Dietary anthocyanins mitigate high-fat diet-induced hippocampal inflammation in mice.

BACKGROUND: Obesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls the responses to stress, downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation. OBJECTIVE: This work investigated if a dietary supplementation with a cyanidin- and delphinidin-rich extract (CDRE) could counteract HFD/obesity-induced hippocampal inflammation in mice. METHODS: C57BL/6J male mice were fed for 14 weeks either: i) a control diet containing 10% total calories from fat (C); ii) a HFD containing 60% total calories from fat (lard) (HF); iii) the HFD supplemented with 2, 20 or 40 mg AC/kg body weight (BW) (HFA2, HFA20, HFA40, respectively). In plasma and in the hippocampus, parameters of neuroinflammation and the underlying cause (endotoxemia) and consequences (alterations to the HPA and BDNF downregulation) were measured. RESULTS: Consumption of the HFD caused endotoxemia. Accordingly, hippocampal Tlr4 mRNA levels were 110% higher in the HF group, which were both prevented by CDRE supplementation. Consumption of the HFD also caused: i) microgliosis and increased expression of genes involved in neuroinflammation, i.e. Iba-1, Nox4, Tnfɑ, and Il-1ß, ii) alterations of HPA axis regulation, i.e. low expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors; and iii) decreased Bdnf expression. Supplementation of HFD-fed mice with CDRE mitigated neuroinflammation, microgliosis, and MR and BDNF decreases. CONCLUSION: CDRE supplementation mitigates the negative effects associated with HFD consumption and obesity in mouse hippocampus, in part by decreasing inflammation, improving glucocorticoid metabolism, and upregulating BDNF.

Risk factors and prognostic value of endotoxemia in patients with acute myocardial infarction.

Background: There is increasing evidence regarding the association between endotoxemia and the pathogenesis of atherosclerosis and myocardial infarction (MI). During the acute phase of MI, endotoxemia might increase inflammation and drive adverse cardiovascular (CV) outcomes. We aimed to explore the risk factors and prognostic value of endotoxemia in patients admitted for acute MI. Methods: Patients admitted to the coronary care unit of Dijon University Hospital for type 1 acute MI between 2013 and 2015 were included. Endotoxemia, assessed by plasma lipopolysaccharide (LPS) concentration, was measured by mass spectrometry. Major adverse CV events were recorded in the year following hospital admission. Results: Data from 245 consecutive MI patients were analyzed. LPS concentration at admission markedly increased with age and diabetes. High LPS concentration was correlated with metabolic biomarkers (glycemia, triglyceride, and total cholesterol) but not with CV (troponin Ic peak and N-terminal pro-brain natriuretic peptide) or inflammatory biomarkers (C-reactive protein, IL6, IL8, and TNFα). LPS concentration was not associated with in-hospital or 1-year outcomes. Conclusions: In patients admitted for MI, higher levels of endotoxins were related to pre-existing conditions rather than acute clinical severity. Therefore, endotoxins measured on the day of MI could reflect metabolic chronic endotoxemia rather than MI-related acute gut translocation.

Gut barrier dysfunction, endotoxemia and inflammatory response in STEMI patients and effect of primary PCI.

BACKGROUND: Gut-derived bacterial and endotoxin translocation induce systemic inflammation, which exerts a pivotal pathogenetic role in all phases of atherosclerosis. OBJECTIVES: To investigate prospectively the gut barrier function, endotoxin translocation and inflammatory response in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary artery intervention (PPCI). METHODS: Twenty-seven patients with STEMI that underwent successful PPCI were subjected to peripheral blood sampling at 3-time points; before PPCI (day0), 24 h (day1) and 96 h (day4) after PPCI and were compared with 20 chronic coronary syndrome (CCS) patients and 11 healthy controls. Serum ZO-1, I-FABP and endotoxin concentrations were determined by ELISA. Concentrations of cytokines IL-1ß, -6, -8, -10 and TNF-α were determined by flow cytometry. RESULTS: Patients with STEMI before PPCI (day0) had increased serum ZO-1 and endotoxin, both at significantly higher levels compared to CCS patients. STEMI induced also significant increases of the cytokines IL-6, -8 and -10. After PPCI, a significant improvement of gut barrier integrity (ZO-1) and endotoxemia was observed from the first day. At day4 post PPCI, systemic endotoxin and cytokines IL-6, -8 and -10 levels were reduced to control levels. Serum ZO-1 levels were positively correlated with systemic IL-10 concentrations (r = 0.471). CONCLUSION: STEMI is associated with gut barrier dysfunction, systemic endotoxemia and inflammatory response, which improve rapidly following successful PPCI.

Metabolic Endotoxemia: From the Gut to Neurodegeneration.

Metabolic endotoxemia is a severe health problem for residents in developed countries who follow a Western diet, disrupting intestinal microbiota and the whole organism's homeostasis. Although the effect of endotoxin on the human immune system is well known, its long-term impact on the human body, lasting many months or even years, is unknown. This is due to the difficulty of conducting in vitro and in vivo studies on the prolonged effect of endotoxin on the central nervous system. In this article, based on the available literature, we traced the path of endotoxin from the intestines to the blood through the intestinal epithelium and factors promoting the development of metabolic endotoxemia. The presence of endotoxin in the bloodstream and the inflammation it induces may contribute to lowering the blood-brain barrier, potentially allowing its penetration into the central nervous system; although, the theory is still controversial. Microglia, guarding the central nervous system, are the first line of defense and respond to endotoxin with activation, which may contribute to the development of neurodegenerative diseases. We traced the pro-inflammatory role of endotoxin in neurodegenerative diseases and its impact on the epigenetic regulation of microglial phenotypes.

Gestationally administered RAS modulators reprogram endotoxic cardiovascular and inflammatory profiles in adult male offspring of preeclamptic rats.

Previous studies showed that preeclampsia (PE) amplifies cardiovascular dysfunction induced by endotoxemia in adult male, but not female, offspring. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of Nω-nitro-L-arginine methyl ester(L-NAME, a nitric oxide synthase inhibitor). Adult male offspring of PE mothers treated gestationally with angiotensin 1-7 (Ang1-7, angiotensin II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (peroxisome proliferator-activated receptor gamma, PPARγ, agonist), or combined losartan/pioglitazone were instrumented with femoral indwelling catheters and challenged intravenously with a 5-mg/kg dose of lipopolysaccharides (LPS, 5 mg/kg). LPS caused significant decreases in blood pressure (BP) and spectral index of overall heart rate variability and increases in heart rate and left ventricular contractility (dP/dtmax). These effects were mostly reduced to similar magnitudes by individual drug therapies. In offspring born to Ang1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Immunohistochemistry revealed that Ang1-7, but not losartan/pioglitazone, abolished the exaggerated increases in toll-like receptor 4 (TLR-4) expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla (RVLM). By contrast, the losartan/pioglitazone regimen, but not Ang1-7, decreased and increased angiotensin converting enzyme (ACE) and ACE2 expression, respectively. Together, gestational fetal reprogramming of Ang II (depression) and Ang1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult male offspring of PE rats.

PI3K/AKT and STAT3 pathways mediate the neuroprotective effect of dasatinib from acute cerebral injury in endotoxemic mice.

Background and purpose: Sepsis induces brain dysfunction and there is still a requirement for an unemployed viable restorative approach. This study aimed to investigate the role of dasatinib in the modulation of proinflammatory mediators, attenuating neuroinflammatory response, and it's signaling pathway during endotoxemia. Experimental approach: Twenty-four adult male Swiss-albino mice were randomized into four groups: sham (undergo laparotomy without cecal ligation and puncture, sepsis (laparotomy with cecal ligation and puncture), vehicle-dimethyl sulfoxide, dasatinib (20 mg/kg/day) intraperitoneally. Brain tissue used for assessment of interleukin (IL)-6, IL-1ß, tumor necrosis factor-alpha (TNF-α), IL-10, Toll-like receptor 4 (TLR4), protein kinase B (AKT), phosphoinositide 3-kinases (PI3K), signal transducer and activator of transcription 3 (STAT3), and histopathological examination. Findings/Results: Brain tissue levels of TNF-α, IL-6, and IL1 ß were higher in the sepsis group than in the sham and vehicle groups. The dasatinib group had considerably lower tissue levels of these markers and significantly higher tissue values of IL-10 than the sepsis and vehicle groups. The sham group had much lower tissue values of TLR4, AKT, STAT3, and PI3k than in sepsis and vehicle groups. Furthermore, tissue levels of these markers in the dasatinib group were considerably lower than those in the sepsis and vehicle groups. Histopathology demonstrated that dasatinib might considerably reduce brain damage and the intensity of neuroinflammation when compared to sepsis and vehicle groups that showed extensive brain inflammation and damage. Conclusion and implication: Dasatinib attenuated endotoxemia-induced acute brain damage in mice via modulating effects on TLR4, PI3K, AKT, and STAT3 downstream signaling pathways.

Impact of O-acetylation on chitin oligosaccharides modulating inflammatory responses in LPS-induced RAW264.7 cells and mice.

Chitin oligosaccharides have garnered significant attention due to their biological activities, particularly their immunomodulatory properties. However, O-acetylation in chemically preparing chitin oligosaccharides seems inevitable and leads to some uncertainty on the bioactivity of chitin oligosaccharides. In this study, an O-acetyl-free chitin oligosaccharides and three different O-acetylated chitin oligosaccharides with degree of polymerization ranging from 2 to 6 were prepared using ammonia hydrolysis, and their structures and detailed components were further characterized with FTIR, NMR and MS. Subsequently, the effects of O-acetylation on the immunomodulatory activity of chitin oligosaccharides were investigated in vitro and in vivo. The results suggested that the chitin oligosaccharides with O-acetylation exhibited better inflammatory inhibition than pure chitin oligosaccharides, significantly reducing the expression of inflammatory factors, such as IL-6 and iNOS, in the LPS-induced RAW264.7 macrophage. The chitin oligosaccharides with a degree of O-acetylation of 93 % was found to effectively alleviate LPS-induced endotoxemia in mice, including serum inflammation indices reduction and damage repairment of the intestinal liver, and kidney tissues.

Hepatic ketogenesis is not required for starvation adaptation in mice.

OBJECTIVE: In response to bacterial inflammation, anorexia of acute illness is protective and is associated with the induction of fasting metabolic programs such as ketogenesis. Forced feeding during the anorectic period induced by bacterial inflammation is associated with suppressed ketogenesis and increased mortality. As ketogenesis is considered essential in fasting adaptation, we sought to determine the role of ketogenesis in illness-induced anorexia. METHODS: A mouse model of inducible hepatic specific deletion of the rate limiting enzyme for ketogenesis (HMG-CoA synthase 2, Hmgcs2) was used to investigate the role of ketogenesis in endotoxemia, a model of bacterial inflammation, and in prolonged starvation. RESULTS: Mice deficient of hepatic Hmgcs2 failed to develop ketosis during endotoxemia and during prolonged fasting. Surprisingly, hepatic HMGCS2 deficiency and the lack of ketosis did not affect survival, glycemia, or body temperature in response to endotoxemia. Mice with hepatic ketogenic deficiency also did not exhibit any defects in starvation adaptation and were able to maintain blood glucose, body temperature, and lean mass compared to littermate wild-type controls. Mice with hepatic HMGCS2 deficiency exhibited higher levels of plasma acetate levels in response to fasting. CONCLUSIONS: Circulating hepatic-derived ketones do not provide protection against endotoxemia, suggesting that alternative mechanisms drive the increased mortality from forced feeding during illness-induced anorexia. Hepatic ketones are also dispensable for surviving prolonged starvation in the absence of inflammation. Our study challenges the notion that hepatic ketogenesis is required to maintain blood glucose and preserve lean mass during starvation, raising the possibility of extrahepatic ketogenesis and use of alternative fuels as potential means of metabolic compensation.

Links Between Adipose Tissue Gene Expression of Gut Leakage Markers, Circulating Levels, Anthropometrics, and Diet in Patients with Coronary Artery Disease.

Background: Recent studies suggest gut-derived lipopolysaccharide (LPS)-translocation to play a role in both systemic inflammation and in inflammatory adipose tissue. We aimed to investigate whether circulating LPS-related inflammatory markers and corresponding genetic expression in adipose tissue were associated with obesity, cardiometabolic risk factors, and dietary habits in patients with coronary artery disease. Methods: Patients (n=382) suffering a myocardial infarction 2-8 weeks prior to inclusion were enrolled in this cross-sectional study. Subcutaneous adipose tissue (SAT), taken from the gluteal region, and fasting blood samples were collected at inclusion for determination of genetic expression of LPS-binding protein (LBP), CD14, toll-like receptor 2 (TLR2), and TLR4 in SAT, and LPS, LBP, and soluble cluster of differentiation 14 (sCD14) in the circulation. All patients filled out a dietary registration form. Results: Patients (median age 74 years, 25% women), had a median body mass index (BMI) of 25.9 kg/m2. Circulating levels of LBP correlated to BMI (p=0.02), were significantly higher in overweight or obese (BMI≥25 kg/m2) compared to normal- or underweight patients (BMI<25 kg/m2), and were significantly elevated in patients with T2DM, hypertension, and MetS, compared to patients without (p≤0.04, all). In SAT, gene expression of CD14 and LBP correlated significantly to BMI (p≤0.001, both), and CD14 and TLR2 expressions were significantly higher in patients with T2DM and MetS compared to patients without (p≤0.001, both). Circulating and genetically expressed CD14 associated with use of n-3 PUFAs (p=0.008 and p=0.003, respectively). No other significant associations were found between the measured markers and dietary habits. Conclusion: In patients with established CAD, circulating levels of LBP and gene expression of CD14 and TLR2 in SAT were related to obesity, MetS, T2DM, and hypertension. This suggests that the LPS-LBP-CD14 inflammatory axis is activated in the chronic low-grade inflammation associated with cardiometabolic abnormalities, whereas no significant associations with dietary habits were observed.

Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes.

BACKGROUND: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. METHODS: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. RESULTS: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. CONCLUSIONS: These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.

Inhibiting the CB1 receptor in CIH-induced animal model alleviates colon injury.

Obstructive sleep apnea (OSA) can lead to intestinal injury, endotoxemia, and disturbance of intestinal flora. Additionally, as a crucial component of the endocannabinoid system, some studies have demonstrated that cannabinoid 1 (CB1) receptors are closely linked to the multiple organ dysfunction triggered by OSA. However, the role of the CB1 receptor in alleviating OSA-induced colon injury remains unclear. Here, through the construction of the OSA classic model, we found that the colon tissue of chronic intermittent hypoxia (CIH)-induced mice exhibited an overexpression of the CB1 receptor. The results of hematoxylin-eosin staining and transmission electron microscopy revealed that inhibition of the CB1 receptor could decrease the gap between the mucosa and muscularis mucosae, alleviate mitochondrial swelling, reduce microvilli shedding, and promote the recovery of tight junctions of CIH-induced mice. Furthermore, CB1 receptor inhibition reduced the levels of metabolic endotoxemia and inflammatory responses, exhibiting significant protective effects on the colon injury caused by CIH. At the molecular level, through western blotting and real-time polymerase chain reaction techniques, we found that inhibiting the CB1 receptor can significantly increase the expression of ZO-1 and Occludin proteins, which are closely related to the maintenance of intestinal mucosal barrier function. Through 16S rRNA high-throughput sequencing and short-chain fatty acid (SCFA) determination, we found that inhibition of the CB1 receptor increased the diversity of the microbial flora and controlled the makeup of intestinal flora. Moreover, butyric acid concentration and the amount of SCFA-producing bacteria, such as Ruminococcaceae and Lachnospiraceae, were both markedly elevated by CB1 receptor inhibition. The results of the spearman correlation study indicated that Lachnospiraceae showed a positive association with both ZO-1 and Occludin but was negatively correlated with the colon CB1 receptor, IL-1ß, and TNF-α. According to this study, we found that inhibiting CB1 receptor can improve CIH-induced colon injury by regulating gut microbiota, reducing mucosal damage and promoting tight junction recovery. KEY POINTS: •CIH leads to overexpression of CB1 receptor in colon tissue. •CIH causes intestinal flora disorder, intestinal mucosal damage, and disruption of tight junctions. •Inhibition of CB1 receptor can alleviate the colon injury caused by CIH through regulating the gut microbiota, reducing mucosal injury, and promoting tight junction recovery.

Nutritional and microbiota-based therapeutic interventions for alcohol-associated liver disease: From pathogenesis to therapeutic insights.

Alcohol-associated liver disease (ALD) manifests as a consequence of prolonged and excessive alcohol consumption. This disease is closely associated with the interplay between gut health and liver function, which can lead to complex pathophysiological changes in the body. This review offers a comprehensive exploration of ALD's multifaceted nature, with a keen focus on its pathogenesis and the potential of nutritional and microbiota-based therapies. Insights derived from diverse case studies are utilized to shed light on how interventions can rebalance the gut microbiome and enhance liver function in ALD patients. Furthermore, the feasibility of liver transplantation and stem cell therapy as ultimate measures for ALD has been discussed, with acknowledgment of the inherent risks and challenges accompanying them. ALD's complexity underscores the necessity for a thorough understanding of its etiology and progression to devise effective treatments that mitigate its profound impact on an individual's health.

Thrombomodulin Improves Cognitive Deficits in Heat-Stressed Mice.

BACKGROUND: Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed (HS) mice. METHODS: Adult male mice were exposed to HS (33°C for 2 hours daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble TM (1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide (LPS), high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were biochemically measured. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined. RESULTS: Compared with controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice. CONCLUSIONS: The findings suggest that HS can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. TM, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice.

Abnormalities of Coagulation and Fibrinolysis Assessed by Thromboelastometry in an Endotoxic Shock Model in Piglets Treated with Nitric Oxide and Hydrocortisone.

This is an animal model study to investigate changes in hemostasis during endotoxemic shock and to determine whether the combination of inhaled nitric oxide (iNO) + intravenous hydrocortisone had an effect on clot formation and fibrinolysis. iNO selectively decreases pulmonary artery pressure, without affecting cardiac index or systemic vascular resistance; however, the results of studies on the possible consequences of iNO administration on coagulation are inconsistent and require further research. Thirty-four piglets were included. Administering endotoxin caused severe hypodynamic shock. Half of the animals received iNO (30 ppm) + hydrocortisone, starting 3 h after endotoxin infusion and continuing to the end of the study. All animals developed coagulation disorders, manifested by a tendency to hypocoagulation; at the same time, fibrinolysis was impaired. Coagulation and fibrinolysis disorders persisted after endotoxin infusion was discontinued, with worse severity in the animals that died before the study was terminated. Administering iNO + hydrocortisone did not cause further changes in coagulation and fibrinolysis parameters, either during or after the endotoxin challenge, suggesting that potential therapeutic interventions with iNO to lower pulmonary arterial pressure will not affect hemostasis.

Obesity and polycystic ovary syndrome influence on intestinal permeability at fasting, and modify the effect of diverse macronutrients on the gut barrier.

Women with the extremely prevalent polycystic ovary syndromegather multiple cardiovascular risk factors and chronic subclinical inflammation. Interactions between diet, adiposity, and gut microbiota modulate intestinal permeabilityand bacterial product translocation, and may contribute to the chronic inflammation process associated with the polycystic ovary syndrome. In the present study, we aimed to address the effects of obesity, functional hyperandrogenism, and diverse oral macronutrients on intestinal permeabilityby measuring circulating markers of gut barrier dysfunction and endotoxemia. Participants included 17 non-hyperandrogenic control women, 17 women with polycystic ovary syndrome, and 19 men that were submitted to glucose, lipid, and protein oral loads. Lipopolysaccharide-binding protein, plasma soluble CD14, succinate, zonulin family peptide, and glucagon-like peptide-2 were determined at fasting and after oral challenges. Macronutrient challenges induced diverse changes on circulating intestinal permeabilitybiomarkers in the acute postprancial period, with lipids and proteins showing the most unfavorable and favorable effects, respectively. Particularly, lipopolysaccharide-binding protein, zonulin family peptide, and glucagon-like peptide-2 responses were deregulated by the presence of obesity after glucose and lipid challenges. Obese subjects showed higher fasting intestinal permeabilitybiomarkers levels than non-obese individuals, except for plasma soluble CD14. The polycystic ovary syndromeexacerbated the effect of obesity further increasing fasting glucagon-like peptide-2, lipopolysaccharide-binding protein, and succinate concentrations. We observed specific interactions of the polycystic ovary syndromewith obesity in the postprandial response of succinate, zonulin family peptide, and glucagon-like peptide-2. In summary, obesity and polycystic ovary syndromemodify the effect of diverse macronutrients on the gut barrier, and alsoinfluence intestinal permeabilityat fasting,contributing to the morbidity of functional hyperandrogenism by inducing endotoxemia and subclinical chronic inflammation.

Mogroside Alleviates Diabetes Mellitus and Modulates Intestinal Microflora in Type 2 Diabetic Mice.

Mogroside, the main component of Siraitia grosvenorii (Swingle) C. Jeffrey (Cucurbitaceae) is a natural product with hypoglycemic and intestinal microbiota regulating properties. However, whether the alteration of intestinal microbiota is associated with the antidiabetic effect of mogroside remains poorly understood. This study investigated the mechanism underlying the hypoglycemic effect of mogroside in regulating intestinal flora and attenuating metabolic endotoxemia. Kunming mice with type 2 diabetes mellitus (T2DM) induced by high-fat diet and intraperitoneal injection of streptozotocin were randomly divided into model, pioglitazone (2.57 mg/kg) and mogroside (200, 100, and 50 mg/kg) groups. After 28 d of administration, molecular changes related to glucose metabolism and metabolic endotoxemia in mice were evaluated. The levels of insulin receptor substrate-1 (IRS-1), cluster of differentiation 14 (CD14) and toll-like receptor 4 (TLR4) mRNAs were measured, and the composition of intestinal microflora was determined by 16s ribosomal DNA (rDNA) sequencing. The results showed that mogroside treatment significantly improved hepatic glucose metabolism in T2DM mice. More importantly, mogroside treatment considerably reduced plasma endotoxin (inhibition rate 65.93%, high-dose group) and inflammatory factor levels, with a concomitant decrease in CD14 and TLR4 mRNA levels. Moreover, mogroside treatment reduced the relative abundance of Firmicutes and Proteobacteria (the inhibition rate of Proteobacteria was 85.17% in the low-dose group) and increased the relative abundance of Bacteroidetes (growth rate up to 40.57%, high-dose group) in the intestines of diabetic mice. This study reveals that mogroside can relieve T2DM, regulating intestinal flora and improving intestinal mucosal barrier, indicating that mogroside can be a potential therapeutic agent or intestinal microbiota regulator in the treatment of T2DM.

Nucleolin myocardial-specific knockout exacerbates glucose metabolism disorder in endotoxemia-induced myocardial injury.

Background: Sepsis-induced myocardial injury, as one of the important complications of sepsis, can significantly increase the mortality of septic patients. Our previous study found that nucleolin affected mitochondrial function in energy synthesis and had a protective effect on septic cardiomyopathy in mice. During sepsis, glucose metabolism disorders aggravated myocardial injury and had a negative effect on septic patients. Objectives: We investigated whether nucleolin could regulate glucose metabolism during endotoxemia-induced myocardial injury. Methods: The study tested whether the nucleolin cardiac-specific knockout in the mice could affect glucose metabolism through untargeted metabolomics, and the results of metabolomics were verified experimentally in H9C2 cells. The ATP content, lactate production, and oxygen consumption rate (OCR) were evaluated. Results: The metabolomics results suggested that glycolytic products were increased in endotoxemia-induced myocardial injury, and that nucleolin myocardial-specific knockout altered oxidative phosphorylation-related pathways. The experiment data showed that TNF-α combined with LPS stimulation could increase the lactate content and the OCR values by about 25%, and decrease the ATP content by about 25%. However, interference with nucleolin expression could further decrease ATP content and OCR values by about 10-20% and partially increase the lactate level in the presence of TNF-α and LPS. However, nucleolin overexpression had the opposite protective effect, which partially reversed the decrease in ATP content and the increase in lactate level. Conclusion: Down-regulation of nucleolin can exacerbate glucose metabolism disorders in endotoxemia-induced myocardial injury. Improving glucose metabolism by regulating nucleolin was expected to provide new therapeutic ideas for patients with septic cardiomyopathy.

Dose-Dependent Effects of Lipopolysaccharide on the Endothelium-Sepsis versus Metabolic Endotoxemia-Induced Cellular Senescence.

The endothelium, the innermost cell layer of blood vessels, is not only a physical barrier between the bloodstream and the surrounding tissues but has also essential functions in vascular homeostasis. Therefore, it is not surprising that endothelial dysfunction is associated with most cardiovascular diseases. The functionality of the endothelium is compromised by endotoxemia, the presence of bacterial endotoxins in the bloodstream with the main endotoxin lipopolysaccharide (LPS). Therefore, this review will focus on the effects of LPS on the endothelium. Depending on the LPS concentration, the outcomes are either sepsis or, at lower concentrations, so-called low-dose or metabolic endotoxemia. Sepsis, a life-threatening condition evoked by hyperactivation of the immune response, includes breakdown of the endothelial barrier resulting in failure of multiple organs. A deeper understanding of the underlying mechanisms in the endothelium might help pave the way to new therapeutic options in sepsis treatment to prevent endothelial leakage and fatal septic shock. Low-dose endotoxemia or metabolic endotoxemia results in chronic inflammation leading to endothelial cell senescence, which entails endothelial dysfunction and thus plays a critical role in cardiovascular diseases. The identification of compounds counteracting senescence induction in endothelial cells might therefore help in delaying the onset or progression of age-related pathologies. Interestingly, two natural plant-derived substances, caffeine and curcumin, have shown potential in preventing endothelial cell senescence.

Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis.

Background: Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation. Methods: A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1+ and GFAP+ cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of ptgs2 and chac1; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated. Conclusion: The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.

Periodontitis, Dental Procedures, and Young-Onset Cryptogenic Stroke.

Periodontitis is associated with an increased risk of ischemic stroke, and the risk may be particularly high among young people with unexplained stroke etiology. Thus, we investigated in a case-control study whether periodontitis or recent invasive dental treatments are associated with young-onset cryptogenic ischemic stroke (CIS). We enrolled participants from a multicenter case-control SECRETO study including adults aged 18 to 49 y presenting with an imaging-positive first-ever CIS and stroke-free age- and sex-matched controls. Thorough clinical and radiographic oral examination was performed. Furthermore, we measured serum lipopolysaccharide (LPS) and lipotechoic acid (LTA) levels. Multivariate conditional regression models were adjusted for stroke risk factors, regular dentist visits, and patent foramen ovale (PFO) status. We enrolled 146 case-control pairs (median age 41.9 y; 58.2% males). Periodontitis was diagnosed in 27.5% of CIS patients and 20.1% of controls (P < 0.001). In the fully adjusted models, CIS was associated with high periodontal inflammation burden (odds ratio [OR], 95% confidence interval) with an OR of 10.48 (3.18-34.5) and severe periodontitis with an OR of 7.48 (1.24-44.9). Stroke severity increased with the severity of periodontitis, having an OR of 6.43 (1.87-23.0) in stage III to IV, grade C. Invasive dental treatments performed within 3 mo prestroke were associated with CIS, with an OR of 2.54 (1.01-6.39). Association between CIS and invasive dental treatments was especially strong among those with PFO showing an OR of 6.26 (1.72-40.2). LPS/LTA did not differ between CIS patients and controls but displayed an increasing trend with periodontitis severity. Periodontitis and recent invasive dental procedures were associated with CIS after controlling for multiple confounders. However, the role of bacteremia as a mediator of this risk was not confirmed.