Reduction In Systemic Inflammation Research Articles

The impact of maternal anti-inflammatory drugs on surgical anesthesia-induced neuroinflammation and cognitive impairment in offspring mice.

The impact of maternal surgery combined with general anesthesia on neuroinflammation and the development of learning and memory impairment in offspring remains unclear. This study utilized a pathogen-free laparotomy model to investigate these changes during the second trimester, as well as their response to anti-inflammatory therapy. C57BL/6 pregnant mice at the 14.5-day embryo stage (E 14.5) were either exposed to sevoflurane anesthesia alone or underwent laparotomy procedure. The neuroinflammatory response was evaluated at 7, 14, 21, and 28 days postnatal (P7, P14, P21, P28). Tau phosphorylation and cognitive ability were assessed at P28 and P30, respectively. The impact of perioperative administration of ibuprofen (60 mg/kg) on these aforementioned changes was subsequently evaluated. In the laparotomy group, levels of inflammatory factors (IL-4, IL-8, IL-17A, TGF-β, M-CSF, CCL2) in the brains of offspring mice, including the cerebral cortex and hippocampus, remained consistently elevated from P7 to P28. At P14, while the majority of inflammatory cytokine has no statistical difference, there was still a significant reactivation of inflammatory cytokines observed in the frontal cortex and hippocampus at P28. Furthermore, abnormal phosphorylation of tau and deficits in learning and memory were observed at P28 and P30. Administration of perioperative ibuprofen led to improvements in cognitive performance, reduction of systemic inflammation, and inhibiting abnormal phosphorylation of tau in the frontal cortex and hippocampus. Our findings indicate that cognitive dysfunction is correlated with elevated levels of inflammatory cytokines and tau phosphorylation. Cognitive impairment and tau phosphorylation after laparotomy can persist at least until P28. Anti-inflammatory medications have been shown to enhance cognitive function by rapidly reducing inflammation in the brain, while also impacting neurological changes. This discovery may have implications for the development of treatment strategies aimed at managing cognitive impairment in post-operative patients.

Interleukin-1 blockade with RPH-104 (goflikicept) in patients with ST-segment elevation myocardial infarction (STEMI): secondary endpoints from an international, double blind, randomized, placebo-controlled, phase IIa study.

In a randomized double-blinded clinical trial of patients with ST segment elevation myocardial infarction (STEMI), goflikicept, an Interleukin-1 (IL-1) blocker, significantly reduced systemic inflammation, measured as the area-under-the-curve (AUC) for high-sensitivity C reactive protein (hsCRP) at 14 days. We report secondary analyses of biomarkers at 28 days, and cardiac function and clinical endpoints at 1 year. Patients received a single administration of goflikicept 80 mg (n=34), goflikicept 160 mg (n=34), or placebo (n=34). Both doses of goflikicept significantly reduced the AUC for hsCRP at 28 days compared with placebo, without statistically significant differences between the doses. There we no statistically significant differences between groups in the AUC for natriuretic peptides at 28 days. There were no significant differences between placebo, goflikicept 80 mg and 160 mg groups in deaths (2.9%, 2.9% and 0%), hospitalization for cardiovascular reasons (9.1%, 5.9%, and 0%), new-onset or progression of heart failure (9.1%, 5.9%, and 5.9%), and new or increased use of loop diuretics (24.2%, 14.7%, and 17.6%), nor in the number of patients with treatment emergent adverse events, with no treatment-related serious adverse events in any group. In conclusion, in patients with STEMI, IL-1 blockade with goflikicept 80 mg or 160 mg was well tolerated and associated with significant reduction of systemic inflammation. Further adequately powered studies are warranted to determine whether the reduction in systemic inflammation with goflikicept translates into a clinical benefit in patients with STEMI.

Improved Wound Healing: The Healing Power of Blood Transfusions for Individuals with HIV

Wound healing in individuals with HIV is often compromised due to impaired immune function, chronic inflammation, and common comorbidities like anemia. Blood transfusions, traditionally used to manage anemia, have shown promise in enhancing wound healing through multiple mechanisms. This review explores the role of blood transfusions in improving wound healing for HIV-positive patients, focusing on their impact on oxygen delivery, immune modulation, inflammation reduction, and tissue repair. By restoring adequate hemoglobin levels, blood transfusions can improve oxygenation, support cellular metabolism, and promote collagen synthesis and angiogenesis, all crucial for effective wound healing. In addition to addressing anemia, blood transfusions may offer broader benefits, including the modulation of immune responses and the reduction of systemic inflammation. These effects can create a more favorable environment for wound healing, helping to mitigate prolonged inflammation and tissue damage commonly seen in HIV-positive individuals. Clinical studies and case reports have highlighted significant improvements in wound healing outcomes following transfusion therapy, underscoring its potential as a complementary intervention in HIV care. Keywords: anemia, blood transfusions, HIV, immune response, wound healing,

Treatment of hidradenitis suppurativa with adalimumab in the PIONEER I and II trials reduced indices of systemic inflammation, recognised risk factors for cardiovascular disease.

Hidradenitis suppurativa (HS) is associated with increased cardiovascular disease (CVD) risk. Systemic immune inflammation index (SII), neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR) and monocyte/lymphocyte ratios (MLR) are biomarkers of systemic inflammation and CVD. One small study identified a lower NLR and PLR in patients treated with adalimumab. Our aim was to assess changes in SII, NLR, PLR and MLR in a larger cohort, and to evaluate their association with disease severity and treatment response. This was a post-hoc analysis of PIONEER I and PIONEER II, two phase 3 randomised placebo-controlled clinical trials of adalimumab for HS. SII, NLR, PLR and MLR were log10-transformed and linear mixed model was used to estimate treatment effect. SII, NLR, PLR and MLR reduced from baseline levels with adalimumab treatment by week 12, when the primary response endpoint was assessed. Significant changes first appeared at week 4 and were maintained to week 36. In contrast, no significant changes were observed in placebo-treated patients. In patients re-randomised at week 12 from placebo to adalimumab, SII, NLR, PLR and MLR also reduced within 4 weeks. In patients re-randomised from adalimumab to placebo, these biomarkers returned to baseline by week 36. In addition, SII, NLR and PLR correlated with draining fistula count (r=0.26-0.43, p<0.001). Adalimumab non-responders in PIONEER I had a higher SII, NLR and PLR at baseline and week 12, but this was not significant when adjusted for draining fistulae. Treatment of HS patients with adalimumab results in rapid sustained reduction in systemic inflammation measured by SII, NLR, PLR and MLR which correlate with CVD risk. SII, NLR and PLR may predict adalimumab response, although dependent on their interaction with the number of draining fistulae.

Dapagliflozin, inflammation and left ventricular remodelling in patients with type 2 diabetes and left ventricular hypertrophy

Background and AimsSodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation.MethodsWe measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation.ResultsFollowing 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months.ConclusionsDapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin.Trial registrationClinicaltrials.gov NCT02956811 (06/11/2016).

Healthy lifestyles and better periodontal health: Results from two large population-based surveys.

To ascertain whether healthy lifestyles are associated with periodontal diseases in two large-scale surveys in the US (National Health and Nutrition Examination Survey - NHANES) and the UK Biobank. 9854 US adults and 111 679 UK adults were included in the analyses. A healthy lifestyle score (HLS), ranging between 0 and 5, was calculated based on the reported number of healthy behaviours, including never smoking, no heavy alcohol consumption, top third of leisure-time physical activity, higher dietary quality, and ideal sleep duration. The prevalence of periodontal diseases was the primary outcome in both surveys. In the NHANES, periodontal status was assessed through a full-mouth periodontal examination, while in the UKB, only self-reported periodontal status was available. Multiple regression analyses confirmed that the presence of at least 2-3 healthy behaviours (vs. 0-1) was associated with lower odds of overall and severe periodontitis (ORs 0.5, 0.4-0.6; p < .001 and 0.5, 0.3-0.8; p = .003, respectively) in the NHANES, and of bleeding gums (OR = 0.9, 0.8-1.0; p = .092) and loose teeth (OR = 0.6, 0.5-0.7; p < .001) in UKB. This association increased when considering prevalence of 4-5 healthy behaviours (vs. 0-1) in both the NHANES (periodontitis: OR = 0.3, 0.2-0.4; p < .001; severe periodontitis: OR = 0.1, 0.01-0.2; p < .001) and the UKB (bleeding gums: OR = 0.8, 0.7-0.9; p < .001; loose teeth: OR = 0.5, 0.4-0.6; p < .001). Mediation analyses revealed how these protective associations could be partially mediated (1-14%) by differences in biomarkers of systemic inflammation (white blood cells and neutrophils count as well as C-reactive protein). Adoption of healthy lifestyle behaviours is associated with a lower prevalence of periodontal diseases within two large population-based samples. This relationship exhibits a dose-response pattern, implying that greater adherence to healthy habits leads to a more significant protective effect against the odds of periodontal diseases. Additionally, our findings suggest that this protective effect is, in part, mediated by reductions in systemic inflammation.

Serum and CSF metabolomics analysis shows Mediterranean Ketogenic Diet mitigates risk factors of Alzheimer’s disease

Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.

A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.

Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose. We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials. HuMAIN will test a promising novel agent for obesity-related HFpEF.

Dietary supplementation with probiotics promotes weight loss by reshaping the gut microbiome and energy metabolism in obese dogs.

Obesity and overweight among companion animals are significant concerns, paralleling the issues observed in human populations. Recent research has highlighted the potential benefits of various probiotics in addressing weight-related changes, obesity, and associated pathologies. In this study, we delved into the beneficial probiotic mechanisms in high-fat-induced obese canines, revealing that Enterococcus faecium IDCC 2102 (IDCC 2102) and Bifidobacterium lactis IDCC 4301 (IDCC 4301) have the capacity to mitigate the increase in body weight and lipid accumulation in obese canines subjected to a high-fat diet and hyperlipidemic Caenorhabditis elegans (C. elegans) strain VS29. Both IDCC 2102 and IDCC 4301 demonstrated the ability to reduce systemic inflammation and hormonal disruptions induced by obesity. Notably, these probiotics induced modifications in the microbiota by promoting lactic acid bacteria, including Lactobacillaceae, Ruminococcaceae, and S24-7, with concomitant activation of pyruvate metabolism. IDCC 4301, through the generation of bacterial short-chain fatty acids and carboxylic acids, facilitated glycolysis and contributed to ATP synthesis. Meanwhile, IDCC 2102 produced bacterial metabolites such as acetic acid and butyric acid, exhibiting a particular ability to stimulate dopamine synthesis in a canine model. This stimulation led to the restoration of eating behavior and improvements in glucose and insulin tolerance. In summary, we propose novel probiotics for the treatment of obese animals based on the modifications induced by IDCC 2102 and IDCC 4301. These probiotics enhanced systemic energy utilization in response to high caloric intake, thereby preventing lipid accumulation and restoring stability to the fecal microbiota. Consequently, this intervention resulted in a reduction in systemic inflammation caused by the high-fat diet.IMPORTANCEProbiotic supplementation affected commensal bacterial proliferation, and administering probiotics increased glycolysis and activated pyruvate metabolism in the body, which is related to propanate metabolism as a result of pyruvate metabolism activation boosting bacterial fatty acid production via dopamine and carboxylic acid specialized pathways, hence contributing to increased ATP synthesis and energy metabolism activity.

To Boost or to Reset: The Role of Lactoferrin in Energy Metabolism.

Many pathological conditions, including obesity, diabetes, hypertension, heart disease, and cancer, are associated with abnormal metabolic states. The progressive loss of metabolic control is commonly characterized by insulin resistance, atherogenic dyslipidemia, inflammation, central obesity, and hypertension, a cluster of metabolic dysregulations usually referred to as the "metabolic syndrome". Recently, nutraceuticals have gained attention for the generalized perception that natural substances may be synonymous with health and balance, thus becoming favorable candidates for the adjuvant treatment of metabolic dysregulations. Among nutraceutical proteins, lactoferrin (Lf), an iron-binding glycoprotein of the innate immune system, has been widely recognized for its multifaceted activities and high tolerance. As this review shows, Lf can exert a dual role in human metabolism, either boosting or resetting it under physiological and pathological conditions, respectively. Lf consumption is safe and is associated with several benefits for human health, including the promotion of oral and gastrointestinal homeostasis, control of glucose and lipid metabolism, reduction of systemic inflammation, and regulation of iron absorption and balance. Overall, Lf can be recommended as a promising natural, completely non-toxic adjuvant for application as a long-term prophylaxis in the therapy for metabolic disorders, such as insulin resistance/type II diabetes and the metabolic syndrome.

134 Clinical response to IL-22RA1 blockade is associated with reduction of systemic inflammation

134 Clinical response to IL-22RA1 blockade is associated with reduction of systemic inflammation

Inflammatory markers in serum and placenta in a randomized controlled trial of group prenatal care

Racial and socioeconomic disparities in preterm birth and small for gestational age births are growing in the United States, increasing the burden of morbidity and mortality particularly among Black women and birthing persons and their infants. Group prenatal care is one of the only interventions to show potential to reduce the disparity, but the mechanism is unclear. The goal of this project was to identify if group prenatal care, when compared with individual prenatal care, was associated with a reduction in systemic inflammation during pregnancy and a lower prevalence of inflammatory lesions in the placenta at delivery. The Psychosocial Intervention and Inflammation in Centering Study was a prospective cohort study that exclusively enrolled participants from a large randomized controlled trial of group prenatal care (the Cradle study, R01HD082311, ClinicalTrials.gov: NCT02640638) that was performed at a single site in Greenville, South Carolina, from 2016 to 2020. In the Cradle study, patients were randomized to either group prenatal care or individual prenatal care, and survey data were collected during the second and third trimesters. The Psychosocial Intervention and Inflammation in Centering Study cohort additionally provided serum samples at these 2 survey time points and permitted collection of placental biopsies for inflammatory and histologic analysis, respectively. We examined associations between group prenatal care treatment and a composite of z scored serum inflammatory biomarkers (C-reactive protein, interleukin-6, interleukin-1 receptor antagonist, interleukin-10, and tumor necrosis factor α) in both the second and third trimesters and the association with the prevalence of acute and chronic maternal placental inflammatory lesions. Analyses were conducted using the intent to treat principle, and the results were also examined by attendance of visits in the assigned treatment group (modified intent to treat and median or more number of visits) and were stratified by race and ethnicity. A total of 1256 of 1375 (92%) Cradle participants who were approached enrolled in the Psychosocial Intervention and Inflammation in Centering Study, which included 54% of all the Cradle participants. The Psychosocial Intervention and Inflammation in Centering Study cohort did not differ from the Cradle cohort by demographic or clinical characteristics. Among the 1256 Psychosocial Intervention and Inflammation in Centering Study participants, 1133 (89.6%) had placental data available for analysis. Among those, 549 were assigned to group prenatal care and 584 of 1133 were assigned to individual prenatal care. In the intent to treat and modified intent to treat cohorts, participation in group prenatal care was associated with a higher serum inflammatory score, but it was not associated with an increased prevalence of placental inflammatory lesions. In the stratified analyses, group prenatal care was associated with a higher second trimester inflammatory biomarker composite (modified intent to treat: B=1.17; P=.02; and median or more visits: B=1.24; P=.05) among Hispanic or Latine participants. Unexpectedly, group prenatal care was associated with higher maternal serum inflammation during pregnancy, especially among Hispanic or Latine participants.

Successful treatment of JAK1-associated inflammatory disease

Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia. This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition. The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. Amolecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. Avariant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.

Cyclophilins modify their profile depending on the organ or tissue in a murine inflammatory model

Inflammation is the leading subjacent cause of many chronic diseases. Despite several studies in the last decades, the molecular mechanism involving its pathophysiology is not fully known. Recently, the implication of cyclophilins in inflammatory-based diseases has been demonstrated. However, the main role of cyclophilins in these processes remains elusive. Hence, a mouse model of systemic inflammation was used to better understand the relationship between cyclophilins and their tissue distribution. To induce inflammation, mice were fed with high-fat diet for 10 weeks. In these conditions, serum levels of interleukins 2 and 6, tumour necrosis factor-α, interferon-ϒ, and the monocyte chemoattractant protein 1 were elevated, evidencing a systemic inflammatory state. Then, in this inflammatory model, cyclophilins and CD147 profiles in the aorta, liver, and kidney were studied. The results demonstrate that, upon inflammatory conditions, cyclophilins A and C expression levels were increased in the aorta. Cyclophilins A and D were augmented in the liver, meanwhile, cyclophilins B and C were diminished. In the kidney, cyclophilins B and C levels were elevated. Furthermore, CD147 receptor was also increased in the aorta, liver, and kidney. In addition, when cyclophilin A was modulated, serum levels of inflammatory mediators were decreased, indicating a reduction in systemic inflammation. Besides, the expression levels of cyclophilin A and CD147 were also reduced in the aorta and liver, when cyclophilin A was modulated. Therefore, these results suggest that each cyclophilin has a different profile depending on the tissue, under inflammatory conditions.

Dietary Intake and Systemic Inflammation: Can We Use Food as Medicine?

This review summarizes the current literature regarding the association between diet and systemic inflammation. Data in humans suggests that consumption of plant-based nutrients is associated with a reduction in systemic inflammation, while consumption of red meat and excessive dairy has the opposite effect and may increase risk of acute flares in those that suffer from certain chronic diseases like inflammatory bowel disease or psoriasis and certain cancers. There is a known association between diet and systemic inflammation; thus, we recommend that clinicians discuss plant-based, whole food diets with patients, particularly those that suffer from chronic inflammatory diseases as an adjunct treatment for these conditions. Future research should evaluate whether adherence to these types of diets is sustainable in the long term and how these changes affect important quality of life concerns.

Abstract 12116: Effects of Interleukin-1 Blockade With Anakinra on Peak Oxygen Consumption in Patients With Heart Failure an Analysis of On-Treatment and Off-Treatment Assessments

Introduction: Interleukin-1 (IL-1) blockade may improve exercise capacity in the subset of heart failure (HF) patient with high inflammation. Accordingly, modulating systemic inflammation with IL-1 inhibition could result in physiologic adaptations that have a beneficial effect on exercise capacity in this population. Hypothesis: Primary objective of the study was to determine changes in peak oxygen consumption (VO2) on-treatment with anakinra, an IL-1 blocker, and after treatment cessation. Methods: Cardiopulmonary exercise testing (CPET) was performed in 52 patients with HF at baseline, during daily treatment and after suspension of treatment with 100 mg anakinra. High-sensitivity C-reactive protein (CRP) was measured at the time of each CPET. Data are presented as median and interquartile range or number and percentage. Results: The cohort included twenty-six (50%) females, 36 (69%) self-identified as Black/African-American, 55 [52-62] years. Left ventricular ejection fraction (LVEF) was 43% [34-60%], CRP was 7.1 [3.7-15.8] mg/L and peak VO2 was 14.5 [12.6-17.4] ml•kg-1•min-1. Treatment duration was 4 [2-12] weeks, while time between treatment discontinuation and off-treatment CPET was 12 [6-12] weeks. Treatment with anakinra significantly reduced CRP (7.1 [3.7-15.8] to 1.5 [1.0-3.8] mg/L, p&lt;0.001) and improved peak VO2 (14.5 [12.6-17.4] ml•kg-1•min-1to 16.0 [14.0-18.6] ml•kg-1•min-1, p=0.011-Figures A and B, respectively). CRP significantly increased to 3.8 [1.4-10.7] mg/L, p=0.007, and peak VO2 significantly decreased to 15.5 [12-17.8] ml•kg-1•min-1 (p= 0.004) after anakinra suspension. Conclusions: IL-1 blockade with anakinra is associated with a reduction in systemic inflammation (CRP levels) and in an improvement in exercise capacity (i.e., peak VO2) among patients with HF during treatment. These data validate IL-1 blockade as a mediator of exercise capacity in HF; however long-term effects require further investigation.

Rifaximin Modifies Gut Microbiota and Attenuates Inflammation in Parkinson's Disease: Preclinical and Clinical Studies.

Patients with Parkinson's disease (PD) exhibit distinct gut microbiota, which may promote gut-derived inflammation. Rifaximin is a nonabsorbable antibiotic that can modify gut microbiota. The present study investigated the effect of rifaximin on gut microbiota and inflammation status in PD. The study examined the effect of long-term rifaximin treatment on in vivo transgenic PD mice (MitoPark) and short-term rifaximin treatment on patients with PD. Rifaximin treatment caused a significant change in gut microbiota in the transgenic PD mice; in particular, it reduced the relative abundance of Prevotellaceae UCG-001 and increased the relative abundance of Bacteroides, Muribaculum, and Lachnospiraceae UCG-001. Rifaximin treatment attenuated serum interleukin-1β, interleukin-6 and tumor necrosis factor-α, claudin-5 and occludin, which indicated the reduction of systemic inflammation and the protection of the blood-brain barrier integrity. The rifaximin-treated MitoPark mice exhibited better motor and memory performance than did the control mice, with lower microglial activation and increased neuronal survival in the hippocampus. In the patients with PD, 7-day rifaximin treatment caused an increase in the relative abundance of Flavonifractor 6 months after treatment, and the change in plasma proinflammatory cytokine levels was negatively associated with the baseline plasma interleukin-1α level. In conclusion, the present study demonstrated that rifaximin exerted a neuroprotective effect on the transgenic PD mice by modulating gut microbiota. We observed that patients with higher baseline inflammation possibly benefited from rifaximin treatment. With consideration for the tolerability and safety of rifaximin, randomized controlled trials should investigate the disease-modification effect of long-term treatment on select patients with PD.

Reduction of Systemic Inflammation by Notch3 Inhibition in HIV-Associated Nephropathy

Reduction of Systemic Inflammation by Notch3 Inhibition in HIV-Associated Nephropathy

Empagliflozin treatment differentially modifies visceral and subcutaneous adipose tissue lipidomes and pro-inflammatory cytokines in zucker fatty diabetic rats

Abstract EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial) trial highlighted the relevance of pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus (T2DM) and/or cardiovascular disease. Although the pathways through which SGLT2 inhibitors exert a beneficial effect on the cardiovascular system are still unknown, it has been suggested that energy metabolism regulation and a reduction of systemic inflammation could be some of the mechanisms implicated. Available data also suggests that empagliflozin treatment could be able to exert regulatory effects on adipose tissue (AT) depots. The aim of our study was to evaluate the impact of empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) depots in a rat model of obesity and T2DM. Diabetic obese Zucker Fatty (ZDF) rats were treated with 30 mg/kg/day of empagliflozin p.o for 6 weeks. The lipidomes of VAT and SAT depots were analyzed using ultra-high performance liquid chromatography coupled to mass spectrometry. Empagliflozin's effect on pro-inflammatory markers in AT was analyzed by RT-PCR. In VAT, 18 metabolites were significantly altered in empagliflozin-treated rats vs. controls. Nearly all diglycerides tested (13 of 14) were significantly increased in treated rats, as the most notable altered chemical class. Furthermore, 3 oxidized fatty acids (FA) and FA like gadoleic acid and linoleic acid were also significantly increased. In SAT, a total of 14 metabolites were significantly altered. Most of them (13 of 14) were glycerophospholipids. Significantly lower levels of 4 lysophosphatidylethanolamines, 4 lysophosphatidylcholines, and 3 lysophosphatidylinositols and higher levels of 2 phosphatidylcholines were shown. In contrast to VAT, a significant decrease in most of these metabolites was observed in empagliflozin-treated samples. Several ratios of metabolites were also calculated to infer the potential enzyme activities related to lipid metabolism in both VAT and SAT. However, the ratios studied were only statistically significant in VAT of empagliflozin-treated rats vs. control, where the main potential enzyme activities altered were desaturases and elongases. Empagliflozin treatment also reduces the expression of the pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα) and monocyte-chemotactic protein-1 (MCP-1) in VAT, with no changes in SAT, except for interleukin-13 (IL-13), which also decreases compared to untreated diabetic ZDF rats. In conclusion, empagliflozin increased oxidized FA and diglycerides in VAT and decreased glycerophospholipid levels in SAT. The anti-inflammatory effect of empagliflozin in VAT is not observed in SAT. The effect of empagliflozin on the regulation of the adipose tissue lipidome and inflammatory profile is different depending on the localization of the depots. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH and Co

Edible Insect Consumption for Human and Planetary Health: A Systematic Review.

This systematic review aimed to examine the health outcomes and environmental impact of edible insect consumption. Following PRISMA-P guidelines, PubMed, Medline ProQuest, and Cochrane Library databases were searched until February 2021. Twenty-five articles met inclusion criteria: twelve animal and six human studies (randomized, non-randomized, and crossover control trials), and seven studies on sustainability outcomes. In animal studies, a supplement (in powdered form) of 0.5 g/kg of glycosaminoglycans significantly reduced abdominal and epididymal fat weight (5–40% and 5–24%, respectively), blood glucose (10–22%), and total cholesterol levels (9–10%), and a supplement of 5 mg/kg chitin/chitosan reduced body weight (1–4%) and abdominal fat accumulation (4%) versus control diets. In other animal studies, doses up to 7–15% of edible insect inclusion level significantly improved the live weight (9–33%), reduced levels of triglycerides (44%), cholesterol (14%), and blood glucose (8%), and increased microbiota diversity (2%) versus control diet. In human studies, doses up to 7% of edible insect inclusion level produced a significant improvement in gut health (6%) and reduction in systemic inflammation (2%) versus control diets and a significant increase in blood concentrations of essential and branched-chain amino acids and slowing of digestion (40%) versus whey treatment. Environmental indicators (land use, water footprint, and greenhouse gas emissions) were 40–60% lower for the feed and food of edible insects than for traditional animal livestock. More research is warranted on the edible insect dose responsible for health effects and on environmental indicators of edible insects for human nutrition. This research demonstrates how edible insects can be an alternative protein source not only to improve human and animal nutrition but also to exert positive effects on planetary health.