State Of Chronic Low-grade Inflammation Research Articles

Significant early and long-term improvement of neuropsychiatry symptomatology in HCV-infected patients after viral eradication with DAA

IntroductionChronic Hepatitis C infection is considered a systemic disease with extrahepatic manifestations, mainly neuropsychiatric symptoms, which is associated with a chronic low-grade inflammatory state. Hepatitis C virus (HCV) eradication is currently achieved in >98% of cases with oral direct-acting antivirals (DAA).ObjectivesTo study potential clinical neuropsychiatric changes (mood, cognition, sleep, gastrointestinal, sickness, and motion) in HCV-infected patients after HCV eradication with DAA.MethodsDesign: Cohort study. Subjects: 37 HCV-infected patients, aged<55 years old, with non-advanced liver disease receiving DAA; free of current mental disorder. 24 healthy controls were included at baseline. Assessment: -Baseline (BL) (socio-demographic and clinical variables, MINI-DSM-IV, and Neurotoxicity Scale (NRS), (mood, cognitive, sleep, gastrointestinal, sickness and motor dimensions). Follow-up: End-of-treatment, 12weeks-after and 48weeks-after DAA: NRS. Analysis: Descriptive and bivariate non-parametrical analysis.ResultsNRS total score and dimensions where different between cases and controls (.000) at baseline. NRS total score (.000) and mood (.000), cognition (.000), sleep (.002), gastrointestinal (.017), and sickness (.003), except motor dimension score (.130) showed significant longitudinal improvement.ConclusionsHCV-infected patients with mild liver disease presented significantly worse scores for neurotoxicity symptomatology in all dimensions compared to healthy individuals. After HCV eradication with DAA, both at short and long follow-up a significant improvement of the NRS total score and each of the dimensions (except motor) were observed. However, they did not reach the values of healthy individuals, suggesting a not complete neuropsychiatric restoration in the period studied. Grant: ICIII-FIS:PI17/02297.(One way to make Europe) (RMS) and Gilead Fellowship-GLD17/00273 (ZM); and the support of SGR17/1798 (RMS)DisclosureNo significant relationships.

8-Hydroxyeicosapentaenoic Acid Reduces Adipogenesis and Inflammation in 3T3-L1 Adipocytes

ObjectivesObesity is a complex disease and a chronic low-grade inflammatory state, which contributes to metabolic dysfunctions. Eicosapentaenoic acid (EPA), an n-3 fatty acid in fish oil, exerts anti-obesity and anti-inflammatory effects. Our previous study indicated that EPA lowered fat mass in obese female mice, potentially through increased biosynthesis of 8-hydroxyeicosapentaenoic acid (HEPE), an EPA-derived metabolite. Therefore, the objective of this study was to elucidate mechanisms underlying 8-HEPE effects on adipogenesis and inflammation using cultured 3T3-L1 cells. We hypothesized that 8-HEPE is more effective than EPA in reducing lipid accumulation and inflammatory genes in vitro. MethodsMurine 3T3-L1 adipocytes were cultured and differentiated with 5μM EPA, 18-HEPE, 8-HEPE, or control. Differentiated adipocytes were fixed and stained with Oil-Red-O solution and lipid content measured spectrophotometrically. To determine anti-inflammatory effects, 3T3-L1 pre- and differentiated cells were treated as above with or without lipopolysaccharide (LPS). Medium and cells were collected to measure interleukin-6 (IL-6) levels and genes involved in adipogenesis and inflammation. Results were analyzed by one-way ANOVA followed by a Tukey post-hoc test (GraphPad Prism).Results3T3-L1 cells differentiated with 8-HEPE had lower lipid content than control (p < 0.01). Consistently, 8-HEPE treated cells expressed a lower level of fatty acid synthesis gene, like acetyl-CoA carboxylase and fatty acid synthase than control (p = 0.059 and p = 0.042). And 8-HEPE exhibited promising anti-inflammatory effects by downregulating the IL-6 cytokine level in both LPS stimulated pre- and differentiated 3T3-L1 cells (p < 0.05). LPS-stimulated differentiated cells treated with 8-HEPE expressed a lower level of the inflammatory gene, IL-6 (p = 0.017), and a trend toward a higher level of the anti-inflammatory gene, arginase 1 (p = 0.067), than LPS control.ConclusionsOur findings indicate that the 8-HEPE has potent antiadipogenic and anti-inflammatory effects in vitro, and merit further investigations in vivo to determine whether EPA's effects are mediated by its downstream metabolite 8-HEPE. Our findings further demonstrate the importance of studying the role of EPA-derived metabolites in obesity and inflammation.Funding SourcesNone.

Mediatory Effect of Inflammatory Markers (IL-1β and PAI-1) on Association of Dietary Total Antioxidant Capacity and Body Composition in Overweight and Obese Women: A Cross-Sectional Study

Background. Obesity is considered a state of chronic low-grade inflammation. Different components of the diet, like antioxidants, can have anti-inflammatory effects or cause chronic inflammation. This study investigated the dietary TAC and inflammatory markers and body composition in obese and overweight women. Methods. This cross-sectional study was conducted on 259 women with overweight and obesity. Dietary intake was assessed by using an FFQ with 147 items, and DTAC was used to evaluate the antioxidant capacity of the diet. The anthropometric measurements, body composition, and biochemical assessments were measured by standard protocols. Results. We observed a significant positive association between DTAC and consumption of fruits (P = 0.021), vegetable oils (P &lt; 0.001), potassium (P = 0.006), manganese (P = 0.003), and caffeine (P &lt; 0.001), after adjusting confounders. After adjusting for age, energy intake, and physical activity, there was a significant correlation between DTAC and fat-free mass (FFM) (P:0.054), fat-free mass index (FFMI) (P:0.012), waist circumference (WC) (P:0.002), and visceral fat level (VFL) (P:0.063). FFM, FFMI, waist circumference (WC), and visceral fat area (VFA) were mediated by IL-1β. FFM, VFL, VFA, and WC were mediated by PAI-1. Conclusion. Some anthropometric indices were associated with DTAC, mediated by augmenting serum levels of IL-1β and PAI-1. Intake of foods rich in antioxidants could represent a protective strategy against chronic diseases, such as cardiovascular disease.

Obesity as a Risk Factor for Dementia and Alzheimer's Disease: The Role of Leptin.

Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.

Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice.

Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.

Metabotropic glutamate receptor 5 knockout rescues obesity phenotype in a mouse model of Huntington\u2019s disease

Obesity represents a global health problem and is characterized by metabolic dysfunctions and a low-grade chronic inflammatory state, which can increase the risk of comorbidities, such as atherosclerosis, diabetes and insulin resistance. Here we tested the hypothesis that the genetic deletion of metabotropic glutamate receptor 5 (mGluR5) may rescue metabolic and inflammatory features present in BACHD mice, a mouse model of Huntington’s disease (HD) with an obese phenotype. For that, we crossed BACHD and mGluR5 knockout mice (mGluR5−/−) in order to obtain the following groups: Wild type (WT), mGluR5−/−, BACHD and BACHD/mGluR5−/− (double mutant mice). Our results showed that the double mutant mice present decreased body weight as compared to BACHD mice in all tested ages and reduced visceral adiposity as compared to BACHD at 6 months of age. Additionally, 12-month-old double mutant mice present increased adipose tissue levels of adiponectin, decreased leptin levels, and increased IL-10/TNF ratio as compared to BACHD mice. Taken together, our preliminary data propose that the absence of mGluR5 reduce weight gain and visceral adiposity in BACHD mice, along with a decrease in the inflammatory state in the visceral adipose tissue (VAT), which may indicate that mGluR5 may play a role in adiposity modulation.

Immune-instructive copolymer scaffolds using plant-derived nanoparticles to promote bone regeneration

BackgroundAge-driven immune signals cause a state of chronic low-grade inflammation and in consequence affect bone healing and cause challenges for clinicians when repairing critical-sized bone defects in elderly patients.MethodsPoly(l-lactide-co-ɛ-caprolactone) (PLCA) scaffolds are functionalized with plant-derived nanoparticles from potato, rhamnogalacturonan-I (RG-I), to investigate their ability to modulate inflammation in vitro in neutrophils and macrophages at gene and protein levels. The scaffolds’ early and late host response at gene, protein and histological levels is tested in vivo in a subcutaneous rat model and their potential to promote bone regeneration in an aged rodent was tested in a critical-sized calvaria bone defect. Significant differences were tested using one-way ANOVA, followed by a multiple-comparison Tukey’s test with a p value ≤ 0.05 considered significant.ResultsGene expressions revealed PLCA scaffold functionalized with plant-derived RG-I with a relatively higher amount of galactose than arabinose (potato dearabinated (PA)) to reduce the inflammatory state stimulated by bacterial LPS in neutrophils and macrophages in vitro. LPS-stimulated neutrophils show a significantly decreased intracellular accumulation of galectin-3 in the presence of PA functionalization compared to Control (unmodified PLCA scaffolds). The in vivo gene and protein expressions revealed comparable results to in vitro. The host response is modulated towards anti-inflammatory/ healing at early and late time points at gene and protein levels. A reduced foreign body reaction and fibrous capsule formation is observed when PLCA scaffolds functionalized with PA were implanted in vivo subcutaneously. PLCA scaffolds functionalized with PA modulated the cytokine and chemokine expressions in vivo during early and late inflammatory phases. PLCA scaffolds functionalized with PA implanted in calvaria defects of aged rats downregulating pro-inflammatory gene markers while promoting osteogenic markers after 2 weeks in vivo.ConclusionWe have shown that PLCA scaffolds functionalized with plant-derived RG-I with a relatively higher amount of galactose play a role in the modulation of inflammatory responses both in vitro and in vivo subcutaneously and promote the initiation of bone formation in a critical-sized bone defect of an aged rodent. Our study addresses the increasing demand in bone tissue engineering for immunomodulatory 3D scaffolds that promote osteogenesis and modulate immune responses.

Impact of Age on Systemic Inflammatory Profile of Patients With ST-Segment-Elevation Myocardial Infarction and Acute Ischemic Stroke.

Aging is associated with a chronic low-grade inflammatory state. This condition may affect the acute inflammatory response involved in ST-segment-elevation myocardial infarction (STEMI) or acute ischemic stroke (AIS). We sought to compare the profile of a set of circulating inflammatory markers between young and older patients admitted for STEMI or AIS. HIBISCUS-STEMI (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in ST Elevation Myocardial Infarction) and HIBISCUS-STROKE (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke) are 2 cohort studies that enrolled patients with STEMI treated with primary percutaneous coronary intervention in the cardiac intensive care unit of Lyon and patients with AIS treated with mechanical thrombectomy in the Lyon Stroke Center, respectively from 2016 to 2019. Patients were classified as older if they were ≥65 years and as young if they were <65 years. In both cohorts, CRP (C-reactive protein), IL (interleukin)-6, IL-8, IL-10, MCP (monocyte chemoattractant protein), sTNF-RI (soluble tumor necrosis factor receptor I), sST2 (soluble form suppression of tumorigenicity 2), and VCAM-1 (vascular cellular adhesion molecule-1) were measured on serum collected at 5 time points using enzyme-linked immunosorbent assay. A multiple logistic regression model was performed to detect an association between area under the curve of circulating inflammatory markers within the first 48 hours and older age. A total of 260 patients with STEMI and 164 patients with AIS were included. Of them, there were 76 (29%) and 105 (64%) older patients with STEMI and AIS, respectively. Following multivariable analysis, a high area under the curve of IL-6 and sTNF-RI, a low lymphocyte count, and a high neutrophil-lymphocyte ratio at 24 hours were associated with older age in patients with STEMI and AIS. Older patients had higher IL-6 and sTFN-RI levels within the first 48 hours associated with a lower lymphocyte count and a higher neutrophil-lymphocyte ratio at 24 hours in both cohorts.

Respiratory Syncytial Virus Infection Modeled in Aging Cotton Rats (Sigmodon hispidus) and Mice (Mus musculus).

Serious infection with respiratory syncytial virus (RSV) is associated with high risk in infants, children, and elderly. There is currently no approved vaccine against RSV infection, and the only available prevention is immunoprophylaxis utilized in high-risk infants, leaving the elderly without many options. In the elderly, the chronic low-grade inflammatory state of the body can play a significant role during infection. The cotton rat and mouse have emerged as the preferred small animal models to study RSV infection in the elderly. These animal models of aging have shown an age-dependent time course for clearance of virus correlating with a significantly diminished cytotoxic T lymphocyte and humoral immune response in old animals compared to adult animals. In addition, protection through vaccination is reduced in aging rodents. These results mirror the findings in humans. In mice and cotton rats, treatment with ibuprofen, a nonselective nonsteroidal anti-inflammatory drug (NSAID), to decrease the chronic low-grade inflammation of the elderly immune system has proven successful in restoring the function of cytotoxic lymphocytes. While more research is required, these treatment types promise a beneficial effect in addition to a putative vaccine. Choosing an appropriate animal model to study RSV infection in the aging immune system is essential to benefit the growing population of elderly in the world. This review focuses on the current research of RSV infection in the cotton rat and mouse as model systems for an aging immune system.

Abstract 133: Correlation of inflammatory markers with metabolic and hormonal parameters in first degree relatives of PCOS patients

Background: PCOS is a state of chronic low-grade inflammation. There is familial clustering of PCOS. Relatively few studies have investigated inflammatory markers in the first-degree relatives of PCOS patients.Aims and Objectives: The aim of the current study was to estimate the levels of inflammatory markers in first degree relatives of PCOS patient and its correlation with various Metabolic and Hormonal parameters.Results: Total 66 (41 female and 25 male) first degree relatives of PCOS patients were included. Mean age was 39.3±9.5 years. 22.7% of patient had normal BMI while 48.4% were overweight and 28.7% were obese. The mean hsCRP was 2.47±1.07 mg/L, IL-6 was 3.53±1.07 pg/ml and TWBC was 7.24 x 103/ul. The mean hsCRP was >2 mg/L in all three BMI subgroups. There was significant positive correlation of LH with hsCRP (r=0.428, p<0.001), IL-6 (r=0.680, p<0.001) and TWBC (r=0.738, p<0.001) and significant negative correlation of SHBG levels with hsCRP (r= -0.325, p<0.001), IL-6 (r= -0.560, p<0.001) and TWBC (r= -0.465, p<0.001). There was no correlation of inflammatory markers with weight, BMI, waist circumference, SBP, DBP, FPG, LDL, HDL and HOMA IR.Conclusion: High mean hsCRP levels suggests that first degree relatives of PCOS patient are at increased risk of future CVD and the higher levels were independent of BMI category. There was significant correlation between the inflammatory markers and SHBG and LH levels but not with metabolic parameters. So, first degree relatives of PCOS patient have chronic low-grade inflammation.

Impact of 12-Week Moderate-Intensity Aerobic Training on Inflammasome Complex Activation in Elderly Women.

Aging often associates with a chronic low-grade inflammatory status that can be consequent to the activation of Toll-like receptors (TLRs) and the downstream NLR family pyrin domain containing 3 (NLRP3) inflammasome and causes a chronic secretion of pro-inflammatory cytokines. Since exercise has known anti-inflammatory effects, we investigated the effect of Nordic walking training on inflammasome activation and downstream effectors in elderly women. A population of elderly women was divided into EXP (n = 29) that completed 12 weeks of the moderate-intensity aerobic training program and CTRL (n = 29), performing no activity. Blood samples were taken before and after the first (T1-pre and T1-post, respectively) and last (T2-pre and T2-post, respectively) exercise unit. Inflammasome activation status was assessed by whole blood NLRP3 and TLR4 expression by RT-qPCR. Serum levels of IL-1β, IL-6, TNFα, and IL-18 cytokines were assayed by multiplex fluorescent beads-based immunoassays or ELISA. NLRP3 and TLR4 levels were reduced 2 folds between T1-pre and T2-pre and induced at T2-post, compared to T2-pre, by 2.6- and 2.9-fold, respectively. A single exercise bout elicited a 1. 38-, 1. 5-, and 1.36-fold rise of IL-1β, TNFα, and IL-6 concentration, respectively, although not significant, at the beginning of the training (T1-pre vs. T1-post), a 1.4-fold decrease for IL-1β and TNFα at the end of the training (T1-pre vs. T2-pre), and a 2-, 1.8- and 1.26-fold increase after the last exercise session (T2-pre vs. T2-post) for the three cytokines. When stratifying the population based on BMI in normal weight (NW) and overweight (OW), NLRP3 and TLR4 expression was affected only in NW. As for inflammatory cytokines, IL-1β was modulated in NW at the beginning of the training, whereas in OW at the end of the training; for TNFα, this time-dependent modulation was significant only in OW. Applied aerobic training affected the resting expression of inflammasome constituents (NLRP3 and TLR4) and levels of downstream effectors (IL-1β, TNFα, and IL-6). However, at the end of the program, participants acquire an acute inflammatory response to exercise that was absent at baseline. Future studies would have to define the molecular mechanisms associated with, and how to potentiate, the exercise-associated inflammatory response.

Organokines and Exosomes: Integrators of Adipose Tissue Macrophage Polarization and Recruitment in Obesity.

The prevalence of obesity is escalating and has become a worldwide health challenge coinciding with the development of metabolic diseases. Emerging evidence has shown that obesity is accompanied by the infiltration of macrophages into adipose tissue, contributing to a state of low-grade chronic inflammation and dysregulated metabolism. Moreover, in the state of obesity, the phenotype of adipose tissue macrophages switches from the M2 polarized state to the M1 state, thereby contributing to chronic inflammation. Notably, multiple metabolic organs (adipose tissue, gut, skeletal muscle, and the liver) communicate with adipose tissue macrophages via secreting organokines or exosomes. In this review, we systematically summarize how the organokines (adipokines, gut microbiota and its metabolites, gut cytokines, myokines, and hepatokines) and exosomes (adipocyte-, skeletal muscle-, and hepatocyte-derived exosomes) act as important triggers for macrophage recruitment in adipose tissue and adipose tissue macrophage polarization, thus providing further insight into obesity treatment. In addition, we also highlight the complex interaction of organokines with organokines and organokines with exosomes, revealing new paths in understanding adipose tissue macrophage recruitment and polarization.

PCOS: A Chronic Disease That Fails to Produce Adequately Specialized Pro-Resolving Lipid Mediators (SPMs).

Introduction: Polycystic ovary syndrome (PCOS) is an endocrinological disorder that affects 5–15% of women of their reproductive age and is a frequent cause of infertility. Major symptoms include hyperandrogenism, ovulatory dysfunction, and often obesity and/or insulin resistance. PCOS also represents a state of chronic low-grade inflammation that is closely interlinked with the metabolic features. “Classical” pro-inflammatory lipid mediators such as prostaglandins (PG), leukotrienes (LT), or thromboxanes (TX) are derived from arachidonic acid (AA) and are crucial for the initial response. Resolution processes are driven by four families of so-called specialized pro-resolving mediators (SPMs): resolvins, maresins, lipoxins, and protectins. The study aimed to establish lipid mediator profiles of PCOS patients compared to healthy women to identify differences in their resolutive and pro-inflammatory lipid parameters. Material and Methods: Fifteen female patients (18–45 years) were diagnosed with PCOS according to Rotterdam criteria, and five healthy women, as a comparator group, were recruited for the study. The main outcome measures were: pro-inflammatory lipid mediators (PG, LT, TX) and their precursor AA, SPMs (resolvins, maresins, protectins, lipoxins), their precursors EPA, DHA, DPA, and their active biosynthesis pathway intermediates (18-HEPE, 17-HDHA, 14-HDHA). Results: The level of pro-inflammatory parameters in serum was significantly higher in PCOS-affected women. The ratio (sum of pro-inflammatory molecules)/(sum of SPMs plus hydroxylated intermediates) reflecting the inflammatory state was significantly lower in the group of healthy women. Conclusion: There is a strong pro-inflammatory state in PCOS patients. Further research will clarify whether supplementation with SPMs or their precursors may improve this state.

Inflammation and Cardiovascular Diseases in the Elderly: The Role of Epicardial Adipose Tissue.

Human aging is a complex phenomenon characterized by a wide spectrum of biological changes which impact on behavioral and social aspects. Age-related changes are accompanied by a decline in biological function and increased vulnerability leading to frailty, thereby advanced age is identified among the major risk factors of the main chronic human diseases. Aging is characterized by a state of chronic low-grade inflammation, also referred as inflammaging. It recognizes a multifactorial pathogenesis with a prominent role of the innate immune system activation, resulting in tissue degeneration and contributing to adverse outcomes. It is widely recognized that inflammation plays a central role in the development and progression of numerous chronic and cardiovascular diseases. In particular, low-grade inflammation, through an increased risk of atherosclerosis and insulin resistance, promote cardiovascular diseases in the elderly. Low-grade inflammation is also promoted by visceral adiposity, whose accumulation is paralleled by an increased inflammatory status. Aging is associated to increase in epicardial adipose tissue (EAT), the visceral fat depot of the heart. Structural and functional changes in EAT have been shown to be associated with several heart diseases, including coronary artery disease, aortic stenosis, atrial fibrillation, and heart failure. EAT increase is associated with a greater production and secretion of pro-inflammatory mediators and neuro-hormones, so that thickened EAT can pathologically influence, in a paracrine and vasocrine manner, the structure and function of the heart and is associated to a worse cardiovascular outcome. In this review, we will discuss the evidence underlying the interplay between inflammaging, EAT accumulation and cardiovascular diseases. We will examine and discuss the importance of EAT quantification, its characteristics and changes with age and its clinical implication.

Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice

High-fat diet (HFD) consumption leads to obesity and a chronic state of low-grade inflammation, named metainflammation. Notably, metainflammation contributes to neuroinflammation due to the increased levels of circulating free fatty acids and cytokines. It indicates a strict interplay between peripheral and central counterparts in the pathogenic mechanisms of obesity-related mood disorders. In this context, the impairment of internal hypothalamic circuitry runs in tandem with the alteration of other brain areas associated with emotional processing (i.e., hippocampus and amygdala). Palmitoylethanolamide (PEA), an endogenous lipid mediator belonging to the N-acylethanolamines family, has been extensively studied for its pleiotropic effects both at central and peripheral level.Our study aimed to elucidate PEA capability in limiting obesity-induced anxiety-like behavior and neuroinflammation-related features in an experimental model of HFD-fed obese mice.PEA treatment promoted an improvement in anxiety-like behavior of obese mice and the systemic inflammation, reducing serum pro-inflammatory mediators (i.e., TNF-α, IL-1β, MCP-1, LPS). In the amygdala, PEA increased dopamine turnover, as well as GABA levels. PEA also counteracted the overactivation of HPA axis, reducing the expression of hypothalamic corticotropin-releasing hormone and its type 1 receptor. Moreover, PEA attenuated the immunoreactivity of Iba-1 and GFAP and reduced pro-inflammatory pathways and cytokine production in both the hypothalamus and hippocampus. This finding, together with the reduced transcription of mast cell markers (chymase 1 and tryptase β2) in the hippocampus, indicated the weakening of immune cell activation underlying the neuroprotective effect of PEA. Obesity-driven neuroinflammation was also associated with the disruption of blood–brain barrier (BBB) in the hippocampus. PEA limited the albumin extravasation and restored tight junction transcription modified by HFD. To gain mechanistic insight, we designed an in vitro model of metabolic injury using human neuroblastoma SH-SY5Y cells insulted by a mix of glucosamine and glucose. Here, PEA directly counteracted inflammation and mitochondrial dysfunction in a PPAR-α-dependent manner since the pharmacological blockade of the receptor reverted its effects.Our results strengthen the therapeutic potential of PEA in obesity-related neuropsychiatric comorbidities, controlling neuroinflammation, BBB disruption, and neurotransmitter imbalance involved in behavioral dysfunctions.

Correlation of markers of inflammation with hormonal, metabolic parameters, insulin resistance and adiposity indices in first-degree relatives of patient with polycystic ovary syndrome.

<b>Background:</b> Polycystic ovary syndrome (PCOS) is a state of chronic low-grade inflammation. Low-grade inflammation has been linked to the development of cardiovascular disease (CVD). There is evidence of clustering for metabolic syndrome, hypertension, dyslipidaemia in type 2 diabetes mellitus and insulin resistance (IR) in mothers, fathers, sisters and brothers of women with PCOS. <b>Aims:</b> The aim is to study the levels of inflammatory markers and IR in first-degree relatives of patients with PCOS and find any correlation with hormonal parameters, metabolic parameters and adiposity indices in them. <b>Settings and Design:</b> A total of 66 first-degree relatives of a patient with PCOS were included in this cross-sectional study. <b>Materials and Methods:</b> All participants underwent detailed clinical evaluation and biochemical investigations, including high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), luteinising hormone (LH), follicle-stimulating hormone (FSH) and total testosterone (only in females). Homeostasis model assessment of IR (HOMA-IR), lipid accumulation product and visceral adiposity index were calculated using standard equations. Visceral adipose tissue thickness and subcutaneous adipose tissue thickness were assessed using ultrasonography. <b>Statistical Analysis Used:</b> Spearman's and Pearson's correlation coefficients were used to analyse the correlation between different non-parametric and parametric data, respectively. Multiple linear regression was used to correlate multiple dependent factors. <b>Results:</b> The mean hs-CRP level was 2.4 ± 1.1 mg/L, which is greater than the cut-off of 2 mg/L and hs-CRP >2 mg/L was found in 62% (<i>n</i> = 41) participants. The mean IL-6 (3.5 ± 1.1 pg/ml) and total white blood cell count (7244 ± 2190/mm³) were in the normal range. The mean HOMA-IR was 2.35 ± 0.76, which is elevated, considering HOMA IR >2 as a predictor of IR and metabolic syndrome. HOMA IR >2 was found in 64% (<i>n</i> = 42) of the participants. Inflammatory markers were significantly correlated with LH and HOMA IR, even after multiple linear regression was fitted for each marker individually. <b><b>Conclusion:</b></b> Apparently, healthy first-degree relatives of PCOS patients had evidence of chronic low-grade inflammation. The chronic inflammation in them correlated well with HOMA-IR and LH but was independent of body mass index. This low-grade inflammation may predispose the first-degree relatives of PCOS to CVD.

Correlation of Markers of Inflammation with Hormonal, Metabolic Parameters, Insulin Resistance and Adiposity Indices in First-Degree Relatives of Patient with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a state of chronic low-grade inflammation. Low-grade inflammation has been linked to the development of cardiovascular disease (CVD). There is evidence of clustering for metabolic syndrome, hypertension, dyslipidaemia in type 2 diabetes mellitus and insulin resistance (IR) in mothers, fathers, sisters and brothers of women with PCOS. The aim is to study the levels of inflammatory markers and IR in first-degree relatives of patients with PCOS and find any correlation with hormonal parameters, metabolic parameters and adiposity indices in them. A total of 66 first-degree relatives of a patient with PCOS were included in this cross-sectional study. All participants underwent detailed clinical evaluation and biochemical investigations, including high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), luteinising hormone (LH), follicle-stimulating hormone (FSH) and total testosterone (only in females). Homeostasis model assessment of IR (HOMA-IR), lipid accumulation product and visceral adiposity index were calculated using standard equations. Visceral adipose tissue thickness and subcutaneous adipose tissue thickness were assessed using ultrasonography. Spearman's and Pearson's correlation coefficients were used to analyse the correlation between different non-parametric and parametric data, respectively. Multiple linear regression was used to correlate multiple dependent factors. The mean hs-CRP level was 2.4 ± 1.1 mg/L, which is greater than the cut-off of 2 mg/L and hs-CRP >2 mg/L was found in 62% (n = 41) participants. The mean IL-6 (3.5 ± 1.1 pg/ml) and total white blood cell count (7244 ± 2190/mm3) were in the normal range. The mean HOMA-IR was 2.35 ± 0.76, which is elevated, considering HOMA IR >2 as a predictor of IR and metabolic syndrome. HOMA IR >2 was found in 64% (n = 42) of the participants. Inflammatory markers were significantly correlated with LH and HOMA IR, even after multiple linear regression was fitted for each marker individually. Apparently, healthy first-degree relatives of PCOS patients had evidence of chronic low-grade inflammation. The chronic inflammation in them correlated well with HOMA-IR and LH but was independent of body mass index. This low-grade inflammation may predispose the first-degree relatives of PCOS to CVD.

506 Role of inflammation and comorbidities in the association between heart failure and incident cancer in the HUNT3 cohort

Abstract Aims Conflicting data exist regarding the risk of cancer in patients with heart failure (HF). It was first reported that incident cancer is more common among patients with than without HF, whereas more recent studies indicate that this association is primarily driven by comorbidities. HF, cancer, and comorbidities, such as chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), share numerous risk factors, including a state of chronic low-grade inflammation reflected by elevated circulating levels of pro-inflammatory cytokines. The objective of this analysis was to assess whether chronic low-grade inflammation, as measured by levels of high-sensitivity C-reactive protein (hsCRP), and comorbidities mediate the association of HF with incident cancer. Methods We used data from the 3rd wave of the Nord-Trøndelag Health Study (HUNT3), a population-based study that enrolled 50 803 individuals ≥18-year-old between October 2006 and June 2008 in the Nord-Trøndelag County (Norway), and from the administrative health care records of the same region. Associations between baseline characteristics and the development of cancer were assessed using Cox proportional hazards regression models, using time from HUNT3 enrolment as the time scale. Analyses were performed using R statistical software, version 4.0.2. Results In HUNT3, hsCRP was measured in 47 571 individuals at the time of enrolment. Of these, we excluded 2308 patients because of missing information, leaving a cohort of 45 263 subjects. The prevalence of cardiovascular disease, comorbidities, and obesity was progressively higher with increasing concentrations of hsCRP. During a median follow-up of 12 years, there were 66/408 cases of incident cancer in patients with HF at baseline and 5024/47 163 in subjects without HF, with a more than 2-fold (HR 2.30; 95% CI 1.80–2.93; P &amp;lt; 0.001) increase in risk of developing cancer. After adjusting for age and sex, the excess risk decreased to 43% (HR 1.43; 95% CI 1.12–1.82). When including hsCRP in the model, the HF-related risk of cancer was 33% (HR 1.33; 95% CI 1.04–1.70; P = 0.022). Furthermore, when body mass index, CKD, COPD, and smoking and drinking habits were included in the model, the risk of cancer in HF patients compared to individuals without HF was no longer significant (HR 1.23; 95% CI 0.94–1.60; P = 0.127). Age, male sex, hsCRP, COPD, obesity, and smoking habits were all associated with an increased risk of cancer. Conclusions The increased risk of cancer in HF patients compared with the general population is at least in part explained by concomitant inflammation and comorbidities.

Role of inflammation and comorbidities in the association of heart failure with incident cancer in the HUNT3 cohort

Abstract Background Conflicting data exist regarding the risk of cancer in patients with heart failure (HF). It was first reported that incident cancer is more common among patients with than without HF, whereas more recent studies indicate that this association is primarily driven by comorbidities. HF, cancer, and comorbidities, such as chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), share numerous risk factors, including a state of chronic low-grade inflammation reflected by elevated circulating levels of pro-inflammatory cytokines. The objective of this analysis was to assess whether chronic low-grade inflammation, as measured by levels of high-sensitivity C-reactive protein (hsCRP), and comorbidities mediate the association of HF with incident cancer. Methods We used data from the 3rd wave of the Nord-Trøndelag Health Study (HUNT3), a population-based study that enrolled 50,803 individuals ≥18-year-old between October 2006 and June 2008 in the Nord-Trøndelag County (Norway), from the Cancer Registry of Norway and from the administrative health care records of the same region. Associations between baseline characteristics and the development of cancer were assessed using Cox proportional hazards regression models, using time from HUNT3 enrollment as the time scale. Analyses were performed using R statistical software, version 4.0.2. Results In HUNT3, hsCRP was measured in 47,571 individuals at the time of enrollment. Of these, we excluded 2,308 patients because of missing information, leaving a cohort of 45,263 subjects. Figure 1 shows the characteristics of the study population at baseline stratified by hsCRP tertiles. The prevalence of cardiovascular disease, comorbidities, and obesity was progressively higher with increasing concentrations of hsCRP. During a median follow-up of 12 years, there were 66/408 cases of incident cancer in patients with HF at baseline and 5,024/47,163 in subjects without HF, with a more than 2-fold (HR 2.30; 95% CI 1.80–2.93; p&amp;lt;0.001) increase in risk of developing cancer. After adjusting for age and sex, the excess risk decreased to 43% (HR 1.43; 95% CI 1.12–1.82). When including hsCRP in the model, the HF-related risk of cancer was 33% (HR 1.33; CI 1.04–1.70; p=0.022). Furthermore, when body mass index, CKD, COPD, and smoking and drinking habits were included in the model, the risk of cancer in HF patients compared to individuals without HF was no longer significant (HR 1.23; 95% CI 0.94–1.60; p=0.127). Age, male sex, hsCRP, COPD, obesity, and smoking habits were all associated with an increased risk of cancer (Figure 2). Conclusions The increased risk of cancer in HF patients compared with the general population is at least in part explained by concomitant inflammation and comorbidities. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

HIV-Associated Interactions Between Oral Microbiota and Mucosal Immune Cells: Knowledge Gaps and Future Directions.

Even with sustained use of antiretroviral therapy (ART), HIV-infected individuals have an increased risk of systemic comorbid conditions and oral pathologies, including opportunistic infections, oral mucosal inflammation, and gingival and periodontal diseases. The immune-mediated mechanisms that drive this increased risk, in the context of sustained viral suppression, are unclear. HIV infection, even when controlled, alters microbial communities contributing to a chronic low-grade inflammatory state that underlies these non-HIV co-morbidities. The higher prevalence of dental caries, and mucosal and periodontal inflammation reported in HIV-infected individuals on ART is often associated with differentially abundant oral microbial communities, possibly leading to a heightened susceptibility to inflammation. This mini-review highlights current gaps in knowledge regarding the microbe-mediated oral mucosal immunity with HIV infection while discussing opportunities for future research investigations and implementation of novel approaches to elucidate these gaps. Interventions targeting both inflammation and microbial diversity are needed to mitigate oral inflammation-related comorbidities, particularly in HIV-infected individuals. More broadly, additional research is needed to bolster general models of microbiome-mediated chronic immune activation and aid the development of precise microbiota-targeted interventions to reverse or mitigate adverse outcomes.