic effects of ESEE on the NAFLD/NASH model in C57BL/6J mice induced by a high-fat, high cholesterol, and fructose diet. These effects were observed through improvements in liver function, inhibition of fibrosis, and inflammatory responses. Changes in blood glucose levels, blood lipid metabolism, liver histopathological staining, liver fibrosis staining, and related pathological scores further supported the therapeutic effects of ESEE. Therefore, this study has important implications for the exploration of novel drugs for nonalcoholic fatty liver disease.

Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements.MethodsTime-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed.ResultsGoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level.ConclusionsThis prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.Graphical abstract

MULTIDISCIPLINARY APPROACH TO A DIFFICULT CASE OF ACUTE HEART FAILURE DUE TO POSSIBILE ISOLATED CARDIAC SARCOIDOSIS

Abstract Background Cardiac sarcoidosis (CS) is a rare, infiltrative cardiomyopathy that results from granulomatous inflammation affecting the heart with high morbidity and mortality. It is usually associated with a systemic (i.e. pulmonary) involvement, but lone heart involvement has been described. Even with extensive multidisciplinary evaluation making a firm diagnosis is difficult, especially in case of isolated CS where the endomyocardial biopsy (EBM) diagnostic yield is low (20–30%). Case Description A 71–year–old patient, heavy smoker with no previously known diseases, was admitted with a 3–month history of dyspnea. On admission he showed typical features of heart failure with reduced ejection fraction (HFrEF). A coronary angiography excluded coronary artery disease, while echocardiography (TTE), cardiac magnetic resonance (CMR), and positron emission tomography (FDG–PET) showed a pattern consistent with a non–ischemic dilated cardiomyopathy with reduction in systolic function, and signs of active inflammation (highly suspected CS). Two electroanatomic mapping driven EBM were made but no clear histological signs of CS (i.e., granulomatous inflammation) were detected. The patient was treated with corticosteroids and HFrEF optimal medical therapy (sacubitril/valsartan, mineralocorticoid receptor antagonists, beta–blockers, dapagliflozin) and a temporary wearable defibrillator (LifeVest) was applied. At 2–month follow–up, despite a moderate improvement in the systolic function and HF symptoms, after a multidisciplinary discussion, considering the extensive left ventricle scar, inflammatory involvement, and the presence of multiple non–sustained ventricular tachycardia, a permanent cardioverter–defibrillator (ICD) was implanted. Conclusion This case highlights how, even with (repeated) extensive multidisciplinary evaluation (TTE, CRM, FGD–PET, EBM), a definitive diagnosis of isolated CS often remains presumptive. The presence of an experienced cardiomyopathy team (HF specialists, cardiac imager, electrophysiologists, internal medicine doctor) can help in the diagnostic–therapeutic management of these patients with inflammatory heart disease.

Clinical outcomes and clinico-pathological correlations in children with MPO-ANCA-associated glomerulonephritis showing renal arteritis.

The aim of this study was to evaluate the clinical features, pathological characteristics, and prognosis in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) with renal arteritis. The study involved 97 children from five pediatric clinical centers with MPO-AAGN who exhibited distinct clinical features. The patients were divided into AAGN-A+ and AAGN-A-, based on the presence or absence of arteritis, and the disparities in clinical, histopathological characteristics, and prognosis between the two groups was evaluated. In contrast to the AAGN-A- group, the children in the AAGN-A+ group exhibited more pronounced clinical symptoms and renal pathological injury. Arteritis positively moderately correlated with the serum creatinine, interleukin-6, urinary neutrophil gelatinase-associated lipocalin, negatively moderately correlated with serum complement C3. The renal survival rate in the AAGN-A+ group was significantly poorer than AAGN-A- group (χ2 = 4.278, p = 0.039). Arteritis showed a good predictive value for end-stage kidney disease (ESKD), and C3 deposition, ANCA renal risk score and arteritis were independent risk factors for the development of ESKD in children with MPO-AAGN. Arteritis is a significant pathological change observed in children with MPO-AAGN, and the formation of arteritis may be related to the inflammatory response and activation of the complement system.

Citrus reticulata fruit peel extract ameliorates testesterone-induced benign prostatic hyperplasia-like phenotypes in rats

Benign prostatic hyperplasia is a major pathophysiologic event that presents a high risk for prostate cancer (the second most frequently diagnosed cancer in men). The prognosis of conventional therapy for BPH remains poor due to treatment failures. Thus, natural remedies such as botanical drugs remain a promising alternative therapy to be explored for the treatment of BPH and prostate cancer. Citrus fruits, specifically fruit peels of Citrus reticulata (CRE) contain bioactive compounds that exhibit anti-inflammatory properties and have been used in crude form in traditional settings to manage benign prostatic hyperplasia and prostate cancer, however, scientific scrutiny of this ethnobotanical claim remains incomplete. This study assessed the protective effect of CRE in testosterone-induced benign prostatic hyperplasia-like phenotypes in rats. Male Wistar rats (n = 30, 150-200 g) were randomly assigned into six groups (n = 5), and treated for 28 days as follows: control group (normal saline, 5 mg/kg s.c.), model group (testosterone,5 mg/kg, i.p.), the finasteride (1 mg/kg, p.o.), and CRE (50, 100, and 200 mg/kg, p.o.) groups received testosterone (5 mg/kg, i.p.) in the morning and their respective treatments (either finasteride or CRE). All rats were given chow and water ad libitum. On the 28th day, the rats were sacrificed following deep anesthesia. Blood and the prostate gland were collected. Full blood count, serum levels of prostate-specific antigen (PSA), testosterone, C-reactive protein (CRP), and histology of the prostate gland were assessed. Compared to the model, treatment with C. reticulata peel extracts markedly reduced prostate weight, attenuated atresia of the prostatic glands, stromal fibrosis, and mast cell infiltration, and increased glandular secretion. Additionally, serum levels of testosterone, CRP, PSA, and white blood count were reduced in the high-dose C. reticulata peel extract-treated group. Fruit peels of C. reticulata exhibited a protective effect against BPH partly by attenuating inflammatory activity. Thus, this finding provides a rationale for further exploration of CRE for novel anti-BPH molecules that could be used to develop therapeutics against prostate cancer.

Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis

BackgroundMultiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology.MethodsThrough biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.ResultsWe demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects.ConclusionsThe data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.

Distinct metabolic responses to heme in inflammatory human and mouse macrophages – Role of nitric oxide

Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.

Neutrophils Expressing Programmed Death-Ligand 1 Play an Indispensable Role in Effective Bacterial Elimination and Resolving Inflammation in Methicillin-Resistant Staphylococcus aureus Infection.

Programmed death ligand 1 (PD-L1) is a co-inhibitory molecule expressed on the surface of various cell types and known for its suppressive effect on T cells through its interaction with PD-1. Neutrophils also express PD-L1, and its expression is elevated in specific situations; however, the immunobiological role of PD-L1+ neutrophils has not been fully characterized. Here, we report that PD-L1-expressing neutrophils increased in methicillin-resistant Staphylococcus aureus (MRSA) infection are highly functional in bacterial elimination and supporting inflammatory resolution. The frequency of PD-L1+ neutrophils was dramatically increased in MRSA-infected mice, and this population exhibited enhanced activity in bacterial elimination compared to PD-L1- neutrophils. The administration of PD-L1 monoclonal antibody did not impair PD-L1+ neutrophil function, suggesting that PD-L1 expression itself does not influence neutrophil activity. However, PD-1/PD-L1 blockade significantly delayed liver inflammation resolution in MRSA-infected mice, as indicated by their increased plasma alanine transaminase (ALT) levels and frequencies of inflammatory leukocytes in the liver, implying that neutrophil PD-L1 suppresses the inflammatory response of these cells during the acute phase of MRSA infection. Our results reveal that elevated PD-L1 expression can be a marker for the enhanced anti-bacterial function of neutrophils. Moreover, PD-L1+ neutrophils are an indispensable population attenuating inflammatory leukocyte activities, assisting in a smooth transition into the resolution phase in MRSA infection.

Proportion of inflammatory bowel diseases patients withsuboptimal disease control in daily clinical practice-Real-world evidence from the inflammatory bowel diseases-podcast study.

Crohn's disease and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by a progressive nature of the disease resulting in subsequent intestinal damage, limited efficacy of current treatments and suboptimal disease management and a significant burden for patients. The IBD-PODCAST study aims to estimate the proportion of Crohn's disease and UC patients with suboptimal disease control (SDC) in a real-world setting. A non-interventional and cross-sectional study was conducted across 103 sites in 10 countries (Austria, Belgium, Canada, Germany, Greece, Italy, Portugal, Spain, Turkey, and UK). Criteria for SDC were based on STRIDE-II criteria and adapted by an expert panel. 2185 patients (Crohn's disease: n=1,108, UC: n=1077) with a mean (SD) age of 44.0 (14.8) years and mean (SD) disease duration of 12.4 (9.2) years were included (52.2% male). Ileal involvement was present in 39.1% of Crohn's disease patients, 35.3% of UC patients had extensive colitis. 77.3% of Crohn's disease and 65.3% of UC patients were on targeted immunomodulators and, according to STRIDE-II-based treatment phases, 85.6% of Crohn's disease and 85.4% of UC patients were assigned to the long-term treatment phase. SDC was detected in 52.2% of Crohn's disease and 44.3% of UC patients predominantly due to impaired quality of life (QoL), clinically significant extraintestinal manifestations, steroid overuse, signs of active inflammation in UC and Crohn's disease, and active fistulas in Crohn's disease. More than one criterion was seen in 37% of patients with SDC. Opportunities for on-label treatment optimization were observed in 49% of Crohn's disease and 61% of UC patients on advanced therapy. The high percentage of SDC in this global, real-world cohort suggests a large disease burden and high unmet medical need in IBD patients. Future analysis should focus on monitoring and responding to SDC in this cohort and on patients' QoL.

Structural transitions enable interleukin-18 maturation and signaling

Several interleukin-1 (IL-1) family members, including IL-1β and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.

Multi‐omics approaches reveal inflammatory response and intestinal damage mediated by sRNA SaaS during Salmonella invasion in mice

AbstractSalmonella Enteritidis is a foodborne enteric pathogen that infects humans and animals, and bacterial small RNAs (sRNAs) have been found to play critical roles in the virulence of Salmonella. However, the specific mechanism by which sRNAs contribute to the host–pathogen interaction in the intestine remains unclear. In this study, a combination of transcriptomic and proteomic analysis was used to investigate the effect of a particular sRNA known as Salmonella adhesive‐associated sRNA (SaaS) on the intestinal damage induced by Salmonella. The results revealed that SaaS sRNA could suppress the host's inflammatory response through various gene sets, mainly including tumor necrosis factor (TNF)‐α signaling via NF‐κB, IL‐6 JAK‐STAT3 signaling, and interferon gamma responses. This suppressive effect was further confirmed by ELISA analysis, which showed the lowest levels of TNF‐α, IL‐6, and interferon gamma (IFN‐γ). Meanwhile, the work has identified several crucial factors, peptidoglycan recognition protein short, transferrin receptor protein 1, and corticosteroid 11‐beta‐dehydrogenase isozyme 2, that are specifically targeted by SaaS to regulate inflammatory response, neutrophils activity, and diseases. Furthermore, combining hematologic analysis and correlation analysis, this study demonstrated that SaaS led to a decrease in the percentage of neutrophils and revealed a strong correlation between the three crucial factors and various markers of inflammation and intestinal barrier function. These findings provide a comprehensive understanding of how SaaS sRNA modulates Salmonella invasion in the animal intestine and further present a strategy on controlling foodborne Salmonella based on the new targets, sRNAs.

Correction of Nitrosative Stress During Reparative Regeneration of the Nasal Cavity Mucosa in an Experimental

Introduction. Nitric oxide metabolites play an important role in prolongation of the inflammatory reaction, disorders of epithelial regeneration in diseases of the upper respiratory tract. One of the promising approaches to regulating the bioactivity of nitric oxide is the use of antioxidants.The objective of the study is to evaluate the effectiveness of antioxidant therapy for the correction of nitrosative stress during reparative regeneration of the nasal mucosa in an experiment.Methods. A preclinical randomized experimental study is conducted on 160 rats, divided into 4 groups. The control group (n = 40) consists of intact animals. Animals in experimental group 1 (n = 40) do not receive treatment aſter injury; in group 2 (n = 40) anti-inflammatory treatment is prescribed. The third group consists of laboratory rats (n = 40), which are additionally injected into the nasal cavity with an antioxidant — a 15 % solution of 1,1-dimethyl-3-oxobutylphosphonic acid dimethyl ester. On days 2, 5, 10, and 14 of observation, the concentration of nitrates and nitrites and C-reactive protein in the blood of animals are determined.Results. In group 3, aſter an increase in the level of nitric oxide metabolites on day 2 aſter injury on day 5, a significant (p &lt; 0.05) decrease was noted in comparison with other groups, and by day 10— normalization of the indicator. An increase in the level of C-reactive protein in blood serum correlated with the concentration of nitric oxide metabolites.Discussion. The optimal therapeutic effect when taking antioxidants develops when administered in the first hours aſter injury to reduce the excessive formation of reactive nitrogen radicals. However, the duration of administration should not exceed 4–5 days to avoid a significant decrease in the level of nitric oxide metabolites and deterioration of mucosal regeneration.Conclusions. Assessment of nitric oxide metabolitesin the blood at different times aſter injury is an important marker of inflammatory activity. The use of antioxidants helps to reduce the concentration of active nitrogen radicals.

Markers of hemophagocytic lymphohistiocytosis are associated with survival in critically ill patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Association for the Promotion of Research on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) and the Ludwig Boltzmann Cluster for Cardiovascular Research Background/Introduction Patients admitted to the intensive care unit (ICU) often show systemic immune dysregulation paired with significantly increased inflammatory activity. Haemophagocytic lymphohistiocytosis (HLH) represents a rare syndrome characterized by fever, inflammation, cytopenia, and organ dysfunction. Inappropriate survival of cytotoxic T cells as well as histiocytes triggers cytokine storm, accompanied by the occurrence of hemophagocytosis and multi-organ failure. prevalence of HLH in critical illness continues to be a topic of discussion but most certainly remains underreported. This circumstance often leads to delays in the necessary immunosuppressive therapy due to difficulty in early diagnosis. Purpose In the present study, we aimed to illuminate the prospective value of the individual HLH criteria in a cohort of critically ill patients. Although the prevalence of this syndrome might be low, isolated markers of HLH could help to assess the extent of inflammatory activation and further be of use in predicting the outcome of patients admitted to the ICU. Methods This was a prospective, observational cohort study. 176 consecutive patients admitted to a cardiac ICU were included over the course of one year. Available HLH criteria were recorded except for biopsy samples of bone marrow and measurements of low or absent natural killer cell activity. For soluble CD25 (sCD25) a specific ELISA kit was used according to the manufacturer's instructions. Results The median age was 67.51 years (IQR: 57.50-77.41) and 38.64% of the included patients were female. The total 30-day mortality was calculated to be 25.57% and positivity for two or more criteria of HLH was found to be associated with depicted mortality (p = 0.033). Analyzing the individual parameters, only sCD25 was found to be a predictor of death within the first 30 days (p &amp;lt; 0.001). The combination of triglycerides and fibrinogen did not predict outcomes. However, low fibrinogen values were found to possess prognostic merit in regard to mortality (p= 0.019). In multivariate analysis, both sCD25 and fibrinogen remained a significant predictor of 30-day survival after adjustment for age, sex, and BMI (sCD25 p &amp;lt; 0.001, fibrinogen p = 0.042). Finally, the addition of fibrinogen was able to improve the prognostic value of the SAPS II score significantly (ROC curve, SAPS II – AUC: 0.790, SAPS II &amp; fibrinogen – AUC: 0.827, p = 0.045). Conclusion We provided evidence for the prognostic value of certain markers of HLH in critically ill patients. Positivity for two or more criteria was found to be associated with an increased 30-day mortality. Moreover, sCD25 and fibrinogen independently predicted outcomes in multivariate analysis after adjustment for age, sex, and BMI. The addition of fibrinogen was able to improve the prognostic properties of the SAPS II score.Figure 1Figure 2

Evaluation of the antioxidant and anti-inflammatory properties of the hydroethanolic extract of the leaves of &lt;i&gt;Blighia sapida&lt;/i&gt; KD Koenig

Blighia sapida is widely used in traditional medicine for the treatment of several diseases in Togo. This study aimed to assess the antioxidant and anti-inflammatory properties of Blighia sapida. To this end, a phytochemical screening was carried out, followed by an assessment of DPPH, total antioxidant capacity, ex vivo lipoperoxidation tests on Sprague Dawley rats, and an evaluation of anti- inflammatory activity by the egg albumin denaturation test. The leaves extract scavenged the DPPH free radical with an IC50 of 172 ± 0.577µg/mL and its total antioxidant capacity value was 40.174 ± 0.638 mg Eq AA/g. In the ex vivo lipoperoxidation test on the kidney and liver, the extract showed a significant inhibitory effect. Phytochemical tests revealed the presence of tannins, flavonoids, alkaloids, saponosides, and carbohydrate compounds. The present results showed that Blighia sapida leaves possess antioxidant and anti- inflammatory properties which may be linked to the bioactive compounds they contain, suggesting their use to prevent oxidative and inflammatory processes.