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Purpose: To date, the relationship between systemic inflammation and muscle changes observed by ultrasonography in septic patients in clinical studies is not known. Furthermore, the role of vitamin D on muscle changes in these patients needs to be investigated., Materials and Methods: Forty-five patients admitted to the ICU due to severe sepsis or septic shock. Blood samples were collected to evaluate systemic inflammation (interleukin (IL)-10, IL-1β, IL-1α, IL-6, IL-8 and tumor necrosis factor-α(TNF-α)) and vitamin D. Muscle mass was evaluated by ultrasound during hospitalization. Clinical tests of muscle strength (Medical Research Council (MRC) scale and handgrip) were performed after the awakening of patients., Results: There was a reduction in day 2 values to hospital discharge on TNF-alpha, IL-8, IL-6 and IL-10 (p < .05). The muscle mass showed a significant decline from day 6 of the ICU. After awakening, the patients had a significant increase in muscle strength (p < .05). There was a positive association between muscle mass variation (day 2 - ICU) with absolute values of IL-8 (r = 0.38 p = .05). For muscle strength, there was a negative association between handgrip strength with IL-8 (r = -0.36 p < .05) on ICU discharge. The vitamin D showed a positive association with the handgrip strength of the day 1 of the awakening (r = 0.51 p < .05)., Conclusions: In septic patients, there is an association between inflammation and changes in muscle mass and strength during ICU stay, which is similar to those observed in experimental studies. In addition, there was an association of vitamin D with recovery of muscle strength during hospitalization., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The cholinergic anti-inflammatory pathway controls the inflammatory response and nonreflexive consciousness through bidirectional communication between the brain and immune system. Moreover, brain acetylcholinesterase activity may have a role in regulating the vagus nerve in this pathway. Thus, we analyzed the role of acetylcholine (ACh) in the inflammatory response 15 days after induction of sepsis by cecal ligation and puncture (CLP). Balb/c mice were pretreated with or without donepezil (5 mg/kg/day, orally) 7 days before CLP, and mice homozygous for vesicular ACh transporter (VAChT) knockdown (KD) were subjected to CLP. All animals were sacrificed 15 days after CLP, and the plasma, spleen, and hippocampus were collected. Characterization of splenic lymphocytes and cytokine levels in the plasma, spleen, and hippocampus was determined. Our results showed a splenomegaly in group CLP. The numbers of cytotoxic T cells, helper T cells, regulatory T cells, B cells, and Th17 cells differed between mice subjected to CLP and to sham operation in both untreated and donepezil-treated groups. In VAChT-KD mice, CLP resulted in decreased cytotoxic and helper T cells and increased in Th17 cells compared with the sham. Additionally, in VAChT-KD mice, the levels of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, were increased following CLP. Thus, we concluded that ACh affected the inflammatory response at 15 days after CLP since stimulation of cholinergic transmission increased the proliferation of lymphocytes, including regulatory T cells, in association with a lower inflammatory profile and VAChT-KD decreased the number of lymphocytes and increased inflammation.

Circulating dipeptidyl peptidase IV (DPPIV) activity correlates with cardiac dysfunction in humans and experimental heart failure (HF) models. Similarly, inflammatory markers are associated with poorer outcomes in HF patients. However, the contributions of DPPIV to inflammation in HF remain elusive. Therefore, this study aimed to investigate whether the cardioprotective effects of DPPIV inhibition after myocardial injury are accompanied by reduced cardiac inflammation, whether circulating DPPIV activity correlates with the levels of systemic inflammatory markers in HF patients, and whether leukocytes and/or splenocytes may be one of the sources of circulating DPPIV in HF. Experimental HF was induced in male Wistar rats by left ventricular myocardial injury after radiofrequency catheter ablation. The rats were divided into three groups: sham, HF, and HF + DPPIV inhibitor (sitagliptin). Six weeks after surgery, cardiac function, perfusion and inflammatory status were evaluated. Sitagliptin treatment improved cardiac function and perfusion, reduced macrophage infiltration, and diminished the levels of inflammatory biomarkers including TNF-α, IL-1β, and CCL2. In HF patients, serum DPPIV activity correlated with CCL2, suggesting that leukocytes may be the source of circulating DPPIV in HF. Unexpectedly, DPPIV release was higher in splenocytes from HF rats and similar in HF circulating mononuclear cells compared with those from sham, suggesting an organ-specific modulation of DPPIV in HF. Collectively, our data provide new evidence that the cardioprotective effects of DPPIV inhibition in HF may be due to suppression of inflammatory cytokines. Moreover, they suggest that a vicious circle between DPPIV and inflammation may contribute to HF development and progression., (Copyright © 2016 the American Physiological Society.)

Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases.

Inflammation is powerful response to destroy invading organisms, and an exaggerated response can lead to death of the host. Macrophages secrete mediators that activated circulating neutrophils leading to its migration into infectious site. Recently, it has been shown that lymphocytes have an action modulating the early phase of inflammatory response. In this article, we analyze the role of B1 in the inflammatory response of different origins and finally focus attention on sepsis. B lymphocyte deficiency has been linked to acute infection presumably owing to the lack of an adaptive immune response to effectively clear pathogens. Individuals with X-linked agammaglobulinemia (XLA) present B1 lymphocyte deficiency caused by mutations in the Bruton tyrosine kinase (Btk). Some data show that B1 cells might contribute to susceptibility in experimental paracoccidioidomycosis. On the other hand, B1 cells are shown to be detrimental in other mouse models of microbial infection, such as experimental Chagas disease, leishmaniasis, and Staphylococcus aureus-induced arthritis. B1 cell plays a protective role in the host of the effects of endotoxemia. In a murine model of endotoxemia by lipopolysaccharide, B1 cell participates in both interleukin 10 and immunoglobulin M secretion with a consequent reduction in mortality.

Lipid emulsion (LE) containing medium/ω-6 long chain triglyceride-based emulsion (MCT/ω-6 LCT LE) has been recommended in the place of ω-6 LCT-based emulsion to prevent impairment of immune function. The impact of MCT/ω-6 LCT LE on lymphocyte and neutrophil death and expression of genes related to inflammation was investigated. Seven volunteers were recruited and infusion of MCT/ω-6 LCT LE was performed for 6 h. Four volunteers received saline and no change was found. Blood samples were collected before, immediately afterwards and 18 h after LE infusion. Lymphocytes and neutrophils were studied immediately after isolation and after 24 and 48 h in culture. The following determinations were carried out: plasma-free fatty acids, triacylglycerol and cholesterol concentrations, plasma fatty acid composition, neutral lipid accumulation in lymphocytes and neutrophils, signs of lymphocyte and neutrophil death and lymphocyte expression of genes related to inflammation. MCT/ω-6 LCT LE induced lymphocyte and neutrophil death. The mechanism for MCT/ω-6 LCT LE-dependent induction of leucocyte death may involve changes in neutral lipid content and modulation of expression of genes related to cell death, proteolysis, cell signalling, inflammatory response, oxidative stress and transcription., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

Sepsis syndrome is caused by inappropriate immune activation due to bacteria and bacterial components released during infection. This syndrome is the leading cause of death in intensive care units. Specialized B-lymphocytes located in the peritoneal and pleural cavities are known as B-1 cells. These cells produce IgM and IL-10, both of which are potent regulators of cell-mediated immunity. It has been suggested that B-1 cells modulate the systemic inflammatory response in sepsis. In this study, we conducted in vitro and in vivo experiments in order to investigate a putative role of B-1 cells in a murine model of LPS-induced sepsis. Macrophages and B-1 cells were studied in monocultures and in co-cultures. The B-1 cells produced the anti-inflammatory cytokine IL-10 in response to LPS. In the B-1 cell-macrophage co-cultures, production of proinflammatory mediators (TNF-α, IL-6 and nitrite) was lower than in the macrophage monocultures, whereas that of IL-10 was higher in the co-cultures. Co-culture of B-1 IL-10(-/-) cells and macrophages did not reduce the production of the proinflammatory mediators (TNF-α, IL-6 and nitrite). After LPS injection, the mortality rate was higher among Balb/Xid mice, which are B-1 cell deficient, than among wild-type mice (65.0% vs. 0.0%). The Balb/Xid mice also presented a proinflammatory profile of TNF-α, IL-6 and nitrite, as well as lower levels of IL-10. In the early phase of LPS stimulation, B-1 cells modulate the macrophage inflammatory response, and the main molecular pathway of that modulation is based on IL-10-mediated intracellular signaling., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Shock and resuscitation render patients more susceptible to acute lung injury due to an exacerbated immune response to subsequent inflammatory stimuli. To study the role of innate immunity in this situation, we investigated acute lung injury in an experimental model of ischemia-reperfusion (I-R) followed by an early challenge with live bacteria. Conscious rats (N = 8 in each group) were submitted to controlled hemorrhage and resuscitated with isotonic saline (SS, 0.9% NaCl) or hypertonic saline (HS, 7.5% NaCl) solution, followed by intratracheal or intraperitoneal inoculation of Escherichia coli. After infection, toll-like receptor (TLR) 2 and 4 mRNA expression was monitored by RT-PCR in infected tissues. Plasma levels of tumor necrosis factor alpha and interleukins 6 and 10 were determined by ELISA. All animals showed similar hemodynamic variables, with mean arterial pressure decreasing to nearly 40 mmHg after bleeding. HS or SS used as resuscitation fluid yielded equal hemodynamic results. Intratracheal E. coli inoculation per se induced a marked neutrophil infiltration in septa and inside the alveoli, while intraperitoneal inoculation-associated neutrophils and edema were restricted to the interseptal space. Previous I-R enhanced lung neutrophil infiltration upon bacterial challenge when SS was used as reperfusion fluid, whereas neutrophil influx was unchanged in HS-treated animals. No difference in TLR expression or cytokine secretion was detected between groups receiving HS or SS. We conclude that HS is effective in reducing the early inflammatory response to infection after I-R, and that this phenomenon is achieved by modulation of factors other than expression of innate immunity components.

Mice expressing human cholesteryl ester transfer protein (huCETP) are more resistant to Escherichia coli bacterial wall LPS because death rates 5 days after intraperitoneal inoculation of LPS were higher in wild-type than in huCETP+/+ mice, whereas all huCETP+/+ mice remained alive. After LPS inoculation, plasma concentrations of TNF-alpha and IL-6 increased less in huCETP+/+ than in wild-type mice. LPS in vitro elicited lower TNF-alpha production by CETP expressing than by wild-type macrophages. In addition, TNF-alpha production by RAW 264.7 murine macrophages increased on incubation with LPS but decreased in a dose-dependent manner when human CETP was added to the medium. Human CETP in vitro enhanced the LPS binding to plasma high-density lipoprotein/low-density lipoprotein. The liver uptake of intravenous infused 14C-LPS from Salmonella typhimurium was greater in huCETP+/+ than in wild-type mice. Present data indicate for the first time that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators.

Background: Morbidly obese patients frequently display asymptomatic chronic activation of acute phase response, with potentially adverse metabolic and cardiovascular consequences. Nutritional preparations to improve this phenomenon have rarely been administered. Aiming to investigate the supplementation of flaxseed flour, a source of omega-3 fatty acids, a prospective randomized double-blind cross-over study was designed., Methods: Outpatient obese subjects (n=41) were clinically and biochemically screened, and results for 24 randomized subjects are shown. Age was 40.8 +/- 11.6 years (83.3% females) and body mass index (BMI) was 47.1 +/- 7.2 kg/m2. Flaxseed flour (Farinha de Linhaca Dourada LinoLive, Cisbra, Brazil) in the amount of 30 g/day (5 g of alpha-linolenic acid - omega-3) and an equal mass of placebo (manioc flour) were administered for 2 weeks each. Variables included general biochemical investigation, white blood cell count (WBC), C-reactive protein (CRP), serum amyloid A (SAA) and fibronectin., Results: No intolerance was registered. Body weight and general biochemical indices remained stable. Initial CRP and SAA were elevated (13.7 +/- 9.9 and 17.4 +/- 8.0 ). WBC (8100 +/- 2100/mm3) and fibronectin (463.2 +/- 61.3 mg/dL) were acceptable but in the upper normal range. Corresponding findings after supplementation of flaxseed were 10.6 +/- 6.2 mg/L, 14.3 +/- 9.2 mg/L, 7300 +/- 1800/mm3 and 412.8 +/- 38.6 respectively (P<0.05). No change during the control period regarding baseline occurred when placebo was randomized to be given first; however, when it followed omega-3 supplementation, CRP and SAA recovered, whereas WBC and fibronection remained depressed during those 2 weeks (7500 +/- 2100/mm3 and 393.2 +/- 75.8 mg/dL, P<0.05)., Conclusions: 1) Various inflammatory markers were elevated in the studied population, although not necessarily exceeding the normal range; 2) Significant reduction could be demonstrated; 3) Some persistent effects of flaxseed supplement 2 weeks after discontinuation were observed.

Flagellin is a recently identified bacterial product that elicits immune response via toll-like receptor 5. Here, we demonstrate that flagellin is an extraordinarily potent proinflammatory stimulus in the lung during sepsis. In vitro, flagellin triggers the production of interleukin (IL)-8 by human lung epithelial (A549) cells, with 50% of the maximal response obtained at a concentration of 2 x 10(-14) M. Flagellin also induces the expression of ICAM-1 in vitro. Intravenous administration of flagellin to mice elicited a severe acute lung inflammation that was significantly more pronounced than following lipopolysaccharide (LPS) administration. Flagellin induced a local release of proinflammatory cytokines, the accumulation of inflammatory cells, and the development of pulmonary hyperpermeability. These effects were associated with the nuclear translocation of the transcription NF-kappaB in the lung. Flagellin remained active in inducing pulmonary inflammation at doses as low as 10 ng/mouse. In the plasma of patients with sepsis, flagellin levels amounted to 7.1 +/- 0.1 ng/mL. Plasma flagellin levels showed a significant positive correlation with the lung injury score, with the alveolar-arterial oxygen difference as well as with the duration of the sepsis. Flagellin emerges as a potent trigger of acute respiratory complications in gram-negative bacterial sepsis.

Inosine is a naturally occurring purine formed from the breakdown of adenosine. Here we have evaluated the effects of inosine in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice subjected to CLP were treated with either inosine (100 mg/kg, intraperitoneally) or vehicle 1 h before and 6 h after CLP. After 12 h tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-10 were measured in plasma. Biochemical markers of organ damage, liver NAD+/NADH (indicator of the mitochondrial redox state), plasma nitrate, tissue myeloperoxidase (MPO, indicator of neutrophil accumulation) and malondialdehyde (MDA, indicator of lipid peroxidation), liver and lung chemokines (macrophage inflammatory protein 1alpha [MIP-1alpha] and MIP-2), and ex vivo vascular reactivity in aortic rings were also measured. Mice treated with inosine had significantly lower levels of circulating cytokines. Organ damage was significantly reduced by inosine treatment, which was associated at the tissue level with an increased hepatic NAD+/NADH ratio, decreased MPO activity in the lung, reduced MDA formation in the gut and liver, and decreased MIP-1alpha and MIP-2 in the lung and liver. Furthermore, inosine significantly improved endothelium-dependent relaxant responses of aortic rings. These effects were associated with significant improvement of the survival of CLP mice treated with inosine, an effect that was still observed when inosine treatment was delayed 1 h after CLP, especially when it was associated with appropriate antibiotic treatment. Thus, inosine reduced systemic inflammation, organ damage, tissue dysoxia, and vascular dysfunction, resulting in improved survival in septic shock.

Abstract: Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory mediators that protect against acute inflammation. Current evidence suggests that BMMNC transplantation can reduce acute tissue injury caused by systemic inflammation and lung dysfunction. This study evaluated the role of BMMNCs in reducing systemic inflammatory responses to vascular endothelial injury in sepsis. Bone marrow cells were harvested from the tibias and femurs of 12-week-old male Wistar rats; BMMNCs were separated by density centrifugation. Additional rats underwent cecal ligation and puncture (CLP) or similar sham surgery. BMMNCs were injected intravenously 30 min after CLP. The Sham and CLP Control groups were administered PBS. The 7-day survival rate improved markedly in the CLP-BMMNC group compared with that in the Control group. BMMNCs markedly suppressed the serum levels of pro-inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and histone H3 at 3, 6, and 12 h after CLP. In the CLP-BMMNC group, the serum levels of syndecan-1, the main component of the vascular endothelial glycocalyx layer, were notably lower than those in the Control group 6 h after CLP. Histological analysis revealed improvement of morphological damages in the CLP-BMMNC group. Ultrastructural analysis revealed that the glycocalyx structure was maintained and the continuity of the vascular endothelial glycocalyx layer was preserved in the BMMNC group, compared with the case for the Control group at 6 and 12 h. Therefore, BMMNC transplantation may provide reduced systemic inflammation and endothelial glycocalyx damage, dramatically improving the survival of rats. These findings provide insights into formulating potential therapeutic strategies against sepsis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Sepsis is defined as a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection, characterized by a systemic inflammatory response to infection. The use of antibiotics, fluid resuscitation, and organ support therapy has limited prognostic benefit in patients with sepsis, and its incidence is not diminishing, which is attracting increased attention in medicine. Sepsis remains one of the most debilitating and expensive illnesses. One of the main reasons of septic mortality is now understood to be disruption of immune homeostasis. Immunotherapy is revolutionizing the treatment of illnesses in which dysregulated immune responses play a significant role. This "trained immunity", which is a potent defense against infection regardless of the type of bacteria, fungus, or virus, is attributed to the discovery that the innate immune cells possess immune memory via metabolic and epigenetic reprogramming. Here we reviewed the immunotherapy of innate immune cells in sepsis, the features of trained immunity, and the relationship between trained immunity and sepsis. [ABSTRACT FROM AUTHOR]

Chorioamnionitis is a common antecedent of preterm birth and induces inflammation and oxidative stress in the fetal lungs. Reducing inflammation and oxidative stress in the fetal lungs may improve respiratory outcomes in preterm infants. Creatine is an organic acid with known anti-inflammatory and antioxidant properties. The objective of the study was to evaluate the efficacy of direct fetal creatine supplementation to reduce inflammation and oxidative stress in fetal lungs arising from an in utero proinflammatory stimulus. Fetal lambs (n = 51) were instrumented at 90 days gestation to receive a continuous infusion of creatine monohydrate (6 mg·kg-1 ·h-1) or saline for 17 days. Maternal chorioamnionitis was induced with intra-amniotic lipopolysaccharide (LPS; 1 mg, O55:H6) or saline 7 days before delivery at 110 days gestation. Tissue creatine content was assessed with capillary electrophoresis, and inflammatory markers were analyzed with Luminex Magpix and immunohistochemistry. Oxidative stress was measured as the level of protein thiol oxidation. The effects of LPS and creatine were analyzed using a two-way ANOVA. Fetal creatine supplementation increased lung creatine content by 149% (PCr < 0.0001) and had no adverse effects on lung morphology. LPS-exposed groups showed increased levels of interleukin-8 in the bronchoalveolar lavage (PLPS < 0.0001) and increased levels of CD45 þ leukocytes (PLPS < 0.0001) and MPO þ (PLPS < 0.0001) cells in the lung parenchyma. Creatine supplementation significantly reduced the levels of CD45 þ (PCr = 0.045) and MPO þ cells (PCr = 0.012) in the lungs and reduced thiol oxidation in plasma (PCr < 0.01) and lung tissue (PCr = 0.02). In conclusion, fetal creatine supplementation reduced markers of inflammation and oxidative stress in the fetal lungs arising from chorioamnionitis.NEW & NOTEWORTHY We evaluated the effect of antenatal creatine supplementation to reduce pulmonary inflammation and oxidative stress in the fetal lamb lungs arising from lipopolysaccharide (LPS)-induced chorioamnionitis. Fetal creatine supplementation increased lung creatine content and had no adverse effects on systemic fetal physiology and overall lung architecture. Importantly, fetuses that received creatine had significantly lower levels of inflammation and oxidative stress in the lungs, suggesting an anti-inflammatory and antioxidant benefit of creatine. [ABSTRACT FROM AUTHOR]

Background: Diabetic foot ulcer (DFU) is a severe complication that occurs in patients with diabetes and is a primary factor that necessitates amputation. Therefore, the occurrence and progression of DFU must be predicted at an early stage to improve patient prognosis and outcomes. In this regard, emerging evidence suggests that inflammation-related markers play a significant role in DFU. One such potential marker, the monocyte-lymphocyte ratio (MLR), has not been extensively studied in relation to DFU. This study aimed to define a connection between MLR and DFU. Methods: A cross-sectional study was conducted using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004. DFU was defined based on survey questionnaires assessing the presence of nonhealing ulcers in the lower extremities for more than 4 weeks in diabetes patients. The MLR was calculated as the ratio of the monocyte count to the lymphocyte count, which was directly obtained from laboratory data files. Logistic regression analysis was performed to assess the relationship between the MLR and DFU. Stratified analysis according to age, sex, body mass index, blood glucose, hemoglobin, and glycated hemoglobin categories was conducted, and multiple imputations were applied to missing data. Results: In total, 1246 participants were included; the prevalence of DFU was 9.4% (117/1246). A multivariable regression model revealed a significant association between DFU and a 0.1 unit increase in MLR after adjusting for all covariates (adjusted odds ratio=1.16, 95% confidence interval: 1.02-1.33). Subgroup analyses revealed consistent findings regarding the impact of MLR on the presence of DFU (p > 0.05). Conclusion: MLR is significantly associated with DFU in diabetes patients, and can be used as one of the indicators for predicting the occurrence of DFU. MLR assessment may be a valuable component in the follow-up of patients with diabetes. [ABSTRACT FROM AUTHOR]

Sepsis is a major life-threatening syndrome of organ dysfunction caused by a dysregulated host response due to infection. Dysregulated immunometabolism is fundamental to the onset of sepsis. Particularly, short-chain fatty acids (SCFAs) are gut microbes derived metabolites serving to drive the communication between gut microbes and the immune system, thereby exerting a profound influence on the pathophysiology of sepsis. Protein post-translational modifications (PTMs) have emerged as key players in shaping protein function, offering novel insights into the intricate connections between metabolism and phenotype regulation that characterize sepsis. Accumulating evidence from recent studies suggests that SCFAs can mediate various PTM-dependent mechanisms, modulating protein activity and influencing cellular signaling events in sepsis. This comprehensive review discusses the roles of SCFAs metabolism in sepsis associated inflammatory and immunosuppressive disorders while highlights recent advancements in SCFAs-mediated lysine acylation modifications, such as substrate supplement and enzyme regulation, which may provide new pharmacological targets for the treatment of sepsis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Polybrominated biphenyls (PBB) and polychlorinated biphenyls (PCB) are persistent organic pollutants with potential endocrine-disrupting effects linked to adverse health outcomes. OBJECTIVES: In this study, we utilize high-resolution metabolomics (HRM) to identify internal exposure and biological responses underlying PCB and multigenerational PBB exposure for participants enrolled in the Michigan PBB Registry. METHODS: HRM profiling was conducted on plasma samples collected from 2013 to 2014 from a subset of participants enrolled in the Michigan PBB Registry, including 369 directly exposed individuals (F0) who were alive when PBB mixtures were accidentally introduced into the food chain and 129 participants exposed to PBB in utero or through breastfeeding, if applicable (F1). Metabolome-wide association studies were performed for PBB- 153 separately for each generation and ΣPCB (PCB-118, PCB-138, PCB-153, and PCB-180) in the two generations combined, as both had direct PCB exposure. Metabolite and metabolic pathway alterations were evaluated following a well-established untargeted HRM workflow. RESULTS: Mean levels were 1.75 ng/mL [standard deviation (SD). 13.9] for PBB-153 and 1.04 ng/mL (SD. 0.788) for ΣPCB. Sixty-two and 26 metabolic features were significantly associated with PBB-153 in F0 and F1 [false discovery rate (FDR) 푝<0.2], respectively. There were 2,861 features associated with ΣPCB (FDR 푝<0.2). Metabolic pathway enrichment analysis using a bioinformatics tool revealed perturbations associated with ΣPCB in numerous oxidative stress and inflammation pathways (e.g., carnitine shuttle, glycosphingolipid, and vitamin B9 metabolism). Metabolic perturbations associated with PBB-153 in F0 were related to oxidative stress (e.g., pentose phosphate and vitamin C metabolism) and in F1 were related to energy production (e.g., pyrimidine, amino sugars, and lysine metabolism). Using authentic chemical standards, we confirmed the chemical identity of 29 metabolites associated with ΣPCB levels (level 1 evidence). CONCLUSIONS: Our results demonstrate that serum PBB-153 is associated with alterations in inflammation and oxidative stress-related pathways, which differed when stratified by generation. We also found that ΣPCB was associated with the downregulation of important neurotransmitters, serotonin, and 4-aminobutanoate. These findings provide novel insights for future investigations of molecular mechanisms underlying PBB and PCB exposure on health. [ABSTRACT FROM AUTHOR]

Cytokine Storm Syndrome (CSs) is a potentially life threatening condition, characterized by robust elevated; of circulating pro-inflammatory cytokines; occurring after a hyperactive immune system. Is a well-known as a worldwide health problem, leading to multi-organ failure and death. Objectives: This study was carried out to investigate the protective role and probability of additive or synergistic anti-inflammatory activity; of ramelteon and in combination with dexamethasone on the lipopolysaccharide (LPS) induced "Cytokine Storm" on mice model and its potential regulatory mechanism(s). Methods: Sixty Swiss albino male mice of; (25 ± 5 grams; 8-12 weeks) had free access to food and water. After 2 weeks of adaptation, mice; randomly separated in five groups (n = 12): Group I, mice received (0.9% N/S i.p.); Group II, mice received (5 mg/kg i.p.) LPS only. Group III, mice received (2.5 mg/kg, i.p.) dexamethasone, Group IV, mice received (100 mg/kg i.p.) ramelteon, Group V, mice received half dose of dexamethasone+ ramelteon combination (1.25 mg/kg i.p +50 mg/kg i.p). For systematic inflammatory stimulation mimicking "cytokine storm" LPS; E. coli O55:B5 (5 mg/kg i.p.) was induced within one hr. After 48 h the effects of interventional agents and vehicle or LPS challenge; on lung, heart, liver, kidney histopathological changes, and levels of inflammatory cytokines: (IL-6, IL8, IL-1β, and TNF-α) in the serum were detected. Results: IL-1β, IL-6, IL8 and TNF-α elevated serum levels significantly reduced (P < 0.001) in all treatment group. Additionally, they ameliorated the histopathological changes induced by (LPS) and improving macroscopic scores (P < 0.001). Conclusion: In conclusion, ramelteon treatment had a diverse protective effects against "Cytokine Storm" with a mechanism based on attenuation serum levels of inflammatory cytokines (IL-1β, IL-6, IL-8 and TNF-α) and through reduction of histopathological damage during endotoxemia induced via LPS challenge on male mice model. RAM/DEX combination had superior advantage than an agent use alone probably via synergistic anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Purpose of Review: To provide a review of emerging literature describing the impact of diet on the respiratory response to air pollution in asthma. Recent Findings: Asthma phenotyping (observable characteristics) and endotyping (mechanistic pathways) have increased the specificity of diagnostic and treatment pathways and opened the doors to the identification of subphenotypes with enhanced susceptibility to exposures and interventions. Mechanisms underlying the airway immune response to air pollution are still being defined but include oxidative stress, inflammation, and activation of adaptive and innate immune responses, with genetic susceptibility highlighted. Of these, neutrophil recruitment and activation appear prominent; however, understanding neutrophil function in response to pollutant exposures is a research gap. Diet may play a role in asthma pathogenesis and morbidity; therefore, diet modification is a potential target opportunity to protect against pollutant-induced lung injury. In particular, in vivo and in vitro data suggest the potential for diet to modify the inflammatory response in the airways, including impacts on neutrophil recruitment and function. Murine models provide compelling results in regard to the potential for dietary components (including fiber, antioxidants, and omega-3 fatty acids) to buffer against the inflammatory response to air pollution in the lung. Summary: Precision lifestyle approaches to asthma management and respiratory protection in the context of air pollution exposures may evolve to include diet, pending the results of further epidemiologic and causal investigation and with neutrophil recruitment and activation as a candidate mechanism. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI), manifested as strong pulmonary inflammation and alveolar epithelial damage, is a life-threatening disease with high morbidity and mortality. Small extracellular vesicles (sEVs), secreted by multiple types of cells, are critical cellular communication mediators and can inhibit inflammation by transferring bioactive molecules, such as microRNAs (miRNAs). Thus, we hypothesized that sEVs derived from mesenchymal stromal cells (MSC sEVs) could transfer miRNAs to attenuate inflammation of lung epithelial cells during ALI. Methods: C57BL/6 male mice were intratracheally administered LPS (10 mg/kg). Six hours later, the mice were randomly administered with MSC sEVs (40 µg per mouse in 150 µl of saline), which were collected by ultracentrifugation. Control group received saline administration. After 48 h, the mice were sacrificed to evaluate pulmonary microvascular permeability and inflammatory responses. In vitro, A549 cells and primary human small airway epithelial cells (SAECs) were stimulated with LPS with or without MSC sEVs treatment. Results: In vitro, MSC sEVs could also inhibit the inflammation induced by LPS in A549 cells and SAECs (reducing TNF-α, IL-1β, IL-6 and MCP-1). Moreover, MSC sEV treatment improved the survival rate, alleviated pulmonary microvascular permeability, and inhibited proinflammatory responses (reducing TNF-α, IL-1β, IL-6 and JE-1) in ALI mice. Notably, miR-223-3p was found to be served as a critical mediator in MSC sEV-induced regulatory effects through inhibition of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) in lung epithelial cells. Conclusions: Overall, these findings suggest that MSC sEVs may offer a novel promising strategy for ALI. [ABSTRACT FROM AUTHOR]

Diet is an important determinant of health and consequently is often implicated in the development of disease, particularly gastrointestinal (GI) diseases, given the high prevalence of meal-related symptoms. The mechanisms underlying diet-driven pathophysiology are not well understood, but recent studies suggest that gut microbiota may mediate the effect of diet on GI physiology. In this review, we focus primarily on two distinct GI diseases where the role of diet has been best studied: irritable bowel syndrome and inflammatory bowel disease. We discuss how the concurrent and sequential utilization of dietary nutrients by the host and gut microbiota determines the eventual bioactive metabolite profiles in the gut and the biological effect of these metabolites on GI physiology. We highlight several concepts that can be gleaned from these findings, such as how distinct effects of an individual metabolite can influence diverse GI diseases, the effect of similar dietary interventions on multiple disease states, and the need for extensive phenotyping and data collection to help make personalized diet recommendations. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM. [ABSTRACT FROM AUTHOR]

Livestock workers experience an increased burden of bioaerosol-induced respiratory disease including a high prevalence of rhinosinusitis. Dairy operations generate bioaerosols spanning the inhalable size fraction (0–100 μm) containing bacterial constituents such as endotoxin. Particles with an aerodynamic diameter between 10 and 100 μm are known to deposit in the nasopharyngeal region and likely affect the upper respiratory tract. We evaluated the effectiveness of a hypertonic saline nasal lavage in reducing inflammatory responses in dairy workers from a high-volume dairy operation. Inhalable personal breathing zone samples and pre-/post-shift nasal lavage samples from each participant over five consecutive days were collected. The treatment group (n = 5) received hypertonic saline while the control group (n = 5) received normotonic saline. Personal breathing zone samples were analyzed for particulate concentrations and endotoxin using gravimetric and enzymatic methods, respectively. Pro- and anti-inflammatory cytokines (i.e., IL-8, IL-10, and TNF-α) were measured from nasal lavage samples using a multiplex assay. Inhalable dust concentrations ranged from 0.15 to 1.9 mg/m3. Concentrations of both pro- and anti-inflammatory cytokines, specifically IL-6, IL-8, and IL-10, were significantly higher in the treatment group compared to the control group (p < 0.02, p < 0.04, and p < 0.01, respectively). Further analysis of IL-10 anti-inflammatory indicates a positive association between hypertonic saline administration and IL-10 production. This pilot study demonstrates that hypertonic saline nasal lavages were successful in upregulating anti-inflammatory cytokines to support larger interventional studies. [ABSTRACT FROM AUTHOR]

Introduction: It is important to control both inflammation and immunosuppression after severe insults, such as sepsis, trauma, and surgery. Endotoxin tolerance is one of the immunosuppressive conditions and it has been known that endotoxin tolerance relates to poorer clinical outcomes in patients with severe insults. This study investigated whether whey protein hydrolysate (WPH) mitigates inflammation and endotoxin tolerance in THP‐1 human monocytic leukemia cells. Methods: Endotoxin tolerance can be experimentally reproduced by two consecutive stimulations with lipopolysaccharide (LPS). THP‐1 cells were incubated with LPS and WPH (first stimulation). After collecting the culture supernatant to evaluate the effect on inflammation, the cells were washed and restimulated by 100 ng/ml LPS (second stimulation). The culture supernatant was again collected to evaluate the effect on endotoxin tolerance. Concentrations of LPS and WPH in the first stimulation were adjusted to evaluate their dose dependency. Cytokine levels in the supernatant were determined by enzyme‐linked immunosorbent assay. Statistical analysis was performed using the student's t‐test or Dunnett's test. Results: Five mg/ml WPH significantly decreased interleukin (IL)‐6 (p =.006) and IL‐10 (p <.001) levels after the first LPS stimulation (1000 ng/ml). WPH significantly increased tumor necrosis factor‐alpha (p <.001) and IL‐10 (p =.014) levels after the second LPS stimulation. The suppressive effect of WPH on inflammation and endotoxin tolerance was dependent on the concentrations of LPS and WPH. The effective dose of WPH for endotoxin tolerance was lower than its effective dose for inflammation. Conclusion: WPH mitigated both inflammation and endotoxin tolerance. Therefore, WPH might be a candidate for valuable food ingredients to control both inflammation and immunosuppression after severe insults. [ABSTRACT FROM AUTHOR]

The rapid and widespread global pandemic of 2019 coronavirus disease (COVID-19) has had unprecedented negative health and economic impacts. Immune responses play a key role in the development of COVID-19, including the disruption of immune balance and cytokine storms caused by excessive inflammatory responses. Due to the effects of cancer itself and treatment, patients often accompanied by immunosuppression appear to be a susceptible population for COVID-19. Worryingly, COVID-19 with cancer is associated with a poor prognosis. Cancer patients are a vulnerable group, threatened by COVID-19, finding a way to combat COVID-19 for them is urgent. Immunonutrition is closely related to balance and strong immune function. Supplementary immunonutrition can improve the immune function and inflammatory response of cancer patients after surgery, which provides evidence for the role of immunonutrition in combating COVID-19. We reviewed possible mechanisms of immunonutrition against COVID-19, including enhancing immune cell function, increasing immune cell count, ameliorating excessive inflammatory response, and regulating gut microbiota. Immunonutrition supplementation in cancer patients may be beneficial to enhance immune function in the early stage of COVID-19 infection and control excessive inflammatory response in the late stage. Therefore, immunonutrition is a potential strategy for the prevention and treatment of COVID-19 in cancer. [ABSTRACT FROM AUTHOR]

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Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD. [ABSTRACT FROM AUTHOR]

Key points: The costs associated with immune and thermal responses may exceed the benefits to the host during severe inflammation. In this case, regulated hypothermia instead of fever can occur in rodents as a beneficial strategy to conserve energy for vital functions with consequent tissue protection and hypoxia prevention.We tested the hypothesis that this phenomenon is not exclusive to mammals, but extends to the other endothermic group, birds.A decrease in metabolic rate without any failure in mitochondrial respiration, nor oxygen delivery, is the main evidence supporting the regulated nature of endotoxin‐induced hypothermia in chicks.Thermolytic mechanisms such as tachypnea and cutaneous vasodilatation can also be recruited to facilitate body temperature decrease under lipopolysaccharide treatment, especially in the cold.Our findings bring a new perspective for evolutionary medicine studies on energy trade‐off in host defence because regulated hypothermia may be a phenomenon spread among vertebrates facing a severe immune challenge. A switch from fever to regulated hypothermia can occur in mammals under circumstances of reduced physiological fitness (e.g. sepsis) to direct energy to defend vital systems. Birds in which the cost to resist a pathogen is additive to the highest metabolic rate and body temperature (Tb) among vertebrates may also benefit from regulated hypothermia during systemic inflammation. Here, we show that the decrease in Tb observed during an immune challenge in birds is a regulated hypothermia, and not a result of metabolic failure. We investigated O2 consumption (thermogenesis index), ventilation (respiratory heat loss), skin temperature (sensible heat loss) and muscle mitochondrial respiration (thermogenic tissue) during Tb fall in chicken chicks challenged with endotoxin [lipopolysaccharide (LPS)]. Chicks injected with LPS were also tested regarding the capacity to raise O2 consumption to meet an increased demand driven by 2,4‐dinitrophenol. LPS decreased Tb and the metabolic rate of chicks without affecting muscle uncoupled, coupled and non‐coupled mitochondrial respiration. LPS‐challenged chicks were indeed capable of increasing metabolic rate in response to 2,4‐dinitrophenol, indicating no O2 delivery limitation. Additionally, chicks did not attempt to prevent Tb from falling during hypothermia but, instead, activated cutaneous and respiratory thermolytic mechanisms, providing an additional cooling force. These data provide the first evidence of the regulated nature of the hypothermic response to endotoxin in birds. Therefore, it changes the current understanding of bird's thermoregulation during severe inflammation, indicating that regulated hypothermia is either a convergent trait for endotherms or a conserved response among vertebrates, which adds a new perspective for evolutionary medicine research. Key points: The costs associated with immune and thermal responses may exceed the benefits to the host during severe inflammation. In this case, regulated hypothermia instead of fever can occur in rodents as a beneficial strategy to conserve energy for vital functions with consequent tissue protection and hypoxia prevention.We tested the hypothesis that this phenomenon is not exclusive to mammals, but extends to the other endothermic group, birds.A decrease in metabolic rate without any failure in mitochondrial respiration, nor oxygen delivery, is the main evidence supporting the regulated nature of endotoxin‐induced hypothermia in chicks.Thermolytic mechanisms such as tachypnea and cutaneous vasodilatation can also be recruited to facilitate body temperature decrease under lipopolysaccharide treatment, especially in the cold.Our findings bring a new perspective for evolutionary medicine studies on energy trade‐off in host defence because regulated hypothermia may be a phenomenon spread among vertebrates facing a severe immune challenge. [ABSTRACT FROM AUTHOR]

Sepsis is not only a threat to the health of individual patients but also presents a serious epidemiological problem. Despite intensive research, modern sepsis therapy remains based primarily on antimicrobial treatment and supporting the functions of failing organs. Finding a cure for sepsis represents a great and as yet unfulfilled need in modern medicine. Research results indicate that the activity of poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) may play an important role in the inflammatory response and the cellular metabolic disorders found in sepsis. Mechanisms by which PARP-1 may contribute to inflammation and metabolic disorders include effects on the regulation of gene expression, impaired metabolism, cell death, and the release of alarmins. These findings suggest that inhibition of this enzyme may be a promising solution for the treatment of sepsis. In studies using experimental sepsis models, inhibition of PARP-1 has been shown to ameliorate the inflammatory response and increase survival. This action was described, among others, for olaparib, a PARP-1 inhibitor approved for use in oncology. While the results of current research are promising, the use of PARP inhibitors in non-oncological diseases raises some concerns, mainly related to the enzyme's role in deoxyribonucleic acid (DNA) repair. However, the results of studies on experimental models indicate the effectiveness of even short-term PARP-1 inhibition and do not confirm concerns regarding its impact on the integrity of nuclear DNA. Current research presents PARP inhibition as a potential solution for the treatment of sepsis and indicates the need for further research. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) has been demonstrated to be linked to atrial fibrillation (AF). However, the underlying mechanisms of the DM-associated increase in AF susceptibility and the potential effects of DM on atrial remodeling remain unclear. Methods and Results: Twenty-five C57BL/6 mice were randomly assigned to the normal/control group (Con, n=10) and model group (n=15). Mice in the model group were administered a high-fat diet combined with multiple injections of low-dose streptozocin (STZ) (35 mg/kg). Eleven mice were ultimately included in DM group. Left atrial tissue structural and inflammatory alterations were assessed. In our study, the atrial weights of DM mice were markedly heavier than those of mice in the Con group. DM mice exhibited significantly increased fasting plasma glucose, fasting insulin, and dyslipidaemia. Furthermore, H&E and Masson's staining revealed broadened interstitial spaces, myocyte disarray and atrial fibrosis in DM mice. The expression levels of the atrial inflammation-associated factor nuclear factor κB (NF-κB) and its pathway were significantly altered in the atria of DM mice. Conclusion: DM could induce atrial structural remodeling and inflammation in mice. [ABSTRACT FROM AUTHOR]

Following infection with Mycobacterium tuberculosis , the causative agent of tuberculosis (TB), most human hosts are able to contain the infection and avoid progression to active TB disease through expression of a balanced, homeostatic immune response. Proinflammatory mechanisms aiming to kill, slow and sequester the pathogen are key to a successful host response. However, an excessive or inappropriate pro-inflammatory response may lead to granuloma enlargement and tissue damage, which may prolong the TB treatment duration and permanently diminish the lung function of TB survivors. The host also expresses certain anti-inflammatory mediators which may play either beneficial or detrimental roles depending on the timing of their deployment. The balance between the timing and expression levels of pro- and anti-inflammatory responses plays an important role in the fate of infection. Interestingly, M. tuberculosis appears to manipulate both sides of the human immune response to remodel the host environment for its own benefit. Consequently, therapies which modulate either end of this spectrum of immune responses at the appropriate time may have the potential to improve the treatment of TB or to reduce the formation of permanent lung damage after microbiological cure. Here, we highlight host-directed TB therapies targeting pro- or anti-inflammatory processes that have been evaluated in pre-clinical models. The repurposing of already available drugs known to modulate these responses may improve the future of TB therapy. [ABSTRACT FROM AUTHOR]

Sepsis is well known to cause a high patient death rate (up to 50%) during the intensive care unit (ICU) stay. In addition, sepsis survival patients also exhibit a very high death rate after hospital discharge compared to patients with any other disease. The addressed question is then: why septic patients remain ill after hospital discharge? The cellular and molecular mechanisms involved in the high rate of septic patient deaths are still unknown. We described herein the studies that investigated the percentage of septic patients that died after hospital discharge ranging from 90 days up to 5 years. We also reported the symptoms of septic patients after hospital discharge and the development of the recently called post-sepsis syndrome (PSS). The most common symptoms of the PSS are cognitive disabilities, physical functioning decline, difficulties in performing routine daily activities, and poor life quality. The PSS also associates with quite often reinfection and re-hospitalization. This condition is the cause of the high rate of death mentioned above. We reported the proportion of patients dying after hospital discharge up to 5 years of followed up and the PSS symptoms associated. The authors also discuss the possible cellular and metabolic reprogramming mechanisms related with the low survival of septic patients and the occurrence of PSS. [ABSTRACT FROM AUTHOR]

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)–specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD. [ABSTRACT FROM AUTHOR]

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI. [ABSTRACT FROM AUTHOR]

Sepsis is a whole-body inflammation and main cause of death in intensive care units worldwide. We aimed to investigate the roles of lncRNA MIAT and miR-330-5p in modulating inflammatory responses and oxidative stress in lipopolysachariden (LPS)-induced septic cardiomyopathy. Serum and heart tissue were collected from in vivo septic mice model, ELISA and qRT-PCR were used to measure the expression of pro-inflammation cytokines, MIAT and miR-330-5p, respectively. The knockdown of MIAT and overexpression of miR-330-5p were conducted to assess their effects on regulating inflammation response and intracellular oxidative stress in LPS-stimulated HL-1 cells. The reactive oxygen (ROS) level, mitochondrial membrane potential (MMP), GSH/GSSH ratio, and lipid peroxidation assessment (MDA) were used to evaluate the intracellular oxidative stress. Dual-luciferase reporter assay was performed to identify the association between MIAT and miR-330-5p, TRAF6 and miR-330-5p, respectively. In septic mice, the expression of MIAT and pro-inflammation cytokines was elevated while the expression of miR-330-5p decreased. Knockdown of MIAT or overexpression of miR-330-5p restrained inflammation and oxidative stress induced by LPS in vitro; MIAT directly targeted miR-330-5p to regulate NF-κB signaling, and miR-330-5p targeted against TRAF6 to suppress the activation of NF-κB signaling. We determined that lncRNA MIAT directly binds to miR-330-5p to activate TRAF6/NF-κB signaling axis and further promotes inflammation response as well as oxidative stress in LPS-induced septic cardiomyopathy. This finding suggests the potential therapeutic role of lncRNA MIAT and miR-330-5p in LPS-induced myocardial injury. [ABSTRACT FROM AUTHOR]

Introduction: Peripheral administration of lipopolysaccharide (LPS), can cause production of cytokines in the brain and subsequently impair learning and memory function. Carvacrol is a phenolic monoterpene that is found in the essential oils of the Lamiaceae family. Anti-inflammatory and antioxidant activities of carvacrol have been demonstrated in previous studies. The aim of the current study was to evaluate the effects of carvacrol on spatial learning performances in LPS-treated rats. Methods: Male Wistar rats were pretreated with carvacrol at doses of 10, 25 and 50mg/kg for a week. Then, the animals received LPS injection (1mg/kg, ip) and treatments continued for 3 more weeks. Spatial learning performances were assessed in rats by the Morris water maze from post-injection days 18 to 21. Biochemical assays (interleukine-1β, lipid peroxidation and total thiol levels) were performed in the hippocampus and cerebral cortex at the end of the experiment. Results: LPS-treated rats displayed higher escape latency and longer traveled distance as compared to control rats. In addition, chronic treatment of LPS-treated rats with carvacrol at a dose of 25mg/kg significantly decreased escape latency and traveled distance as compared to untreated-LPS rats. Biochemical assessments showed no significant difference in inflammatory and oxidative stress markers levels among the groups. Conclusion: Our findings demonstrated that chronic treatment with carvacrol improves spatial learning performances in LPS-treated rats. This might be due to antioxidant, anti-inflammatory and anticholinesterase activities of carvacrol in early LPS challenge. [ABSTRACT FROM AUTHOR]

Background: Dysregulated inflammatory response is common cause of organ damage in critical care patients. Preconditioning/tolerance is a strategy to prevent exacerbated inflammation. The aim of this study is to analyze hypertonic saline 7.5% as a potential inducer of preconditioning that protect from a lethal dose of LPS and modulates systemic inflammatory profile in mice. Methods: Male Balb/C mice received intravenous (i.v.) injections of Hypertonic solution (NaCl 7.5%) (0.8 ml) for 3 days, on day 8th was challenged with LPS 15 mg/kg. Controls with Saline 0.9%, urea and sorbitol were performed. Microarray of mRNA expression was analyzed from HS versus saline from macrophages to identified the pathways activated by HS. Results: HS preconditioning reduced mortality after LPS injection as well reduced the cytokines release in plasma of the animals challenged by LPS. In order to check how HS induces a preconditioning state we measured plasma cytokines after each HS infusion. Repeated HS injections induced a state of preconditioning that reprograms the inflammatory response, resulting in reduced inflammatory cytokine production. A microarray of mRNA demonstrated that Hypertonic solution increased the expression of several genes in special Mapkbp1 and Atf3. Conclusion: hypertonic solution induces preconditioning/tolerance reducing mortality and inflammatory response after LPS challenge. [ABSTRACT FROM AUTHOR]

Respiratory infection can be exacerbated by the high glucose concentration in the airway surface liquid (ASL). We investigated the effects of salbutamol and phlorizin on the pulmonary function, oxidative stress levels and SGLT1 activity in lung, pulmonary histopathological damages and survival rates of rats with sepsis. Sepsis was induced by cecal ligation and puncture surgery (CLP). Twenty-four hours after surgery, CLP rats were intranasally treated with saline, salbutamol or phlorizin. After 2 hours, animals were anesthetized and sacrificed. Sepsis promoted atelectasis and bronchial inflammation, and led to increased expression of SGLT1 on cytoplasm of pneumocytes. Salbutamol treatment reduced bronchial inflammation and promoted hyperinsuflation in CLP rats. The interferon-ɤ and Interleucin-1β concentrations in bronchoalveolar lavage (BAL) were closely related to the bronchial inflammation regulation. Salbutamol stimulated SGLT1 in plasma membrane; whereas, phlorizin promoted the increase of SGLT1 in cytoplasm. Phlorizin reduced catalase activity and induced a significant decrease in the survival rate of CLP rats. Taken together, sepsis promoted atelectasis and lung inflammation, which can be associated with SGLT1 inhibition. The loss of function of SGLT1 by phlorizin are related to the augmented disease severity, increased atelectasis, bronchial inflammation and a significant reduction of survival rate of CLP rats. Alternatively salbutamol reduced BAL inflammatory cytokines, bronchial inflammation, atelectasis, and airway damage in sepsis. These data suggest that this selective β2-adrenergic agonist may protect lung of septic acute effects. [ABSTRACT FROM AUTHOR]

Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW & NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis. [ABSTRACT FROM AUTHOR]

Background: Hospitalisation is associated with adverse health outcomes including loss of muscle strength, muscle mass and functional decline, which might be further aggravated by acute inflammation. This study aimed to determine whether acute inflammation, as denoted by C-reactive protein (CRP), is associated with muscle strength, muscle mass and functional dependency in hospitalised older patients. Methods: The observational, prospective EMPOWER study included 378 hospitalised patients aged 70 years and older. As part of the hospital assessment, 191 patients (50.5%) had CRP measured. Muscle strength and mass were measured using handheld dynamometry and bioelectrical impedance analysis respectively. Activities of Daily Living (ADL) were assessed using Katz score and Instrumental ADL (IADL) by Lawton and Brody score. Linear regression analyses and logistic regression analyses were performed stratified by sex and adjusted for age and comorbidities. Results: Mean age was 79.7 years (SD 6.4) and 50.8% were males. On admission and discharge, males with elevated CRP had significantly lower handgrip strength and lower absolute muscle mass compared with males with normal CRP and those with no CRP measured. At three months post-discharge, males with elevated CRP were more likely to be ADL dependent than those with normal CRP and with no CRP measured. In females, no associations were found between CRP and muscle strength, muscle mass, ADL or IADL. Conclusions: Hospitalised older male patients with acute inflammation had lower muscle strength at admission and discharge and lower absolute muscle mass at admission and higher ADL dependency at three months post-discharge. [ABSTRACT FROM AUTHOR]

A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model. [ABSTRACT FROM AUTHOR]

Several risk factors have been described for the pathogenesis of atherosclerosis. Infectious diseases are suggested to be a causative factor, and some viruses have been studied for their relation with atherosclerotic diseases. Studies report two hypotheses, direct and indirect effects, for the role of viral infections in atherogenesis. Viruses are able to initiate atherosclerosis by two different pathways. They can exert their direct effects on atherogenesis by infecting vascular cells and then inducing inflammation in the endothelium and smooth muscle cells. Alternatively, they can also apply indirect effects by infecting non-vascular cells and inducing systemic inflammation. In this review, we consider the available data about the effects and correlations of DNA and RNA viruses on atherosclerosis. [ABSTRACT FROM AUTHOR]

Circulating neutrophils, rapidly recruited in response to microbial infection, form the first line in host defense. Humans express ~50 chemokines, of which a subset of seven chemokines, characterized by the conserved "Glu-Leu-Arg" motif, mediate neutrophil recruitment. Neutrophil-activating chemokines (NACs) share similar structures, exist as monomers and dimers, activate the CXCR2 receptor on neutrophils, and interact with tissue glycosaminoglycans (GAGs). Considering cellular assays have shown that NACs have similar CXCR2 activity, the question has been and remains, why do humans express so many NACs? In this review, we make the case that NACs are not redundant and that distinct GAG interactions determine chemokine-specific in vivo functions. Structural studies have shown that the GAG-binding interactions of NACs are distinctly different, and that conserved and specific residues in the context of structure determine geometries that could not have been predicted from sequences alone. Animal studies indicate recruitment profiles of monomers and dimers are distinctly different, monomer–dimer equilibrium regulates recruitment, and that recruitment profiles vary between chemokines and between tissues, providing evidence that GAG interactions orchestrate neutrophil recruitment. We propose in vivo GAG interactions impact several chemokine properties including gradients and lifetime, and that these interactions fine-tune and define the functional response of each chemokine that can vary between different cell and tissue types for successful resolution of inflammation. [ABSTRACT FROM AUTHOR]

Systemic inflammation triggered by lipopolysaccharide (LPS) administration disrupts blood-brain barrier (BBB) homeostasis in animal models. This event leads to increased susceptibility of several encephalic structures to potential neurotoxicants present in the bloodstream. In this study, we investigated the effects of alternate intraperitoneal injections of LPS on BBB permeability, social recognition memory and biochemical parameters in the striatum 24 h and 60 days after treatments. In addition, we investigated whether the exposure to a moderate neurotoxic dose of the herbicide paraquat could potentiate LPS-induced neurotoxicity. LPS administration caused a transient disruption of BBB integrity, evidenced by increased levels of exogenously administered sodium fluorescein in the striatum. Also, LPS exposure caused delayed impairment in social recognition memory (evaluated at day 38 after treatments) and increase in the striatal levels of 3-nitrotyrosine. These events were observed in the absence of significant changes in motor coordination and in the levels of tyrosine hydroxylase (TH) in the striatum and substantia nigra. PQ exposure, which caused a long-lasting decrease of striatal mitochondrial complex I activity, did not modify LPS-induced behavioral and striatal biochemical changes. The results indicate that systemic administration of LPS causes delayed social recognition memory deficit and striatal nitrosative stress in adult mice and that the coexposure to a moderately toxic dose of PQ did not magnify these events. In addition, PQ-induced inhibition of striatal mitochondrial complex I was also not magnified by LPS exposure, indicating the absence of synergic neurotoxic effects of LPS and PQ in this experimental model. [ABSTRACT FROM AUTHOR]

Sepsis is defined as life-threatening organ dysfunction induced by a disrupted host response to infecting pathogens. Evidences suggest that oxidative stress is intrinsically related to sepsis progression. Dimethyl fumarate (DMF) is a novel oral therapeutic agent with anti-oxidant properties which exerts protective effects through activation of nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2). Thus, the aim of this study is to evaluate the effect of DMF in different organs of rats submitted to an animal model of sepsis. Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) procedure and sham-operated rats was considered control group. The experimental groups were divided into sham + vehicle, sham + DMF, sham + NAC, CLP + vehicle, CLP + DMF, and CLP + NAC. Rats were treated by oral gavage with DMF immediately after and 12 h after surgery, or NAC (s.c.) at 3, 6, and 12 h after surgery. Twenty-four hours after sepsis induction, neutrophil infiltration, nitrite/nitrate concentrations, oxidative damage to lipids and proteins, superoxide dismutase (SOD), and catalase (CAT) activities were evaluated in the heart, liver, lung, and kidney. Septic animals presented increased neutrophil infiltration, NO metabolism, oxidative damage to lipids and proteins, and decreases of SOD and CAT activities, mainly in the heart, liver, and lung, while DMF-treated animals showed significant reduction in neutrophil infiltration, NO metabolism, and oxidative damage followed by increased SOD and CAT activities. DMF is effective in preventing oxidative stress and inflammation in rats 24 h after sepsis induction. [ABSTRACT FROM AUTHOR]

To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0-20 µg⋅kg-1⋅h-1) or intracerebroventricularly (0-1 µg⋅kg-1⋅h-1). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in vitro experiments to investigate whether an action of leptin on macrophages could parallel our in vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a proinflammatory effect but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted. [ABSTRACT FROM AUTHOR]

Background: Activation of dendritic cells (DCs) is necessary to initiate immune responses. Angiotensin II (Ang II) has been reported to have a proinflammatory and immunomodulatory function. However, the role of Ang II in regulation of DCs and the underlying mechanisms remain illdefined. Methods: The effects of Ang II on the proliferation, maturation, phagocytosis, migration, and communication with T cells of DCs were analysed utilizing MTT, flow cytometry, ELISA, transwell assay and mixed lymphocyte culture. Results: We found that Ang II treatment significantly inhibited proliferation and phagocytic activity of DCs, but promoted the DC maturation and migration well as the expression of pro-inflammatory cytokines by DCs. In addition, Ang II also stimulated DC-mediated T cell proliferation. These effects were associated with activation of p65/NF-κB, ERK1/2 and STAT1 signaling pathways in DCs. Conclusions: Our results demonstrate that Ang II activates DCs partially through p65/NF-κB, ERK1/2 and STAT1 pathways, and suggest a potential therapeutic target of DC-mediated inflammatory disorders. [ABSTRACT FROM AUTHOR]

The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation--contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation--contraction coupling as Ca2+ is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca2+ release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs. [ABSTRACT FROM AUTHOR]