Dysregulated Inflammation Research Articles

Alcaligenes faecalis corrects aberrant matrix metalloproteinase expression to promote reepithelialization of diabetic wounds.

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here, we focused on Alcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes reepithelialization of diabetic keratinocytes, a process that is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

New Potential Pharmacological Options for Endometriosis Associated Pain.

Endometriosis is a chronic inflammatory disorder characterized by the abnormal growth of endometrial-like tissue outside the uterine cavity, affecting 10-15% of women of reproductive age. Pain is the most common symptom. Treatment options include surgery, which has limited effectiveness and high recurrence rates, and pharmacotherapy. Hormonal therapies, commonly used for symptom management, can have side effects and contraceptive outcomes, contributing to the infertility associated with endometriosis, with pain and lesions often reappearing after treatment cessation. Among its etiological factors, immunological and inflammatory dysregulation plays a significant role, representing an interesting target for developing new therapeutic strategies. This review critically analyzes recent studies to provide an updated synthesis of ongoing research into potential new pharmacotherapies focusing on lesion progression, pain relief, and improving quality of life. Immunotherapy, natural anti-inflammatory and antioxidant compounds and drug repurposing show promise in addressing the limitations of current treatments by targeting immunological factors, potentially offering non-invasive solutions for managing pain and infertility in endometriosis. Promising results have been obtained from in vitro and animal model studies, but clinical trials are still limited. More effort is needed to translate these findings into clinical practice to effectively reduce disease progression, alleviate pain symptoms and preserve the reproductive capacity, improving patients' overall wellbeing.

Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation

Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant in the brain, where metabolism must be precisely regulated to maintain appropriate neuronal excitability and synaptic transmission. Direct evidence that microglia can impact on neuronal energy metabolism has been widely lacking, however. Combining molecular profiling, electrophysiology, oxygen microsensor recordings and mathematical modeling, we investigated microglia-mediated disturbances in brain energetics during neuroinflammation. Our results suggest that proinflammatory microglia showing enhanced nitric oxide release and decreased CX3CR1 expression transiently increase the tissue lactate/glucose ratio that depends on transcriptional reprogramming in microglia, not in neurons. In this condition, neuronal network activity such as gamma oscillations (30–70 Hz) can be fueled by increased ATP production in mitochondria, which is reflected by elevated oxygen consumption. During dysregulated inflammation, high energy demand and low glucose availability can be boundary conditions for neuronal metabolic fitness as revealed by kinetic modeling of single neuron energetics. Collectively, these findings indicate that metabolic flexibility protects neuronal network function against alterations in local substrate availability during moderate neuroinflammation.

(003) LOCALIZED PROVOKED VULVODYNIA: THE ROLE OF CYCLOOXYGENASE ENZYMES IN PROMOTING INFLAMMATION AND PAIN SIGNALING

Abstract Introduction Localized provoked vulvodynia (LPV) is a chronic condition in which patients experience disabling pain in the vulvar vestibule. This condition’s mechanisms are poorly understood, and the lack of adequate treatment reflects the misunderstanding of the disease’s origins. Many LPV patients attempt to treat their pain with NSAIDS, but their use has been clinically shown to be ineffective against LPV associated vulvar pain. Recent evidence, utilizing fibroblasts isolated from vestibular and vulvar tissue of LPV patients, supports a link between inflammation and symptomology of LPV. These fibroblasts have shown to be sensitive to pro-inflammatory stimuli and overproduce inflammatory mediators such as Interleukin-6 (IL-6) and Prostaglandin E2 (PGE2). Increased production of IL-6 and PGE2 correlates with decreased pain thresholds, endorsing these levels as a surrogate measure for pain. Lipidomic data collected via mass spectroscopy also demonstrates LPV fibroblast strains have dysregulated arachidonic acid metabolism, resulting in an imbalance in pro-resolving lipids. Utilizing this fibroblast model, different cyclooxygenase (COX) inhibitors were used to better illuminate the mechanism behind fibroblast inflammation in LPV. Objective Using a fibroblast cell model, we set out to better understand pathophysiology of LPV and use that information to guide development of effective and pragmatic medical treatments. Methods Fibroblast strains were generated from vulvar and vestibular tissue samples of LPV patients and non-LPV age and race-matched controls. These cells were then treated with Interleukin 1 beta (IL-1β), selective cyclooxygenase-1 inhibitor (SC560), celecoxib (selective COX-2 inhibitor), and ibuprofen (nonselective COX inhibitor) to investigate differences in cellular response when blocking different enzymes in the inflammatory pathway. IL-1β is known to induce IL-6 and PGE2 which acted as a positive control. Results were then quantified via ELISA assay. Results Vestibular and vulvar tissues showed an increase in IL-6 and PGE2 production following treatment with IL-1B. When concurrently treated with IL-1B (to stimulate inflammation) and SC560 (to inhibit COX-1 signaling) ELISA analysis showed a significant decrease in PGE2. A significant PGE2 decrease was shown with concurrent IL-1B/Ibuprofen treatment as well as with IL-1B/Celecoxib treatments. In all three cases, IL-6 signaling was generally not decreased, while PGE2 was decreased, but not to baseline levels. Ibuprofen treatment in fact showed a trend towards increased IL-6 production. Conclusions Fibroblast response to inflammation in the case of LPV is complex. COX inhibitors do not fully inhibit the pain signaling that contributes to the symptomology of LPV patients (IL-6 production remains elevated). NSAIDs leave patients with dysregulated inflammation cascades, which does not remediate pain. Future areas of study for pharmaceutical targets include investigating lipid regulation, other pain signaling mechanisms, such as transient receptor potential cation channel subfamily V member 4 (TRPV4), and combination topical NSAID use to create more appropriate and robust treatment for patients with LPV. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: SPM Therapeutics.

Combined effect of inflammation and malnutrition for long-term prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cohort study

BackgroundInflammation is a key driver of atherosclerotic diseases and is often accompanied by disease-related malnutrition. However, the long-term burden of dysregulated inflammation with superimposed undernutrition in patients with acute coronary syndrome (ACS) remains unclear. This study sought to investigate the double burden and interplay of inflammation and malnutrition in patients with ACS undergoing percutaneous Coronary Intervention (PCI).MethodsWe retrospectively included 1,743 ACS patients undergoing PCI from June 2016 through November 2017 and grouped them according to their baseline nutritional and inflammatory status. Malnutrition was determined using the nutritional risk index (NRI) with a score lower than 100 and a high-inflamed condition defined as hs-CRP over 2 mg/L. The primary outcome was major adverse cardiovascular events (MACEs), compositing of cardiac mortality, non-fatal myocardial infarction, non-fatal stroke, and unplanned revascularization. Long-term outcomes were examined using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox proportional hazards regression analysis was applied to adjust for confounding. The reclassification index (NRI)/integrated discrimination index (IDI) statistics estimated the incremental prognostic impact of NRI and hs-CRP in addition to the Global Registry of Acute Coronary Events (GRACE) risk score.ResultsDuring a median follow-up of 30 months (ranges 30–36 months), 351 (20.1%) MACEs occurred. Compared with the nourished and uninflamed group, the malnourished and high-inflamed group displayed a significantly increased risk of MACEs with an adjusted hazard ratio of 2.446 (95% CI: 1.464–4.089; P < 0.001). The prognostic implications of NRI were influenced by patients’ baseline inflammatory status, as it was only associated with MACEs among those high-inflamed (P for interaction = 0.005). Incorporating NRI and hs-CRP into the GRACE risk score significantly improved its predictive ability for MACEs (NRI: 0.210, P < 0.001; integrated discrimination index; IDI: 0.010, P < 0.001) and cardiac death (NRI: 0.666, P < 0.001; IDI: 0.023, P = 0.002).ConclusionsAmong patients with ACS undergoing PCI, the double burden of inflammation and malnutrition signifies poorer outcomes. Their prognostic implications may be amplified by each other and jointly improve the GRACE risk score’s risk prediction performance.

Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis.

Physical frailty is a syndrome that typically manifests in later life, although the pathogenic process causing physical frailty likely begins decades earlier. To date, few studies have examined the biological signatures in mid-life associated with physical frailty later in life. Among 4,189 middle-aged participants (57.8 ± 5.0years, 55.8% women) from the Atherosclerosis Risk in Community (ARIC) study, we evaluated the associations of 4,955 plasma proteins (log 2-transformed and standardized) measured using the SomaScan platform with their frailty status approximately 20years later. Using multinomial logistic regression models adjusting for demographics, health behaviors, kidney function, total cholesterol, and comorbidities, 12 and 221 proteins were associated with prefrailty and frailty in later life, respectively (FDR p < 0.05). Top frailty-associated proteins included neurocan core protein (NCAN, OR = 0.66), fatty acid-binding protein heart (FABP3, OR = 1.62) and adipocyte (FABP4, OR = 1.65), as well proteins involved in the contactin-1 (CNTN1), toll-like receptor 5 (TLR5), and neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway relevant to skeletal muscle regeneration, myelination, and inflammation. Pathway analyses suggest midlife dysregulation of inflammation, metabolism, extracellular matrix, angiogenesis, and lysosomal autophagy among those at risk for late-life frailty. After further adjusting for midlife body mass index (BMI) - an established frailty risk factor - only CNTN1 (OR = 0.75) remained significantly associated with frailty. Post-hoc analyses demonstrated that the top 41 midlife frailty-associated proteins mediate 32% of the association between mid-life BMI and late-life frailty. Our findings provide new insights into frailty etiology earlier in the life course, enhancing the potential for prevention.

Age-related changes to macrophage subpopulations and TREM2 dysregulation characterize attenuated fracture healing in old mice.

Fracture healing complications increase with age, with higher rates of delayed unions and nonunions and an associated increase in morbidity and mortality in older adults. Macrophages have a dynamic role in fracture healing, and we have previously demonstrated that age-related changes in macrophages are associated with attenuated fracture repair in old mice. Here, we provide a single cell characterization of the immune cells involved in the early phase of fracture healing. We show that there were multiple transcriptionally distinct macrophage subpopulations present simultaneously within the healing tissue. Fracture healing was attenuated in old mice compared to young, and macrophages from the fracture callus of old mice demonstrated a pro-inflammatory phenotype compared to young. Interestingly, Trem2 expression was decreased in old macrophages compared to young. Young mice lacking Trem2 demonstrated attenuated fracture healing and inflammatory dysregulation similar to old mice. Trem2 dysregulation has previously been implicated in other age-related diseases, but its role in fracture healing is unknown. This work provides a robust characterization of the macrophage subpopulations involved in fracture healing, and further reveals the important role of Trem2 in fracture healing and may be a potential driver of age-related inflammatory dysregulation. Future work may further examine macrophages and Trem2 as potential therapeutic targets for management of fracture repair in older adults.

Proteogenomic profiling of clonal hematopoiesis in the solid tumor microenvironment.

2567 Background: Clonal hematopoiesis (CH) is caused by somatic mutations that provide a fitness advantage in hematopoietic stem cells, contributing to inflammation and disease. CH is common in solid tumor patients, and has shown context-dependent associations with survival; however, its contribution to the tumor microenvironment (TME) remains unclear. Here, we employ proteogenomic methods to define CH-associated alterations in the TME. Methods: We tested 1,550 patients across 10 primary, treatment-naïve cancers in the Clinical Proteomic Tumor Analysis Consortium cohort. CH calls were derived from peripheral blood and tumour whole exome sequencing (WES) data, and CH was defined as the presence of a somatic driver mutation at variant allele frequency (VAF) ≥2% in blood. Overall survival (OS) analysis was conducted using Cox proportional hazard models, controlled for age, sex, tumor type, metastatic status, and smoking. Tumor bulk RNA-sequencing and mass spectrometry proteomics data were processed for differential expression and gene set enrichment analyses. Abundance of immune cell populations was estimated with CibersortX. Results: 349 CH mutations were identified in 283 patients (18.3%). CH was strongly associated with age and mutations were mostly found in the epigenetic regulators DNMT3A(37.8%, n=132) and TET2(20.6%, n=72). CH was most prevalent in ovarian cancer (30%, n=27/90) and colorectal cancer (CRC; 28.3%, n=30/106). 103 blood CH mutations were also detected in tumor WES (CHTum), with presence in the tumor associated with higher tumor immune infiltration and peripheral blood VAF ≥10%. CHTum, but not CH, was associated with worse OS (CHTum HR = 1.74 [1.13-2.69]; CH HR = 1.12 [0.83-1.50]). CHTum was also associated with a reduced likelihood of patients being classified as tumor free at follow up (OR = 0.39 [0.19-0.82]). We did not identify a pan-cancer proteogenomic signature of CH in the TME. At the tumor-specific level, we consistently observed associations between CH and its subtypes with dysregulated inflammation, with high transcriptomic-proteomic concordance. In CRC, TET2-mutant CH was associated with greater infiltration of CD4+ T cells, monocyte/macrophages, NK cells, and B cells, alongside an inflammatory response characterized by IL6/JAK/STAT3 signalling, TNF signalling via NFκB, and IL2/STAT5 signalling. Conclusions: CH is common, even prior to therapy, in solid tumor patients and the infiltration of CH-mutant immune clones into the TME is linked with poor outcomes. Beyond confounding molecular tumor diagnostics, CH in the TME also dysregulates the anti-tumor immune response, highlighting the value of a blood reference in precision oncology. The lack of a pan-cancer CH signature in the TME supports a tumor-specific influence of CH. Further study is needed for mechanistic discovery and biomarker development to realize the potential of CH in immuno-oncology and improve patient outcomes.

Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common cause of pulmonary hypertension (PH) worldwide and is strongly associated with adverse clinical outcomes. The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF.NEW & NOTEWORTHY Our review addresses pulmonary hypertension (PH) attributable to heart failure (HF) with preserved ejection fraction (HFpEF; PH-HFpEF). Current knowledge gaps in PH-HFpEF pathophysiology have led to a lack of therapeutic targets. Thus, we address identified knowledge gaps in a comprehensive review, focusing on current clinical epidemiology, known pathophysiology, and previously studied molecular mechanisms. We also introduce a comprehensive review of polyunsaturated fatty acid (PUFA) lipid inflammatory mediators in PH-HFpEF.

Macronutrient-differential dietary pattern impacts on body weight, hepatic inflammation, and metabolism.

Obesity is a multi-factorial disease frequently associated with poor nutritional habits and linked to many detrimental health outcomes. Individuals with obesity are more likely to have increased levels of persistent inflammatory and metabolic dysregulation. The goal of this study was to compare four dietary patterns differentiated by macronutrient content in a postmenopausal model. Dietary patterns were high carbohydrate (HC), high fat (HF), high carbohydrate plus high fat (HCHF), and high protein (HP) with higher fiber. Changes in body weight and glucose levels were measured in female, ovariectomized C57BL/6 mice after 15 weeks of feeding. One group of five mice fed the HCHF diet was crossed over to the HP diet on day 84, modeling a 21-day intervention. In a follow-up study comparing the HCHF versus HP dietary patterns, systemic changes in inflammation, using an 80-cytokine array and metabolism, by untargeted liquid chromatography-mass spectrometry (LCMS)-based metabolomics were evaluated. Only the HF and HCHF diets resulted in obesity, shown by significant differences in body weights compared to the HP diet. Body weight gains during the two-diet follow-up study were consistent with the four-diet study. On Day 105 of the 4-diet study, glucose levels were significantly lower for mice fed the HP diet than for those fed the HC and HF diets. Mice switched from the HCHF to the HP diet lost an average of 3.7 grams by the end of the 21-day intervention, but this corresponded with decreased food consumption. The HCHF pattern resulted in dramatic inflammatory dysregulation, as all 80 cytokines were elevated significantly in the livers of these mice after 15 weeks of HCHF diet exposure. Comparatively, only 32 markers changed significantly on the HP diet (24 up, 8 down). Metabolic perturbations in several endogenous biological pathways were also observed based on macronutrient differences and revealed dysfunction in several nutritionally relevant biosynthetic pathways. Overall, the HCHF diet promoted detrimental impacts and changes linked to several diseases, including arthritis or breast neoplasms. Identification of dietary pattern-specific impacts in this model provides a means to monitor the effects of disease risk and test interventions to prevent poor health outcomes through nutritional modification.

Cytokine and Microbiome Changes in Adolescents with Anorexia Nervosa at Admission, Discharge, and One-Year Follow-Up.

Anorexia nervosa (AN) is a severe eating disorder that predominantly affects females and typically manifests during adolescence. There is increasing evidence that serum cytokine levels are altered in individuals with AN. Previous research has largely focused on adult patients, assuming a low-grade pro-inflammatory state. The serum levels of the cytokine tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and IL-15, which are pro-inflammatory, were examined in 63 female adolescents with AN and 41 age-matched healthy controls (HC). We included three time points (admission, discharge, and 1-year follow-up) and investigated the clinical data to assess whether the gut microbiota was associated with cytokine alterations. Relative to the HC group, serum levels of IL-1β and IL-6 were significantly lower during the acute phase (admission) of AN. IL-1β expression was normalised to control levels after weight recovery. TNF-α levels were not significantly different between the AN and HC groups. IL-15 levels were significantly elevated in patients with AN at all time points. We found associations between cytokines and bodyweight, illness duration, depressive symptoms, and the microbiome. In contrast to most findings for adults, we observed lower levels of the pro-inflammatory cytokines IL-1β and IL-6 in adolescent patients, whereas the level of IL-15 was consistently increased. Thus, the presence of inflammatory dysregulation suggests a varied rather than uniform pro-inflammatory state.

Potential Role of Inflammasome NLRP3 and IL-1β Gene Expression in COVID-19 Patients: Impact of Ferritin and D –Dimer

Dysregulated inflammation and hypercoagulability underlie the development of severe illness in COVID-19. Biomarkers related to inflammasome activation, including interleukin (IL)-1β and NLRP3, and inflammatory lung cytokine as IL-8. As well as coagulation markers like D-dimer. The aim of this study was to identify associations between the dysregulated immune response biomarkers and the severity of the disease that will help in prognostic and potential therapeutic utility. Twenty five mild/moderate and 25 severe COVID-19 patients were included in this study as well as 25 healthy controls. Survival analysis was done after follow up for one month. Inflammasome (IL-1β, NLRP3), lung cytokine (IL-8), and vitamin D levels were analyzed by real time PCR and ELISA. The mRNA expression levels of IL-1β , NLRP3 and serum level of IL-8 were elevated in cases than controls. COVID-19 patients exhibited lower levels of vitamin D. The severe group showed significant higher levels of D dimer and ferritin. Correlation analyses indicated associations between IL-1β , NLRP3, IL-8, D-dimer and ferritin. ROC curve analyses demonstrated the potential of IL-1β , NLRP3 and IL-8 in distinguishing between mild/moderate and sever cases. Survival analyses indicated a link between high levels of IL-1β , NLRP3 and IL-8 with decreased survival.. The inflammasome appears pivotal in orchestrating detrimental hyperinflammation in severe COVID-19. IL-1β holds particular potential as a prognostic indicator of poor outcomes. In the future, the possible using of these biomarkers inhibitors may improve survival , decrease severity and improve management of the cases.

Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

Rationale: Bronchiectasis is characterized by acute exacerbations, but the biological mechanisms underlying these events are poorly characterized. Objectives: To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. Methods: A total of 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation before receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral, or both. Sputum inflammatory assessments included label-free liquid chromatography-tandem mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16 s rRNA sequencing was used to characterize the microbiome. Measurements and Main Results: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacterium was identified in 103 samples (86%), and a high bacterial load (total bacterial load > 107 copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients, with rhinovirus being the most common virus (31%). PCR testing was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, IL-1β, and CXCL8. These markers were particularly associated with bacterial and bacterial plus viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral, and eosinophilic events in both hypothesis-led and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating four subtypes of exacerbation. Conclusions: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses, and inflammatory dysregulation.

Metabolic dysfunction is associated with alterations in gut microbiota in obese adolescents

Abstract The gut microbiota (MB) has been implicated in adult metabolic dysfunction given evidence of dysbiosis in obesity and type 2 diabetes. However, few studies have investigated the relationship between metabolic disease, inflammation and the gut microbiota in children. We characterized the gut MB and immunometabolic profile of a cohort of obese, non-diabetic adolescents (MI4D) using high throughput fecal DNA sequencing with absolute bacterial quantitation. In the absence of antibiotics, we observed multi-log differences in fecal biomass correlated with stool water content and MB composition. Moreover, fecal bacterial biomass was associated with metabolic measures including serum triglycerides and insulin resistance in a sex-dependent manner. Mass cytometry demonstrated no significant associations of major immune cell subsets to fecal biomass or metabolic markers. In contrast, there were male-specific associations between serum markers of systemic inflammation and neutrophil activity with fecal biomass and waist circumference. Given the infiltration of visceral adipose tissue by myeloid cells in metabolic inflammation, our findings suggest that lower fecal biomass is associated with elevated systemic inflammation, especially in obese adolescent males. This study expands the understanding of sex-specific mechanism driving metabolic dysfunction in obese youth and suggests that gut MB alterations contribute to their metabolic and inflammatory dysregulation before diabetes diagnosis.

Maresin-1 attenuates neuroinflammation in EAE via metabolic reprogramming of disease-associated cell types

Abstract Inflammation resolution is dysregulated in people affected with multiple sclerosis (MS) due to impaired metabolism of docosahexaenoic acid (DHA). We hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in a preclinical mouse model of MS; experimental allergic encephalomyelitis (EAE). Administration of the resolution agonist MaR1 mediated resolution and improved neurological outcome in the relapsing-remitting (RR) model of EAE. MaR1 induced metabolic changes in CD4, macrophages, microglia, and oligodendrocytes. It modulated the phenotype of disease-associated cell types by regulating their effector functions. It restored the impaired efferocytosis in EAE, promoting clearance of damaged myelin and dead cells; thereby lowering the disability with disease course. MaR1 is a potential interventional candidate to attenuate dysregulated inflammation to restore neurological deficits in EAE and other autoimmune diseases.

The beneficial effects of neutrophil elastase inhibitor on gastrointestinal dysfunction in sepsis.

To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non-sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non-sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non-sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4-6), p = 0.008]. The serum levels of d-lactate (p = 0.033), intestinal fatty acid-binding protein (p = 0.005), interleukin-6 (p = 0.001), white blood cells (p = 0.007), C-reactive protein (p = 0.001), and procalcitonin (p < 0.001) of the sivelestat group were lower than those of the non-sivelestat group. The sivelestat group also demonstrated longer ICU-free days [18 (0-22) vs. 13 (0-17), p = 0.004] and ventilator-free days [22 (1-24) vs. 16 (1-19), p = 0.002] compared with the non-sivelestat group. In conclusion, sivelestat sodium administration appears to improve gastrointestinal dysfunction, mitigate dysregulated inflammation, and reduce disease severity in septic patients.

Immune mechanisms in the pathophysiology of hypertension.

Hypertension is a leading risk factor for morbidity and mortality worldwide. Despite current anti-hypertensive therapies, most individuals with hypertension fail to achieve adequate blood pressure control. Moreover, even with adequate control, a residual risk of cardiovascular events and associated organ damage remains. These findings suggest that current treatment modalities are not addressing a key element of the underlying pathology. Emerging evidence implicates immune cells as key mediators in the development and progression of hypertension. In this Review, we discuss our current understanding of the diverse roles of innate and adaptive immune cells in hypertension, highlighting key findings from human and rodent studies. We explore mechanisms by which these immune cells promote hypertensive pathophysiology, shedding light on their multifaceted involvement. In addition, we highlight advances in our understanding of autoimmunity, HIV and immune checkpoints that provide valuable insight into mechanisms of chronic and dysregulated inflammation in hypertension.

Rosacea in Older Adults and Pharmacologic Treatments.

Rosacea is a chronic inflammatory skin condition that is often more severe in older patients. The main clinical features are erythema, telangiectasia, and inflammatory lesions of the face. The pathogenesis of this condition is not fully understood but certainly multifaceted. Immune and inflammatory dysregulation, genetics, neurogenic dysregulation, microbiome dysbiosis, and systemic disease have all been implicated in rosacea pathogenesis. As we better understand the various pathways that lead to rosacea, we acknowledge that the different symptoms may have unique underlying triggers and mechanisms. Aging also impacts rosacea diagnosis and treatment. Older adults have more severe rosacea symptoms while also having more sensitive and fragile skin than younger patients; therefore, rosacea treatments for older patients require a balance between delivering adequate potency while also minimizing skin irritation and other adverse effects. Until recently, rosacea diagnoses were based on concrete subtypes that did not necessarily capture each patient's manifestation of rosacea. There is now an emphasis on more personalized phenotype-based diagnoses and treatments, which allows for more emphasis on treating individual symptoms and accounting for the unique characteristics of older patients. Centrofacial erythema is best treated with brimonidine and oxymetazoline, while phymatous change and telangiectasia are best treated with surgery and laser ablation. Treatment for rosacea papules and pustules ranges from topicals, such as azelaic acid, ivermectin, metronidazole, minocycline, and encapsulated benzoyl peroxide, to systemics, such as doxycycline and isotretinoin. It is important to understand these treatments in relation to adverse effects and drug interactions that may specifically arise in older populations to provide optimal care. As we advance in understanding rosacea's pathogenesis and adopt personalized phenotype-based approaches, optimizing care for older patients becomes crucial. Continued research into novel treatments is essential to address their unique needs.

Oxysophoridine inhibits oxidative stress and inflammation in hepatic fibrosis via regulating Nrf2 and NF-κB pathways

BackgroundHepatic fibrosis (HF) runs through multiple stages of liver diseases and promotes these diseases progression. Oxysophoridine (OSR), derived from Sophora alopecuroides l., is a bioactive alkaloid that has been reported to antagonize alcoholic hepatic injury. However, whether OSR suppresses HF and the mechanisms involved in Nrf2 remain unknown. PurposeSince the dysregulation of inflammation and oxidative stress is responsible for the excessive accumulation of extracellular matrix (ECM) and fibrosis in the liver. We hypothesized that OSR may attenuate HF by inhibiting inflammation and oxidative stress through activating Nrf2 signaling. MethodsIn this study, we employed LPS-stimulated HSC-T6 cells, RAW264.7 cells, and a CCl4-induced C57BL/6 mouse fibrotic model to evaluate its suppressing inflammation and oxidative stress, as well as fibrosis. ResultsThe result showed that OSR significantly reduced α-SMA and TGF-β1 at a low dose of 10 μM in vitro and at a dose of 50 mg/kg in vivo, which is comparable to Silymarin, the only Chinese herbal active ingredient that has been marketed for anti-liver fibrosis. Moreover, OSR effectively suppressed the expression of iNOS at a dose of 10 μM and COX-2 at a dose of 40 μM, respectively. Furthermore, OSR demonstrated inhibitory effects on the IL-1β, IL-6, and TNF-α in vitro and almost extinguished cytokine storm in vivo. OSR exhibited antioxidative effects by reducing MDA and increasing GSH, thereby protecting the cell membrane against oxidative damage and reducing LDH release. Moreover, OSR effectively upregulated the protein levels of Nrf2, HO-1, and p62, but decreased p-NF-κB p65, p-IκBα, and Keap1. Alternatively, mechanisms involved in Nrf2 were verified by siNrf2 interference, siNrf2 interference revealed that the anti-fibrotic effect of OSR was attributed to its activation of Nrf2. ConclusionThe present study provided an effective candidate for HF involved in both activation of Nrf2 and blockage of NF-κB, which has not been reported in the published work. The present study provides new insights for the identification of novel drug development for HF.

Circulating immune cell landscape and T-cell abnormalities in patients with moyamoya disease.

Moyamoya disease (MMD) stands as a prominent cause of stroke among children and adolescents in East Asian populations. Although a growing body of evidence suggests that dysregulated inflammation and autoimmune responses might contribute to the development of MMD, a comprehensive and detailed understanding of the alterations in circulating immune cells associated with MMD remains elusive. In this study, we employed a combination of single-cell RNA sequencing (scRNA-seq), mass cytometry and RNA-sequencing techniques to compare immune cell profiles in peripheral blood samples obtained from patients with MMD and age-matched healthy controls. Our investigation unveiled immune dysfunction in MMD patients, primarily characterized by perturbations in T-cell (TC) subpopulations, including a reduction in effector TCs and an increase in regulatory TCs (Tregs). Additionally, we observed diminished natural killer cells and dendritic cells alongside heightened B cells and monocytes in MMD patients. Notably, within the MMD group, there was an augmented proportion of fragile Tregs, whereas the stable Treg fraction decreased. MMD was also linked to heightened immune activation, as evidenced by elevated expression levels of HLA-DR and p-STAT3. Our findings offer a comprehensive view of the circulating immune cell landscape in MMD patients. Immune dysregulation in patients with MMD was characterized by alterations in T-cell populations, including a decrease in effector T-cells and an increase in regulatory T-cells (Tregs), suggest a potential role for disrupted circulating immunity in the aetiology of MMD.