Search

Tolosa-Hunt syndrome is a rare cause of painful ophthalmoplegia, most commonly presenting with retro-orbital pain and eye motor nerve palsy, most often affecting a single eye. The condition is characterised by an idiopathic process causing granulomatous inflammation to the cavernous sinus affecting, one or multiple cranial nerves that pass therein. The mechanism underlying the inflammation is not well understood, but patients have been observed to respond to steroids during a flare. We present this as a unique case where a multidisciplinary team diagnosed Tolosa-Hunt syndrome despite non-specific MRI findings in the cavernous sinus 1 day following an initially normal MRI.

Wound repair is a systematic biological program characterized by four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Notwithstanding differences between species and distinct anatomical sites, the fundamental phases in the wound healing process are conserved among mammalian species. Oral wound healing is defined as an ideal wound healing model because it resolves rapidly and without scar formation. Understanding the regulation and contribution of the different molecular events that drive rapid wound healing in oral mucosa compared with those of the skin will help us define how these lesions heal more efficiently and may provide new therapeutic strategies that can be translated to the clinical settings for patients with chronic nonhealing wounds. Although all epithelial tissues have remarkable ability for tissue repair, the efficiency of such repair differs between epithelia (oral mucosa vs. cutaneous). This prompts the long-standing, fundamental biological and clinically relevant questions as to why and how does the oral mucosa achieve its enhanced wound healing capacity. In this review, we focus on (1) distinct innate wound healing capabilities of the oral mucosa, (2) lessons learned from comparative transcriptomic studies of oral mucosa versus skin, and (3) translation of findings to therapeutics for enhanced wound healing.

Wound healing requires a complex cascade of highly controlled and conserved cellular and molecular processes. These involve numerous cell types and extracellular matrix molecules regulated by the actin cytoskeleton. This microscopic network of filaments is present within the cytoplasm of all cells and provides the shape and mechanical support required for cell movement and proliferation. Here, an overview of the processes of wound healing are described from the perspective of the cell in relation to the actin cytoskeleton. Key points of discussion include the role of actin, its binding proteins, signaling pathways, and events that play significant roles in the phases of wound healing. The identification of cytoskeletal targets that can be used to manipulate and improve wound healing is included as an emerging area of focus that may inform future therapeutic approaches to improve healing of complex wounds. Refereed/Peer-reviewed

T-cell interaction with the endothelial cells lining the vessel wall is a necessary step in the inflammatory response that allows T cells to extravasate from the circulation and migrate to sites of infectious or sterile inflammation. On one hand, the vascular endothelium is activated and, as a result, switches from an anti-adhesive to a pro-adhesive state, allowing adhesion of T cells and other leukocytes. On the other hand, T cells express ligands of endothelial adhesion molecules to sustain these interactions that eventually result in T-cell extravasation into sites of inflammation. A better understanding of the central players mediating these interactions may help develop novel therapeutics that modulate this process by preventing T-cell migration and inflammation. Here, I summarize current knowledge on the nature of these interactions in the context of inflammation and cancer immunotherapy.

Vitamin C deficiency, historically known as scurvy, was associated with sailors in the Victorian times, however, a global review in 2020 suggests it still exists in certain at-risk groups.A case is presented of a young non-verbal child with learning difficulties and on a restricted diet, in which the primary symptom was gingival inflammation. It posed a diagnostic dilemma due to the non-specific symptoms, and a delay in the diagnosis, until vitamin C deficiency was confirmed.Gingival inflammation is one of the common findings in vitamin C deficiency and dental professionals may be the first point of contact. The importance of dietary evaluation, identifying and looking for other signs and liaising with the medical colleagues are discussed.This case highlights the role of the dentist in identifying latent cases of vitamin C deficiency and to consider this as a differential diagnosis especially in certain at-risk groups.

Temporal arteritis is usually caused by giant cell arteritis (GCA). However, inflammation of the temporal artery can also occur secondary to autoimmune diseases or infections.We present a remarkable case of a man in his 70s with biopsy proven temporal arteritis, who was later diagnosed with meningovascular neurosyphilis. The presentation of an acute onset monocular vision loss with inflammation of the temporal artery on biopsy appeared a GCA, misleading the physicians, as it turned out to be a manifestation of neurosyphilis.

Demyelinating disorders, with a particular focus on multiple sclerosis (MS), have a multitude of detrimental cognitive and physical effects on the patients. Current treatment options that involve substances promoting remyelination fail in the clinics due to difficulties in reaching the central nervous system (CNS). Here, the dual encapsulation of retinoic acid (RA) into lipid nanocapsules with a nominal size of 70 nm, and a low PdI of 0.1, coupled with super paramagnetic iron oxide nanoparticles (SPIONs) was accomplished, and joined by an external functionalization process with a transferrin-receptor binding peptide. This nanosystem showed a 3-fold improved internalization by endothelial cells compared to the free drug, ability to interact with oligodendrocyte progenitor cells and microglia, and improvements in the permeability through the blood-brain barrier by 5-fold. The lipid nanocapsules also induced the differentiation of oligodendrocyte progenitor cells into more mature, myelin producing oligodendrocytes, as evaluated by high-throughput image screening, by 3-5-fold. Furthermore, the ability to tame the inflammatory response was verified in lipopolysaccharide-stimulated microglia, suppressing the production of pro-inflammatory cytokines by 50-70%. Overall, the results show that this nanosystem can act in both the inflammatory microenvironment present at the CNS of affected patients, but also stimulate the differentiation of new oligodendrocytes, paving the way for a promising platform in the therapy of MS.

Neutrophil extracellular trap (NET) release plays a key role in many chronic disease settings, including atherosclerosis. They are critical to innate immune defence, but also contribute to disease by promoting thrombosis and inflammation. Macrophages are known to release extracellular traps or “METs”, but their composition and role in pathological processes are less well defined. In this study, we examined MET release from human THP-1 macrophages exposed to model inflammatory and pathogenic stimuli, including tumour necrosis factor α (TNFα), hypochlorous acid (HOCl) and nigericin. In each case, there was release of DNA from the macrophages, as visualized by fluorescence microscopy with the cell impermeable DNA binding dye SYTOX green, consistent with MET formation. Proteomic analysis on METs released from macrophages exposed to TNFα and nigericin reveals that they are composed of linker and core histones, together with a range of cytosolic and mitochondrial proteins. These include proteins involved in DNA binding, stress responses, cytoskeletal organisation, metabolism, inflammation, anti-microbial activity, and calcium binding. Quinone oxidoreductase in particular, was highly abundant in all METs but has not been reported previously in NETs. Moreover, there was an absence of proteases in METs in contrast to NETs. Some of the MET histones, contained post-translational modifications, including acetylation and methylation of Lys but not citrullination of Arg. These data provide new insight into the potential implications of MET formation in vivo and their contributions to immune defence and pathology.

Interest in using bedside C-reactive protein (CRP) and ferritin levels to identify patients with hyperinflammatory sepsis who might benefit from anti-inflammatory therapies has piqued with the COVID-19 pandemic experience. Our first objective was to identify patterns in CRP and ferritin trajectory among critically ill pediatric sepsis patients. We then examined the association between these different groups of patients in their inflammatory cytokine responses, systemic inflammation, and mortality risks.A prospective, observational cohort study.Children with sepsis and organ failure in nine pediatric intensive care units in the United States.Two hundred and fifty-five children were enrolled. Five distinct clinical multi-trajectory groups were identified. Plasma CRP (mg/dL), ferritin (ng/mL), and 31 cytokine levels were measured at two timepoints during sepsis (median Day 2 and Day 5). Group-based multi-trajectory models (GBMTM) identified groups of children with distinct patterns of CRP and ferritin.Group 1 had normal CRP and ferritin levels ( n = 8; 0% mortality); Group 2 had high CRP levels that became normal, with normal ferritin levels throughout ( n = 80; 5% mortality); Group 3 had high ferritin levels alone ( n = 16; 6% mortality); Group 4 had very high CRP levels, and high ferritin levels ( n = 121; 11% mortality); and Group 5 had very high CRP and very high ferritin levels ( n = 30; 40% mortality). Cytokine responses differed across the five groups, with ferritin levels correlated with macrophage inflammatory protein 1α levels and CRP levels reflective of many cytokines.Bedside CRP and ferritin levels can be used together to distinguish groups of children with sepsis who have different systemic inflammation cytokine responses and mortality risks. These data suggest future potential value in personalized clinical trials with specific targets for anti-inflammatory therapies.

Identify key features of IL-33 immunobiology important in allergic and nonallergic airway inflammatory diseases and potential therapeutic strategies to reduce disease burden.PubMed, clinicaltrials.gov.A systematic and focused literature search was conducted of PubMed from March 2021 to December 2021 using keywords to either PubMed or BioMed Explorer including IL-33/ST2, genetic polymorphisms, transcription, translation, post-translation modification, nuclear protein, allergy, asthma, and lung disease. Clinical trial information on IL-33 was extracted from clinicaltrials.gov in August 2021.In total, 72 publications with relevance to IL-33 immunobiology and/or clinical lung disease were identified (allergic airway inflammation/allergic asthmaAn integral role of IL-33 in the pathogenesis of allergic and nonallergic airway inflammatory disease is evident with several emerging clinical trials investigating therapeutic approaches. Current data support a critical role of IL-33 in damage signaling, repair and regeneration of lungs.

Growing evidence indicates chronic low-grade systemic inflammation as a major pathophysiological mechanism of obesity. Systemic inflammation provokes an immune response in the brain through the activation of microglia that results in the development of neuroinflammation, cellular senescence, and occurrence of neurological dysfunction. In the efforts to identify an innovative intervention with potential efficacy on obesity and associated complications, our aim was to study the capability of the dietary supplement Dekosilhue® (DKS), successfully used for improving the control of body weight, to attenuate microglia senescent phenotype. Microglia senescence was induced by intermittent stimulation of BV2 cells with LPS 500 ng/mL every 72 h for 4 h/day, over a period of 10 days. DKS (100 µg/mL) treatment reduced ß-galactosidase activity and expression, the formation of senescence-associated heterochromatin foci to control levels, and increased cell viability of senescent BV2 (2 folds of control). DSK reduced the expression of Nuclear Factor-kB (NF-kB) (20% lower than control), a key molecule involved in the acquisition of the senescence-associated secretory phenotype (SASP). DKS promoted a neuroprotective effect by increasing the cell viability of SH-SY5Y neuronal cells exposed to the senescent BV2 conditioned medium to values of non-senescent cells. In conclusion, DKS attenuated the senescent microglia phenotype, showing senotherapeutic activity that might be further investigated as adjunctive intervention for obesity and obesity-related neurological disturbances.

The excessive consumption of diets rich in sugar and fat is associated with metabolic manifestations involving adipose tissue and the liver. Bergamot, due to its antioxidant and anti-inflammatory properties, has been used to treat metabolic disorders. This work aimed to verify the effect of Bergamot leaves extract (BLE) on the crosstalk in the adipose tissue–liver axis of obese rats. For 20 weeks, Wistar rats were distributed into two groups: control (Control) and high sugar–fat (HSF) diet groups. Afterwards, the animals were redistributed into three groups for 10 weeks: control diet + vehicle (Control, n = 08), HSF + vehicle (HSF, n = 08), and HSF + BLE (HSF + BLE, n = 08). The BLE was carried out daily by gavage (50 mg/kg). The HSF group presented obesity, hyperglycemia, hypertriglyceridemia, insulin resistance, hepatic microvesicular steatosis, higher inflammation and oxidative stress in the liver and adipose tissue. In comparison to the HSF group, HSF + BLE animals showed protection by reducing the triglyceride levels, insulin resistance, inflammation and oxidative stress in hepatic and adipose tissues. BLE acted on the inflammation and oxidative stress in the adipose tissue–liver axis in obese rats when compared to the HSF group, which may have reflected on the improvement of insulin resistance and dyslipidemia.

Purpose: Osteoarthritis (OA), inflammation of joint and articular cartilage, is a serious joint disorder and a major cause of pain and disability. LncRNAs exert their role in OA progression. The purpose of this present research is to investigate the impact and molecular mechanism of lncRNA regulator of reprogramming (LncRNA-ROR) on inflammatory damage induced by lipopolysaccharide (LPS) in C28/12 cells. Methods: The expressions of lncRNA-ROR and miR-124-3p and the mRNA expressions of COX-2, iNOS, IL-8, C5a, and TNF-α were determined in C28/12 cells stimulated with LPS using RT-qPCR. Viability of C28/12 cells was evaluated using CCK-8 assay and C28/12 cell apoptosis was assessed by flow cytometry in LPS-induced C28/12 cells. Moreover, the concentration of IL-8, C5a, and TNF-α and the protein expressions of TLR4/Myd88/NF-κB pathways were examined using Elisa assay. Results: Results revealed that LPS inhibited the proliferation, enhanced rate of cell apoptosis, and promoted mRNA expressions of iNOS, IL-8, C5a, and TNF-α in C28/12 cells. Besides, the expression of lncRNA-ROR was expressively reduced in C28/12 cells stimulated with LPS and the lncRNA-ROR overexpression markedly reduced the inflammatory injury stimulated by LPS in C28/12 cells. Besides, lncRNA-ROR significantly down-regulated the miR-124-3p expression and miR-124-3p exposure inhibited the protecting impact of lncRNA-ROR on LPS-induced C28/12 cells. Furthermore, lncRNA-ROR suppressed the TLR4/Myd88/NF-κB pathways via suppressing the expression of miR-124-3p in LPS-induced C28/12 cells. Conclusion: The finding revealed that lncRNA-ROR protected against LPS-stimulated inflammatory injury in C28/12 cells by suppressing TLR4/Myd88/NF-κB pathways via inhibiting miR-124-3p suggested an efficient therapeutic strategy for OA treatment.

Purpose: To evaluate the ameliorative effect of Angelica sinensis polysaccharide (ASP) in myocardial ischemia-reperfusion injury (MIRI) rats through Toll-like receptor 4 (TLR4)/Nuclear factor κB (NF-κB) pathway. Methods: The MIRI rat model was established. Sprague-Dawley rats were randomized to sham, MIRI, and ASP low-dose (50 mg/kg) and high-dose (100 mg/kg) groups, and a model of hypoxia-reoxygenation (H/R) injury was established. In in vitro studies, H/R cardiomycetes (derived from neonatal cell culture) were randomized to control, H/R, H/R + ASP low dose (5 μg/mL), H/R + ASP high dose (10 μg/mL), and ASP high dose + TLR4 activator groups. Results: After intragastric administration of ASP for 4 consecutive weeks, creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) were reduced after ASP treatment in MIRI rats (p < 0.05). Both in vivo and in vitro, ASP reduced TNF-α, IL-6, and IL-1β expressions (p < 0.05), and alleviated inflammatory response. Apoptosis was inhibited by ASP, which also increased Bcl2, reduced Bax and cleaved caspase-3 expressions, while TLR-4, p-IκBα, and p-p65 were decreased. Conclusion: The cardioprotective effect of ASP on MIRI results in the inhibition of TLR4/NF-κB pathway. Thus, this study broadens the current body of knowledge on the pharmacological prevention of MIRI and the therapeutic potential of ASP.

International audience; Spirulina species are photosynthetic and filamentous bacteria, commonly called 'blue-green microalgae'. Spirulina has a high nutrient content. It contains 60-70% protein with all essential amino acids present, and is rich in several vitamins, minerals, and bioactive compounds. Spirulina is also rich in essential fatty acids, and antioxidants. This rich nutritional content provides to Spirulina several health benefits including antioxidant, anti-inflammatory, immunomodulation, and insulin-sensitizing properties as well as positive effects in various diseases which could be also interesting for athletes. This paper mainly aims to review the interest and effects of Spirulina supplementation in athletes at rest, and in relation to exercise/training. Spirulina's biochemical composition, health properties/effects in humans, and effects in athletes including nutritional status, body composition, physical performance and intense exercise-related disorders were discussed in this review. Literature data showed that Spirulina seems to have positive effects on body composition especially in overweight and obese subjects which could not be the case in other pathologies and athletes. Spirulina appears to be also effective in improving aerobic fitness especially in untrained and moderately trained subjects. Results reported in the literature suggest that Spirulina may improve strength and power performance despite the minor or no significant effects in highly trained subjects. Most studies have shown that Spirulina improves antioxidant status, prevents and accelerates the recovery of exercise-induced lipid peroxidation, muscle damage and inflammation in trained and untrained subjects. Taken together, the results from these studies are encouraging and may demonstrate the potential benefits of Spirulina supplementation in athletes despite methodological differences.

ObjectiveInflammation may be present with chronic kidney disease CKD and diet composition high in protein intake and fats may affect inflammation thereby impacting kidney health. We investigated whether acid load estimated from urine measures is associated with kidney function decline and whether the effect of acid load on an inflammatory marker, serum albumin, is a pathway to this association.MethodsWe studied 188 postmenopausal women in a randomized clinical trial of potassium bicarbonate treatment for up to 36months. Twenty-four-hour urine and arterialized blood collections were done at baseline and at subsequent follow-up visits at 3months interval. Acid load was estimated from potential renal acid load calculated using urinary measures of chloride, phosphate, sodium, potassium, calcium, and magnesium (UPRAL). Mixed effects model with random-intercept and slope was used to estimate subjects' annual decline rate in creatinine clearance (CrCl), and the association between (i) UPRAL and serum albumin and (ii) serum albumin and CrCl, adjusting for age, body mass index, systolic BP, and glucose. A Cox proportional regression model was used to study the relative hazard (RH) for rapid progression of kidney function decline (defined as loss of ≥5mL/min CrCl/yr based on the last CrCl in the rolling window) with UPRAL, adjusting for the potential covariates and baseline CrCl.ResultsA 25 mEq/day increase in UPRAL was inversely associated with serum albumin (Adjusted β[95% CI]: -0.02[-0.09;-0.001). During a mean follow-up of 28months, 19 women (10%) had a rapid decline in kidney function. For each 25 mEq/day increase in UPRAL, the risk of a rapid decline in CrCl increased by 17% (95% CI: 1.06-1.28). On adjustment for potential confounders, the risk attenuated to 5% (1.02-1.14). Mediation analysis indicated that of the total effect of the association between UPRAL and CrCl, the proportion mediated by serum albumin increased to 0.346 (i.e. 34.6%).ConclusionHigher UPRAL was associated with lower serum albumin as well as greater kidney function decline in postmenopausal women. Our findings suggest inflammatory response may exert a modulatory effect on the association of UPRAL and kidney function and might be a potential pathway explaining the effects of systemic acid load on progression of kidney failure.

Aims: To examine the differences between HbA1c and glucose related variables in predicting weight loss and glycaemic changes following 8 weeks of low energy diet (LED) in individuals with overweight and hyperglycaemia. Research design and methods: 2178 individuals with ADA-defined pre-diabetes -impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) -who started an 8 week LED weight loss diet, were included in this analysis. Participants were enrolled in the PREVIEW (PREVention of diabetes through lifestyle in-terventions and population studies In Europe and around the World) clinical trial. Multivariable linear mixed effects regression models and generalised additive mixed effect logistic models were used. Results: Only 1 in 3 participants (33%) had HbA1c levels defined as pre-diabetes. Neither baseline HbA1c, IFG or IGT were associated with body weight change at 8 weeks. Higher baseline body weight, baseline fasting insulin and weight loss predicted normalisation of fasting plasma glucose (FPG), whilst higher baseline fasting insulin, C-reactive protein (hsCRP) and older age predicted normalisation of HbA1c. Additionally, male sex and higher baseline BMI, body fat and energy intake were positively associated with weight loss, whereas greater age and higher HDL-cholesterol predicted less weight loss. Conclusions: Whilst neither HbA1c nor fasting glucose predicts short-term weight loss success, both may impact the metabolic response to rapid weight loss. We propose a role of inflammation versus total body adiposity since these variables are independent predictors of the normalisation of HbA1c and fasting glucose, respectively.(c) 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3+CD8+ T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3+CD8+ T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient’s mutanome and immune microenvironment.

Background: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. Design: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (e.g., severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The two independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the two co-primary outcomes. Summary: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery. Population Health Research Institute

Objectives: Potential thrombotic and antifibrinolytic influence of endometriosis on haemostasis has been recently reported in the literature, as well as increased cardiovascular morbidity in women suffering from the disease. We performed a pilot study to assess the influence of endometriosis on the thrombus formation process under in vitro flow conditions. Material and methods: This study compared women with confirmed endometriosis (n = 23) surgically and control healthy subjects (n = 10). In both groups, the same exclusion criteria were used: a prior episode of thrombosis diagnosed as acquired or inherited thrombophilia, neoplasm, and an uncertain family history of thrombosis. We evaluated the whole blood thrombogenicity using T-TAS® at a shear rate of 240 s-1 (Total-Thrombus Analysis System, Zacros, Japan). Results: The blood clot formation initiation time (T10) and occlusion time (OT) were significantly shortened in the endometriosis group (p < 0.05). The area under the curve (AUC30) of blood clot time formation values (BCTF) was substantially higher in the patients suffering from a disease (p = 0.03). An increase in AUC (TTAS) values by 100 increases the risk of developing endometriosis by 1.56-fold [adjusted OR = 1.56 (p = 0.01);(95% CI: 1.10–2.18)]. Inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), and the leucocyte, neutrophil, basophil, and neutrophil concentrations) were also substantially higher in the endometriosis group (p < 0.05). Conclusions: The alteration of the T-TAS and NLR values supports the thesis of a shift of the equilibrium towards thrombosis in women who have endometriosis. This phenomenon links to a state of chronic inflammation. It is detectable using a novel system for the quantitative assessment of the platelet thrombus formation process under flow conditions in vitro .

Arterial and venous thrombosis constitute a major source of morbidity and mortality worldwide. Association between thrombotic complications and cardiovascular and other chronic inflammatory diseases are well described. Inflammation and subsequent initiation of thrombotic events, termed immunothrombosis, also receive growing attention but are still incompletely understood. Nevertheless, the clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is evident by an increased risk of thrombosis and cardiovascular events in patients with inflammatory or infectious diseases. Proinflammatory mediators released from platelets, complement activation, and the formation of NETs (neutrophil extracellular traps) initiate and foster immunothrombosis. In this review, we highlight and discuss prominent and emerging interrelationships and functions between NETs and other mediators in immunothrombosis in cardiovascular disease. Also, with patients with chronic kidney disease suffering from increased cardiovascular and thrombotic risk, we summarize current knowledge on neutrophil phenotype, function, and NET formation in chronic kidney disease. In addition, we elaborate on therapeutic targeting of NETs-induced immunothrombosis. A better understanding of the functional relevance of antithrombotic mediators which do not increase bleeding risk may provide opportunities for successful therapeutic interventions to reduce thrombotic risk beyond current treatment options.

Cells respond to perturbations such as inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has long known connections to the inflammatory response. Here we show that depletion of arginine during inflammation decreased levels of arginyl-tRNA synthetase (ArgRS) in the nucleus. We found that nuclear ArgRS interacted with serine/arginine repetitive matrix protein 2 (SRRM2) in membrane-less, condensate-like, SRRM2-dependent nuclear speckles. This interaction impeded SRRM2 speckle trafficking and resulted in changes in alternative mRNA splicing. Splice site usage was regulated in opposite directions by ArgRS and SRRM2. These ArgRS- and SRRM2-dependent splicing changes cumulated in synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings delineate a novel mechanism whereby a tRNA synthetase responds to a metabolic change and modulates the splicing machinery via condensate trafficking for cellular responses to inflammatory injury.

Abstract: The effect of carvacrol (CAR) on oxidative stress, inflammation, and liver dysfunction induced by lipopolysaccharide (LPS) was explored. The rats (n=40) were daily injected (2 weeks) by saline as control, LPS (1 mg/kg, i.p.), and 25, 50 or 100 mg/kg CAR (i.p.) before LPS. LPS increased aspartate transaminase (AST: 162±13 U/L), alanine aminotransferase (ALT: 74.6±2.15 U/L), alkaline phosphatase (ALK-P: 811±51 U/L), interlukine-1β (IL-1β: 1254±51 pg/g tissue), malondialdehyde (MDA: 32±1.09 nM/g tissue), and nitric oxide (NO: 224±13.5 nM/g tissue) (P

Background and objectives: Neutrophil, lymphocyte counts, lactate dehydrogenase (LDH), D-dimer, fibrinogen, and comorbid illness are associated with the course and prognosis of COVID-19. However, the course of acute severe psychiatric disorders overlapping with COVID-19 infection was not investigated and remained as an unclarified research area. This study aimed to demonstrate inflammatory markers and the course of patients suffering from both conditions. Methods: Thirty-eight inpatients with COVID-19 and comorbid acute psychiatric disorders (COVID-19+PD), 31 inpatients with COVID-19, and 38 inpatients with an acute psychiatric disorder (PD) were included in the study. Neutrophil, lymphocyte counts, serum ferritin, lactate dehydrogenase (LDH), D-dimer, fibrinogen, Systemic immune-inflammation index (SII), neutrophil/lymphocyte ratio (NLR), and C-reactive protein (CRP) were compared to evaluate inflammation levels. Results: Patients with SARS-CoV-2 infection had older age compared to the PD group. CALL (Comorbidity, age, lymphocyte, lactate dehydrogenase) scores which predict the progression risk in patients with COVID-19 pneumonia, of both COVID-19 groups were found similar. The COVID-19+PD had higher SII in the study sample. Additionally, the COVID-19+PD group had higher NLR, ferritin, and CRP levels than those of the PD group. Conclusions: The prognosis of COVID-19 is not worse when accompanied by a psychiatric disorder. Laboratory assessment can guide clinicians to distinguish those infected with SARS-CoV-2 within psychiatric inpatient units. The biochemical assessment did not robustly support higher inflammatory levels in the comorbid COVID-19 and psychiatric disorder group compared to the COVID-19 group.

The effects of in ovo injection of L-ascorbic acid (L-AA) on tissue L-AA concentrations, systemic inflammation, plasma mineral concentrations, and tracheal histomorphology of Ross 708 broilers subjected to elevated atmospheric ammonia (NH3) levels after hatch were investigated. The four in ovo treatments included non-injected (control), saline-injected (control), or saline containing 12 or 25 mg of L-AA. The in ovo treatments were applied at 17 days of incubation by injecting a 100 μL volume of each pre-specified treatment into the amnion. At hatch, 12 male chicks were randomly allocated to each of the 12 replicate battery cages belonging to each treatment group. The cages were arranged in a randomized complete block design within a common room. All birds were exposed to 50 ppm of NH3 at 35 days of posthatch age (doa), and the concentration of NH3 in the room was recorded every 20 s. At 0, 7, 14, 21, and 28 doa, one bird from each cage was arbitrarily selected and euthanized for determinations of liver and eye L-AA concentrations at 0, 7, 14, 21, 28 doa; plasma nitric oxide concentrations at 0, 14, 21, and 28 doa; and plasma calcium and trace mineral concentrations at 0 and 21 doa. Tracheal histomorphology evaluations were performed at 0, 21, and 28 doa. There were no significant treatment differences for plasma nitric oxide and mineral concentrations, and for liver and eye L-AA concentrations at each sampling timepoint. In ovo injection of either 12 or 25 mg of L-AA decreased tracheal attenuation incidence at 0 doa compared to the non-injected or saline-injected control groups. Furthermore, the percentage of mild tracheal inflammation scores was lower at 28 doa in response to the in ovo injection of 12 mg of L-AA compared to the non-injected or saline-injected control groups. These results indicate that in ovo injection of 12 mg of L-AA reduces tracheal inflammation in broilers subjected to elevated atmospheric NH3.

Objective: A proinflammatory adipose tissue (AT) microenvironment and systemic low-grade inflammation may differentially affect tissue-specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity. Methods: Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n = 219) and the Maastricht Study (replication cohort; n = 1256) underwent a seven-point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined. In subgroups, flow cytometry was performed to identify circulating and aSAT immune cells, and aSAT gene expression was evaluated. Results: The relative abundances of circulating T cells, nonclassical monocytes, and CD56dim CD16+ natural killer cells were inversely associated with liver, but not muscle, insulin sensitivity in the PERSON Study. The inverse association between circulating (classical) monocytes and liver insulin sensitivity was confirmed in the Maastricht Study. In aSAT, immune cell populations were not related to insulin sensitivity. Furthermore, aSAT gene expression of interleukin 6 and CD14 was positively associated with muscle, but not liver, insulin sensitivity. Conclusions: The present findings demonstrate that circulating immune cell populations and inflammatory gene expression in aSAT show distinct associations with liver and muscle insulin sensitivity.

Aim: Microglial activation is increasingly recognised as a factor in the progression of Alzheimer’s disease (AD) and may be modified by systemic inflammatory signals including serum tumour necrosis factor (TNF)-α. The aim was to investigate whether blockade of peripheral TNF-α with peripheral inhibitors such as etanercept reduces microglial activation in prodromal AD. Methods: A one-year, multi-centre, phase 2, double-blind randomised placebo-controlled trial (RPCT) was performed, to assess the effect of weekly 50 mg s.c. etanercept in amyloid positive mild cognitive impaired participants on the change in microglial activation as measured by [11C](R)-PK11195 positron emission tomography (PET). Secondary objectives were to ascertain the change in cortical amyloid load on PET and the change in the Montreal Cognitive Assessment (MoCA). Results: Forty-four subjects consented to the study. Twenty-eight subjects failed screening including six subjects who were amyloid negative on visual read of the AmyvidTM PET scans. Thirteen of sixteen subjects with mild cognitive impairment (MCI) due to AD completed the baseline [11C](R)-PK11195 PET scan and were randomised to either placebo or etanercept. Three patients who consented were not able to complete screening due to early termination of the study following delays in study commencement. [11C](R)-PK11195 binding potential (BP) at baseline showed an almost global increase in MCI patients as compared to age-matched controls. Compliance to medication was high over the twelve-month trial period with etanercept being well tolerated. The study did not achieve statistical power to show a significant effect of etanercept over 52 weeks in the limited number of patients with MCI on microglial activation as measured by [11C](R)-PK11195 PET. Overall uptake of florbetapir in the follow up (FU) scans remained stable. The study was not powered to show statistical differences in psychometric ratings between groups. Conclusions: This study did not show evidence that treatment with etanercept over one year would modulate microglial activation in amyloid positive MCI patients (EudraCT identifier: 2015-002145-63, https://www.clinicaltrialsregister.eu; International Standard Randomised Controlled Trial Number identifier: ISRCTN12472821, https://www.isrctn.com).

Rosacea is a chronic inflammatory skin disease whose late manifestations have not yet been clearly reported in animal models. The objective of this study is to describe the skin lesions and major histopathological changes in a rosacea-like phenotype in mice induced by prolonged LL-37 administration and furthermore, to assess the potential of long-term LL-37 administration in inducing irreversible rosacea-like skin lesion models. Balb/c mice were continuously injected intradermally with LL-37 every 12 h to induce a rosacea-like phenotype. After LL-37 injections were administered for 20 consecutive days, the area of rosacea-like lesions gradually expanded in the first 13 days, then entered a stable phase. Haematoxylin and eosin (H&E) and Van Gieson’s staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities. The results of immunofluorescence staining and Western blotting showed that the expression of α-SMA, TNF-α, vimentin, and COL1 in the skin of mice was significantly upregulated. Short-term LL-37 administration induced rosacea-like lesions that only featured the aggregation of inflammatory factors and thickening of the epidermis, whereas no collagen hyperplasia was observed, and a full recovery was noticed. However, rosacea-like skin lesions induced by long-term LL-37 administration did not completely recover. Our study compares rosacea-like lesions induced by short-term versus long-term LL-37 administration, and the results suggest that irreversible rosacea-like lesions can be induced by long-term LL-37 administration.

People with HIV (PWH) experience higher rates of cardiovascular events (CVEs) compared with the general population. A substantial body of evidence supports that select biomarkers of inflammation (soluble CD14 [sCD14], soluble CD163 [sCD163], highly sensitive C-reactive protein [hs-CRP], interleukin-6 [IL-6]) and coagulation (D-dimer) are elevated in PWH and related to increased rates of CVEs. Our previous work showed that smoking compared with nonsmoking was associated with significantly elevated sCD14, a biomarker of monocyte activation. We aimed to explore the effect of electronic cigarette (EC) provision on inflammatory biomarkers in PWH who smoked daily and then switched to an EC. Nineteen PWH were enrolled in a pilot study in which an EC and e-liquid were provided weekly for 8 weeks. Blood specimens for inflammatory biomarker analysis were obtained at baseline (BL) and at week 8. Biomarker levels were high at BL and did not differ significantly at week 8. There were small nonsignificant reductions in sCD163 and CRP levels. Non-significant increases in IL-6, D-dimer, and sCD14 levels were also noted. Use of ECs for 8 weeks does not appear to significantly increase or decrease inflammatory biomarker levels in SWH. Further research with larger samples and a control group is needed.

International audience; No abstract available

Helper T (TT‑Helfer(TH)-Lymphozyten spielen eine entscheidende Rolle bei der Auslösung und Aufrechterhaltung chronischer rheumatischer Entzündungen. Über die Ausschüttung von entzündungsfördernden Botenstoffen und die Expression kostimulatorischer Oberflächenmoleküle koordinieren sie die Rekrutierung und Aktivierung von Effektorzellen, die letztendlich die Immunpathologie und Gewebezerstörung auslösen. Allerdings waren Therapieansätze, die auf die Eliminierung von TH-Zellen abzielten, aufgrund ihrer mangelnden Selektivität nicht erfolgreich. Am Deutschen Rheuma-Forschungszentrum (DRFZ) wollen wir deshalb TH-Zellen , die an chronischen Entzündungsreaktionen beteiligt sind, besser verstehen. Unser Ziel ist es, basierend darauf neue therapeutische Strategien zu entwickeln, die pathogene TH-Zellen bei rheumatischen Entzündungen gezielt und selektiv bekämpfen. Die Erkenntnisse des DRFZ zu diesem Thema fasst der vorliegende Beitrag zusammen.

Context: Active acromegaly is characterized by lipolysis-induced insulin resistance, which suggests adipose tissue (AT) as a primary driver of metabolic aberrations.Objective: To study the gene expression landscape in AT in patients with acromegaly before and after disease control in order to understand the changes and to identify disease-specific biomarkers.Methods: RNA sequencing was performed on paired subcutaneous adipose tissue (SAT) biopsies from six patients with acromegaly at time of diagnosis and after curative surgery. Clustering and pathway analyses were performed in order to identify disease activity-dependent genes. In a larger patient cohort (n = 23), the corresponding proteins were measured in serum by immunoassay. Correlations between growth hormone (GH), insulin-like growth factor I (IGF-I), visceral AT (VAT), SAT, total AT, and serum proteins were analyzed.Results: 743 genes were significantly differentially expressed (P-adjusted < .05) in SAT before and after disease control. The patients clustered according to disease activity. Pathways related to inflammation, cell adhesion and extracellular matrix, GH and insulin signaling, and fatty acid oxidation were differentially expressed.Serum levels of HTRA1, METRNL, S100A8/A9, and PDGFD significantly increased after disease control (P < .05). VAT correlated with HTRA1 (R = 0.73) and S100A8/A9 (R = 0.55) (P < .05 for both).Conclusion: AT in active acromegaly is associated with a gene expression profile of fibrosis and inflammation, which may corroborate the hyper-metabolic state and provide a means for identifying novel biomarkers. Context: Active acromegaly is characterized by lipolysis-induced insulin resistance, which suggests adipose tissue (AT) as a primary driver of metabolic aberrations. Objective: To study the gene expression landscape in AT in patients with acromegaly before and after disease control in order to understand the changes and to identify disease-specific biomarkers. Methods: RNA sequencing was performed on paired subcutaneous adipose tissue (SAT) biopsies from six patients with acromegaly at time of diagnosis and after curative surgery. Clustering and pathway analyses were performed in order to identify disease activity-dependent genes. In a larger patient cohort (n = 23), the corresponding proteins were measured in serum by immunoassay. Correlations between growth hormone (GH), insulin-like growth factor I (IGF-I), visceral AT (VAT), SAT, total AT, and serum proteins were analyzed. Results: 743 genes were significantly differentially expressed (P-adjusted < .05) in SAT before and after disease control. The patients clustered according to disease activity. Pathways related to inflammation, cell adhesion and extracellular matrix, GH and insulin signaling, and fatty acid oxidation were differentially expressed. Serum levels of HTRA1, METRNL, S100A8/A9, and PDGFD significantly increased after disease control (P < .05). VAT correlated with HTRA1 (R = 0.73) and S100A8/A9 (R = 0.55) (P < .05 for both). Conclusion: AT in active acromegaly is associated with a gene expression profile of fibrosis and inflammation, which may corroborate the hyper-metabolic state and provide a means for identifying novel biomarkers.

ObjectiveAltering dysbiotic gut flora through synbiotic supplementation has recently been recognized as a potential treatment strategy to reduce the levels of gut-derived uremic toxins and decrease inflammation. Assessing its efficacy and safety has been the main goal of our randomized, double-blind, placebo-controlled study.MethodsA total of 34 nondialyzed chronic kidney disease patients, aged ≥18 years, with an estimated glomerular filtration rate between 15 and 45 mL/minute, were randomized either to an intervention group (n = 17), receiving synbiotic (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium lactis, 32 billion colony forming units per day plus 3.2 g of inulin), or control group (n = 17), receiving placebo during 12 weeks. The impact of treatment on the dynamic of serum levels of gut-derived uremic toxins, total serum indoxyl sulfate, p-cresyl sulfate, and trimethylamine N-oxide, was defined as the primary outcome of the study. Secondary outcomes included changes in the stool microbiome, serum interleukin-6 levels, high-sensitivity C-reactive protein, estimated glomerular filtration rate, albuminuria, diet, gastrointestinal symptom dynamics, and safety. Serum levels of uremic toxins were determined using ultraperformance liquid chromatography. The stool microbiome analysis was performed using the 16S ribosomal ribonucleic acid gene sequencing approach.ResultsSynbiotic treatment significantly modified gut microbiome with Bifidobacteria, Lactobacillus, and Subdoligranulum genera enrichment and consequently reduced serum level of indoxyl sulfate (ΔIS –21.5% vs. 5.3%, P

The newest data on metallic gold have placed the noble metal central in the fight for the safe treatment of autoimmune inflammation. There are two different ways to use gold for the treatment of inflammation: gold microparticles > 20 µm and gold nanoparticles. The injection of gold microparticles (µGold) is a purely local therapy. µGold particles stay put where injected, and gold ions released from them are relatively few and taken up by cells within a sphere of only a few millimeters in diameter from their origin particles. The macrophage-induced release of gold ions may continue for years. Injection of gold nanoparticles (nanoGold), on the other hand, is spread throughout the whole body, and the bio-released gold ions, therefore, affect multitudes of cells all over the body, as when using gold-containing drugs such as Myocrisin. Since macrophages and other phagocytotic cells take up and transport nanoGold and remove it after a short period, repeated treatment is necessary. This review describes the details of the cellular mechanisms that lead to the bio-release of gold ions in µGold and nanoGold.

Electronic cigarette usage has significantly expanded among young people and pregnant women in the last decade. Although there are already some data regarding the short- and long-term consequences of e-cigarettes on human health, their effect on embryo and lung development still needs to be fully disclosed. In this sense, this study describes, for the first time, the impact of electronic cigarette aerosol on early lung development. For this purpose, ex vivo chick (Gallus gallus) embryonic lungs were cultured in vitro for 48h in e-cigarette aerosol exposed-medium or unexposed medium. Chick lung explants were also cultured in a cigarette smoke-exposed medium for comparison purposes. Lung explants were morphologically analyzed to assess the impact on lung growth. Additionally, TNF- levels were determined in the supernatant as a marker of pro-inflammatory response. The results suggest that electronic cigarette aerosol impairs lung growth and promotes lung inflammation. However, its impact on early lung growth seems less detrimental than conventional cigarette smoke. This work provides significant data regarding the impact of e-cig aerosol, adding to the efforts to fully understand its effect on embryo development. The validation of these effects may eventually lead to new tobacco control recommendations for pregnant women., This work has been funded by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020, UIDP/50026/2020, UIDB/04469/2020 and UIDB/04050/2020. Funding bodies did not play any role in the study design, data collection, and analysis, publication decisions or preparation of the manuscript., info:eu-repo/semantics/publishedVersion

Long non-coding RNAs (lncRNAs) are a novel class of non-coding RNA (ncRNA), that have been studied extensively in the field of tumor research in recent years. In the case of tumor-associated lncRNAs, lncRNA cytoskeleton regulator RNA (CYTOR) displays extensive functions in tumorigenesis, including invasion, metastasis, malignant proliferation, glycolysis, and inflammatory response. Moreover, the dysregulation of CYTOR is closely related to clinicopathological characteristics, such as tumor stage, lymph node metastasis and infiltration, and poor prognosis of tumor patients. In this review, we provide a novel strategy to summarize the biological functions and clinical value of CYTOR in tumors through an overview of the literature combined with gene set enrichment analysis. A deeper understanding of the role of CYTOR in tumorigenesis may provide new diagnostic, prognostic and therapeutic markers for human tumors.

Background: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. Methods: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. Results: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis.Conclusions: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.(c) 2023 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Effects of the major ginsenoside Rg1 on mammalian longevity and physical vitality are rarely reported. Purpose To examine longevity, tumor, and spontaneous locomotor activity in rats consuming Rg1. Methods A total of 138 Wistar rats were randomized into 2 groups: control (N = 69) and Rg1 (N = 69). Rg1 (0.1 mg/kg per day) were orally supplemented from 6 months of age until natural death. Spontaneous mobility was measured by video-tracking together with body composition (dual energy x-ray absorptiometry) and inflammation markers at 5, 14, 21, and 28 months of age. Results No significant differences in longevity (control: 706 days; Rg1: 651 days, p = 0.77) and tumor incidence (control: 19%; Rg1: 12%, p = 0.24) were observed between the two groups. Movement distance in the control group declined significantly by ∼60% at 21 months of age, together with decreased TNF-α (p = 0.01) and increased IL-10 (p = 0.02). However, the movement distance in the Rg1 group was maintained ∼50% above the control groups (p = 0.01) at 21 months of age with greater magnitudes of TNF-α decreases and IL-10 increases. Glucose, insulin, and body composition (bone, muscle and fat percentages) were similar for both groups during the entire observation period. Conclusion The results of the study suggest a delay age-dependent decline in physical vitality during late life by lifelong Rg1 consumption. This improvement is associated with inflammatory modulation. Significant effects of Rg1 on longevity and tumorigenesis were not observed.

Our study demonstrates a novel pericyte-based therapy for the injured kidney. The beneficial effect of pericyte delivery appears to be mediated by ameliorating oxidative stress, inflammation, cellular apoptosis, and senescence in the stenotic kidney and improved tissue hypoxia, vascular loss, fibrosis, and tubular atrophy. Our data may form the basis for pericyte-based therapy, and additional research studies are needed to gain further insight into their role in improving renal function.

A surge in the prevalence of obesity and metabolic syndrome, which promote systemic inflammation, underlies an increase in cardiometabolic disease. Free fatty acid receptor 4 is a nutrient sensor for long-chain fatty acids, like ω3-polyunsaturated fatty acids (ω3-PUFAs), that attenuates metabolic disease and resolves inflammation. Clinical trials indicate ω3-PUFAs are cardioprotective, and this review discusses the mechanistic links between ω3-PUFAs, free fatty acid receptor 4, and attenuation of cardiometabolic disease.

Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) stiffness, impaired vascular compliance, and fibrosis. Although systemic inflammation, driven by comorbidities, has been proposed to play a key role, the precise pathogenesis remains elusive. To test the hypothesis that inflammation drives endothelial dysfunction in HFpEF, we used cardiosphere-derived cells (CDCs), which reduce inflammation and fibrosis, improving function, structure, and survival in HFpEF rats. Dahl salt-sensitive rats fed a high-salt diet developed HFpEF, as manifested by diastolic dysfunction, systemic inflammation, and accelerated mortality. Rats were randomly allocated to receive intracoronary infusion of CDCs or vehicle. Two weeks later, inflammation, oxidative stress, and endothelial function were analyzed. Single-cell RNA sequencing of heart tissue was used to assay transcriptomic changes. CDCs improved endothelial-dependent vasodilation while reducing oxidative stress and restoring endothelial nitric oxide synthase (eNOS) expression. RNA sequencing revealed CDC-induced attenuation of pathways underlying endothelial cell leukocyte binding and innate immunity. Exposure of endothelial cells to CDC-secreted extracellular vesicles in vitro reduced VCAM-1 protein expression and attenuated monocyte adhesion and transmigration. Cell therapy with CDCs corrects diastolic dysfunction, reduces oxidative stress, and restores vascular reactivity. These findings lend credence to the hypothesis that inflammatory changes of the vascular endothelium are important, if not central, to HFpEF pathogenesis.

NAFLD and its more-advanced form, steatohepatitis (NASH), is associated with obesity and is an independent risk factor for cardiovascular, liver-related, and all-cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation (FAO) and hepatic mitochondrial turnover in NAFLD and NASH are scant.To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (CTRL; no disease); NAFL (steatosis only); Borderline-NASH (steatosis with lobular inflammation or hepatocellular ballooning); and Definite-NASH (D-NASH; steatosis, lobular inflammation, and hepatocellular ballooning). Hepatic mitochondrial complete FAO to COThese findings suggest that compromised hepatic FAO and mitochondrial turnover are intimately linked to increasing NAFLD severity in patients with obesity.

An exaggerated mean arterial blood pressure (MAP) response to exercise in patients with peripheral artery disease (PAD), likely driven by inflammation and oxidative stress and, perhaps, required to achieve an adequate blood flow response, is well described. However, the blood flow response to exercise in patients with PAD actually remains equivocal. Therefore, eight patients with PAD and eight healthy controls completed 3 min of plantar flexion exercise at both an absolute work rate (WR) (2.7 W, to evaluate blood flow) and a relative intensity (40%WRmax, to evaluate MAP). The exercise-induced change in popliteal artery blood flow (BF, Ultrasound Doppler), MAP (Finapress), and vascular conductance (VC) were quantified. In addition, resting markers of inflammation and oxidative stress were measured in plasma and muscle biopsies. Exercise-induced ΔBF, assessed at 2.7 W, was lower in PAD compared with controls (PAD: 251 ± 150 vs. Controls: 545 ± 187 mL/min, P < 0.001), whereas ΔMAP, assessed at 40%WRmax, was greater for PAD (PAD: 23 ± 14 vs. Controls: 11 ± 6 mmHg, P = 0.028). The exercise-induced ΔVC was lower for PAD during both the absolute WR (PAD: 1.9 ± 1.6 vs. Controls: 4.7 ± 1.9 mL/min/mmHg) and relative intensity exercise (PAD: 1.9 ± 1.8 vs. Controls: 5.0 ± 2.2 mL/min/mmHg) trials (both, P < 0.01). Inflammatory and oxidative stress markers, including plasma interleukin-6 and muscle protein carbonyls, were elevated in PAD (both, P < 0.05), and significantly correlated with the hemodynamic changes during exercise ( r = −0.57 to −0.78, P < 0.05). Thus, despite an exaggerated ΔMAP response, patients with PAD exhibit an impaired exercise-induced ΔBF and ΔVC, and both inflammation and oxidative stress likely play a role in this attenuated hemodynamic response.

Ischemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation.