Search Results (303)

Background: Severe sepsis and septic shock remain major contributors to ICU mortality. Polymyxin B hemoperfusion (PMX-HP) has been widely adopted as adjunctive therapy in Asian ICUs for endotoxemia, but its real-world effectiveness and prognostic factors remain uncertain, especially in high Gram-negative settings. Methods: This retrospective cohort study included 64 adult patients with severe sepsis or septic shock who received at least one session of PMX-HP in a 25-bed tertiary medical ICU in Taiwan between July 2013 and December 2019. Demographic, clinical, microbiological, and treatment data were extracted. The primary outcome was 28-day mortality. Prognostic factors were analyzed using logistic regression. Results: The mean age was 66.1 ± 12.3 years; 67.2% were male. Pneumonia (29.7%) and intra-abdominal infection (18.8%) were the most common sources of sepsis, with E. coli and K. pneumoniae as leading pathogens. Median APACHE II score at ICU admission was 26 (IQR 21–32), and 79.7% received two PMX-HP sessions. The 28-day mortality rate was 46.9%, with ICU and hospital mortality both 53.1%. Non-survivors were older, had higher APACHE II scores, and more frequent use of continuous renal replacement therapy (CRRT). Positive changes in vasoactive-inotropic score (VIS) after PMX-HP were also more common among non-survivors. Multivariate analysis identified advanced age, higher APACHE II score, and CRRT requirement as independent predictors of mortality. Conclusions: In this real-world Asian ICU cohort, PMX-HP was used mainly for severe cases with a high disease burden and Gram-negative predominance. Despite its frequent use, overall mortality remained high. Prognosis was primarily determined by underlying disease severity, organ dysfunction (especially renal failure), and persistent hemodynamic instability. In this high-severity cohort, mortality appeared to be primarily driven by baseline organ dysfunction and persistent hemodynamic instability; PMX-HP session number or sequencing showed no association with survival. Given the absence of a contemporaneous non-PMX-HP control group, mortality observations in this cohort cannot be causally attributed to PMX-HP and should be interpreted with caution as hypothesis-generating rather than definitive evidence of efficacy. Further multicenter studies are needed to clarify the optimal role of PMX-HP in modern sepsis management. Full article

Endotoxemia is commonly observed in donkeys, secondary to colic, pleuropneumonia, or diarrhea among other disorders. Hematologic ratios are new biomarkers widely used in the diagnosis and prognosis of multiple conditions in human medicine, including sepsis. While the utility of these ratios has been proved in septic foals, no data are available on donkeys. Moreover, reference intervals (RIs) have not been studied in this species. In this study, RIs of the most commonly reported hematologic ratios were determined in 73 healthy adult donkeys. In addition, variations in these ratios in response to LPS infusion were also evaluated in six healthy adult donkeys. Most of the ratios evaluated showed significant variations after induced endotoxemia, with most of them showing values outside of the established RIs. Similarly to septic foals, the neutrophil to lymphocyte ratio was significantly reduced after LPS infusion. No significant changes were observed in the red cell distribution width to platelet ratio, contrary to reports on septic foals. Previously reported cut-off values for both of these ratios should not be extrapolated to donkeys. Future studies evaluating these ratios in natural endotoxemia or other diseases in donkeys, as well as establishing species-specific cut-off values, are necessary. Full article

Background: Obese women have a significantly higher risk of bearing breast tumors that are resistant to therapies and are associated with poorer prognoses/treatment outcomes. Breast cancer-promoting action of obesity is often attributed to elevated levels of insulin, glucose, inflammatory mediators, and misbalanced estrogen production in adipose tissue under obese conditions. Metabolic endotoxemia, characterized by chronic presence of extremely low levels of bacterial endotoxin (lipopolysaccharide [LPS]) in the circulation, is a less explored obesity-associated factor. Results: Here, utilizing in vitro and in vivo models of breast carcinoma (BC), we report that subclinical levels of LPS typical for metabolic endotoxemia enhance the malignant phenotype of breast cancer cells and accelerate breast tumor progression. Conclusions: Our study, while focusing primarily on the direct effects of metabolic endotoxemia on breast tumor progression, also suggests that metabolic endotoxemia can contribute to obesity–breast cancer link. Thus, our findings add novel mechanistic insights into how obesity-associated metabolic changes, particularly metabolic endotoxemia, modulate the biological and clinical behavior of breast carcinoma. In turn, understanding of the mechanistic aspects underlying the association between obesity and breast cancer could help inform better strategies to reduce BC risk in an increasingly obese population and to suppress the breast cancer-promoting consequences of excess adiposity. Full article

Background/Objectives: Being overweight and obesity are major public health concerns that demand effective nutritional strategies for weight and body composition management. Beyond excess weight, these conditions are closely linked to chronic inflammation, oxidative stress, and gut dysbiosis, all of which contribute to cardiometabolic risk. Polyphenols—bioactive compounds in plant-based foods—may support improvements in body composition and metabolic health by modulating gut microbiota, reducing oxidative stress, and suppressing inflammation. This systematic review and meta-analysis aimed to evaluate the effects of polyphenol-rich interventions on gut microbiota composition, in combination with either oxidative stress or inflammatory biomarkers, and their potential impact on body composition in overweight or obese adults. Methods: A systematic search of PubMed, Scopus, Cochrane, and Web of Science was conducted through May 2025. Eligible randomized controlled trials included adults (BMI ≥ 25 kg/m²) receiving polyphenol-rich interventions, with reported outcomes on gut microbiota and at least one inflammatory or oxidative stress biomarker. Standardized mean differences (SMDs) were pooled using a random-effects model. Results: Thirteen trials (n = 670) met inclusion criteria. Polyphenol supplementation significantly reduced circulating lipopolysaccharides (LPSs; SMD = −0.56; 95% CI: −1.10 to −0.02; p < 0.04), indicating improved gut barrier function. Effects on cytokines (IL-6, TNF-α) and CRP were inconsistent. Catalase activity improved significantly (SMD = 0.79; 95% CI: 0.30 to 1.28; p < 0.001), indicating enhanced antioxidant defense. Gut microbiota analysis revealed increased butyrate (SMD = 0.57; 95% CI: 0.18 to 0.96; p < 0.001) and acetate (SMD = 0.42; 95% CI: 0.09 to 0.75; p < 0.01), supporting prebiotic effects. However, no significant changes were observed in BMI or body weight. Conclusions: Polyphenol supplementation in overweight or obese adults may reduce metabolic endotoxemia, boost antioxidant activity, and promote SCFAs production. Effects on inflammation and body weight remain unclear. Further long-term trials are needed. Full article

Background: Circadian disruption (CD) aggravates metabolic dysfunction-associated steatohepatitis (MASH), but supplementation with prebiotics inulin and oat β-glucan may mitigate its effects. However, their impact on colonic architecture and hepatic proteome remains unclear. Objectives: We aimed to investigate the effects of prebiotics inulin and oat β-glucan on colonic architecture and hepatic proteome in mice with CD-aggravated MASH. Methods: CD was induced by weekly reversal of the light–dark cycle to simulate shift work. Male C57BL/6J mice were subjected to non-shifted chow, non-shifted fructose, palmitate, cholesterol, and trans-fat (FPC) diet, shifted chow, or shifted FPC diet (SFPC) for 26 weeks. Prebiotics inulin and oat β-glucan supplementation were provided to the SFPC group in the final 10 weeks. Distal colon and serum samples were collected for histological examination and endotoxemia evaluation, respectively. Liver samples were collected for proteomic mass spectrometry analysis. Results: Mice with CD-aggravated MASH were found with colonic crypt loss and a distinct hepatic proteome structure compared to mice with non-CD MASH. Notably, inulin showed better effects than oat β-glucan in preserving colonic crypts in mice with CD-aggravated MASH. Furthermore, inulin supplementation restored the hepatic proteome structure similar to that of non-CD MASH mice, a benefit not observed with oat β-glucan. Conclusions: Given our prior findings showing oat β-glucan’s superior ability to enrich gut bacterial species associated with MASH improvement under CD, this study highlights inulin’s unique benefits for colonic architecture and hepatic proteome regulation in CD-aggravated MASH. Full article

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), unlike pediatric acute-onset neuropsychiatric syndrome (PANS), is triggered by infections. This study aimed to assess the differences in low-grade endotoxemia and oxidative stress between these conditions. A cross-sectional study compared serum levels of soluble NOX2-dp (sNOX-2-dp), isoprostanes, lipopolysaccharide (LPS), and zonulin in 30 PANDAS, 21 PANS, and 30 control (CT) children matched for age and gender. Zonulin was used to assess gut permeability. Patients with PANDAS showed significantly higher serum levels of sNOX2-dp, isoprostanes, LPS, and zonulin than PANS and controls, while no significant differences were found between PANS and controls. sNOX2-dp correlated with isoprostanes (Rs = 0.708; p < 0.001), LPS (Rs = 0.584; p < 0.001), and zonulin (Rs = 0.662; p < 0.001). Multiple regression identified isoprostanes (β = 0.599; p < 0.001) and zonulin (β = 0.295; p = 0.01) as independent predictors of sNOX2-dp (R² = 81%). PANDAS and PANS showed distinct profiles of LPS, zonulin, NOX2, and isoprostanes. Future research should explore therapies targeting endotoxemia and oxidative stress for potential clinical benefits. Full article

Prion diseases are classically attributed to the accumulation of protease-resistant prion protein (PrP^Sc); however, recent evidence suggests that alternative misfolded prion conformers and systemic inflammatory factors may also contribute to neurodegeneration. This study investigated whether recombinant moPrP^Res, generated by incubating wild-type mouse PrP^C with bacterial lipopolysaccharide (LPS), can induce prion-like disease in FVB/N female mice, whether LPS alone causes neurodegeneration, and how LPS modulates disease progression in mice inoculated with the Rocky Mountain Laboratory (RML) strain of prions. Wild-type female FVB/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrP^Res, moPrP^Res + LPS, RML, and RML + LPS. Animals were monitored longitudinally for survival, body weight, and clinical signs. Brain tissues were analyzed histologically and immunohistochemically for vacuolar degeneration, PrP^Sc accumulation, reactive astrogliosis, and amyloid-β plaque deposition. Recombinant moPrP^Res induced a progressive spongiform encephalopathy characterized by widespread vacuolation and astrogliosis, yet with no detectable PrP^Sc by Western blot or immunohistochemistry. LPS alone triggered a distinct neurodegenerative phenotype, including cerebellar amyloid-β plaque accumulation and terminal-stage spongiosis, with approximately 40% mortality by the end of the study. Co-administration of moPrP^Res and LPS resulted in variable regional pathology and intermediate survival (50% at 750 days post-inoculation). Interestingly, RML + LPS co-treatment led to earlier clinical onset and mortality compared to RML alone; however, vacuolation levels were not significantly elevated and, in some brain regions, were reduced. These results demonstrate that chronic endotoxemia and non-infectious misfolded PrP conformers can independently or synergistically induce key neuropathological hallmarks of prion disease, even in the absence of classical PrP^Sc. Targeting inflammatory signaling and toxic prion intermediates may offer novel therapeutic strategies for prion and prion-like disorders. Full article

Cardiac dysfunction is a severe complication of sepsis that significantly increases mortality in affected patients. Previous studies have shown better myocardial responses with preserved cardiac function in female animals compared to males following lipopolysaccharide (LPS)-induced sepsis. Our published findings have revealed that females exhibited less cardiac dysfunction than males when exposed to equivalent doses of tumor necrosis factor (TNF)α, which is markedly elevated in both heart tissue and serum following LPS. These raise the question of whether the observed sex differences in LPS-induced myocardial dysfunction are a direct effect of LPS or a secondary consequence mediated by inflammatory cytokines, like TNFα. In this study, we aimed to uncover sex differences in LPS-caused direct effects on cardiac function. To do so, isolated hearts from aged-matched adult male and female mice were subjected to LPS infusion using a Langendorff method. Left ventricular developed pressure (LVDP) was continuously recorded. The female estrous cycle was determined via vaginal smear. The oxidative phosphorylation (OXPHOS) pathway and estrogen receptors (ERs) were determined in heart tissue using Western blot. We found that males exhibited worse LV function than females following the infusion of LPS at 5.0 mg/kg body weight. However, no significant differences in cardiac function and expression of ERs were observed between female groups at different estrous stages. Interestingly, LV function returned to baseline after the initial depression of LVDP during the rapid response to LPS and then depressed again following the 50 min LPS infusion. Protein levels of OXPHOS were altered differently between male and female hearts after 50 min LPS infusion. Our data demonstrate that male hearts exhibit higher sensitivity to LPS-induced rapid cardiac dysfunction compared to females, although estrogen may have a minimal influence on LPS-induced rapid functional depression. Sex differences may exist in myocardial mitochondrial responses to direct LPS insult via the OXPHOS pathway. Full article

Endotoxemia often leads to microcirculatory derangement. In six sevoflurane anaesthetized Beagle dogs, we investigated the effects of 1 mg/kg of Escherichia coli lipopolysaccharide endotoxin intravenous and blood pressure (mean arterial pressure of 65 mmHg versus 85 mmHg) on microcirculation assessed on buccal mucosa using side stream dark field microscopy. Dogs were afterwards resuscitated with fluids and noradrenaline. We investigated dose requirements of noradrenaline with or without dexmedetomidine. Microcirculatory parameters, and markers of sepsis (cardiac output, mixed venous oxygen saturation, carbon dioxide gap, and lactate) were analysed before endotoxemia, after endotoxemia, after a 30 mL/kg of Ringer’s acetate fluid bolus, and during noradrenaline +/− dexmedetomidine infusion, after a second fluid bolus, and a second time after vasopressor treatment in a cross-over fashion. Endotoxemia and mean arterial pressure had no statistically significant effect on microcirculation; however, endotoxemia resulted in a decrease in cardiac output. Dexmedetomidine neither improved microcirculation nor reduced noradrenaline requirements. Full article

Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results in dissociation of GRP78 from transmembrane proteins (PERK, IRE1α, and ATF6) and generates abundant incorrect protein structures. Phosphoinositide 3-kinase-γ (PI3K-γ) has been demonstrated to modulate ER stress associated with sepsis and acute lung injury (ALI). However, the regulatory mechanisms by which ER stress is involved in VILI remain unclear. In this study, MV was hypothesized to augment lung injury and induce ER stress through the PI3K-γ pathway, regardless of endotoxemia. Wild-type or PI3K-γ-deficient C57BL/6 mice were exposed to 30 mL/kg tidal volume of MV with or without endotoxemia for 5 h. The control group comprised nonventilated mice. MV with endotoxemia increased microvascular permeability, lung edema, interleukin-6 and metalloproteinase-9 production, oxidative loads, ER stress biomarkers (GRP78, IRE-1α, PERK), morphological rearrangement, PI3K-γ expression, and bronchial epithelial apoptosis in rodent lungs. The increase in lung injury was substantially reduced in PI3K-γ-deficient mice and in mice administered 4-phenylbutyric acid. In conclusion, MV-augmented ALI after endotoxemia partially depends on the PI3K-γ pathway. Full article

Background: Type 2 diabetes mellitus (T2DM) represents a major global health burden, with prevalence rates escalating due to rapid urbanization, economic growth, and the obesity epidemic. Despite intensive research, the underlying molecular mechanisms remain incompletely understood, with emerging evidence suggesting multifactorial origins involving genetic, epigenetic, lifestyle, and environmental factors. Methods: This review synthesizes current epidemiological data on T2DM prevalence, risk factors, and demographic patterns from 1990 to 2017, and discusses projected trends through 2030. We examine the role of intestinal barrier dysfunction and gut microbiota dysbiosis in T2DM pathogenesis, highlighting key mechanistic insights. Furthermore, we analyze recent findings on the role of butyrate, a major short-chain fatty acid, in preserving gut integrity and its potential therapeutic effects on metabolic health. Results: Global T2DM prevalence has risen markedly across all age groups, with particularly high rates in Western Europe and Pacific Island nations. Disruption of the intestinal barrier (“leaky gut”) and gut microbiota alterations contribute significantly to systemic inflammation and insulin resistance, which are pivotal features in T2DM development. Butyrate plays a central role in maintaining epithelial barrier function, modulating immune responses, and regulating glucose metabolism. Preclinical studies have demonstrated that sodium butyrate supplementation improves gut integrity, reduces systemic endotoxemia, and ameliorates metabolic parameters. Emerging clinical evidence suggests benefits of sodium butyrate, particularly when combined with prebiotic fibers, in improving glycemic control and reducing inflammatory markers in T2DM patients. Conclusions: Gut barrier integrity and microbiota composition are critical factors in T2DM pathogenesis. Sodium butyrate shows promise as a complementary therapeutic agent in T2DM management, although further large-scale, long-term clinical trials are required to confirm its efficacy and safety. Targeting gut health may represent a novel strategy for the prevention and treatment of T2DM. Full article

Red wine grape pomace (RWGP), a winemaking by-product rich in phenolics, flavonoids, and dietary fiber, has shown promise in mitigating cardiovascular disease (CVD), however, its mechanisms of action remain incompletely understood. This study comprehensively profiled the phenolic composition of RWGP—including free, esterified, etherified, and insoluble-bound fractions—and evaluated the effects of RWGP dietary supplementation on gut barrier integrity, inflammation, oxidative stress, and survival in SR-B1^−/−ApoE-R61^h/h mice, a model of diet-induced lethal ischemic heart disease. RWGP supplementation significantly improved survival rates and restored gut barrier function, as evidenced by lower plasma FITC-dextran and LPS levels, increased circulating ZO-1 levels, and reduced histopathological colon damage. In addition, RWGP reduced pro-inflammatory cytokines (IL-1$\beta$) and showed a trend toward attenuating systemic oxidative stress (TBARS). Analysis of phenolic compounds indicated a significant presence of insoluble-bound phenolics. Nevertheless, the beneficial effects observed are likely attributable to the synergistic actions of RWGP’s complex phytochemical and fiber composition. These results highlight RWGP’s potential as a sustainable, gut-targeted functional food ingredient for CVD prevention and management. Full article

Background/Objectives: Childhood obesity is a growing global concern linked to metabolic disorders such as nonalcoholic fatty liver disease (NAFLD). Small intestinal bacterial overgrowth (SIBO) may exacerbate these conditions by promoting systemic inflammation and metabolic dysfunction. This review evaluates the prevalence of SIBO in obese children, its association with inflammatory and metabolic markers, and the efficacy of diagnostic and therapeutic strategies. Methods: A systematic search of PubMed, Scopus, and Web of Science (2010–present) was conducted using Boolean operators: (‘small intestinal bacterial overgrowth’ OR ‘SIBO’) AND ‘prevalence’ AND (‘low-grade inflammatory markers’ OR ‘metabolic status’) AND ‘gut microbiome’ AND ‘dysbiosis’ AND ‘obese children’. Results: The data show that SIBO is frequently observed in obese pediatric populations and is associated with gut dysbiosis, impaired nutrient absorption, and reduced production of short-chain fatty acids. These changes contribute to increased intestinal permeability, endotoxemia, and chronic low-grade inflammation. Several microbial taxa have been proposed as biomarkers and therapeutic targets. Diagnostic inconsistencies persist, but treatments such as probiotics, prebiotics, dietary interventions, and selective antibiotics show potential, pending further validation. Conclusions: Early identification and treatment of SIBO with tailored strategies may help reduce metabolic complications and improve outcomes in children with obesity. Full article

This review highlights a paradigm shift in our understanding of hypocalcemia during milk fever by introducing the concept of the Calci-Inflammatory Network. Traditionally viewed as a pathological deficiency necessitating rapid correction (e.g., through calcium borogluconate infusions or dietary adjustments like dietary cation-anion difference), periparturient hypocalcemia is reinterpreted here as an adaptive, protective response. Within this new framework, reduced circulating calcium levels may help temper systemic inflammation by limiting lipopolysaccharide (LPS) aggregation and curbing excessive macrophage activation. The review discusses how calcium signaling, the calcium-sensing receptor (CaSR), and immune cell functions adapt under hypocalcemic conditions to modulate inflammatory processes. This integrated perspective not only redefines the role of hypocalcemia but also proposes the Calci-Inflammatory Network as a novel concept through which we can understand how changes in calcium homeostasis mitigate inflammatory cascades—potentially lowering the incidence of periparturient diseases and enhance overall cow health and farm productivity. Future research should investigate the long-term effects of hypocalcemia, the environmental influences on this Calci-Inflammatory Network, and their collective impact on disease susceptibility and inflammation. Full article

Isaridin E, a cyclodepsipeptide derived from the marine fungus Beauveria felina (SYSU-MS7908), has been demonstrated to possess multiple biological properties. In this study, we employed both lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) and a LPS-induced murine endotoxemia model to investigate its anti-inflammatory effects. Our results revealed that isaridin E suppressed the expression of pro-inflammatory cytokines and adhesion molecules in a concentration dependent manner, while also reducing monocyte adhesion to endothelial cells. Furthermore, this compound attenuated vascular hyperpermeability and inflammatory cell infiltration in the lungs, as well as preserving the integrity of the aortic and pulmonary tissues. At the molecular level, isaridin E was found to downregulate TLR4 expression, increase IκBα levels, and inhibit the LPS-induced phosphorylation and nuclear translocation of NF-κB p65. In conclusion, our findings indicate that isaridin E exerts robust anti-inflammatory effects in LPS-induced endotoxemia through the suppression of the TLR4/NF-κB signaling axis, positioning it as a promising therapeutic candidate for vascular inflammatory disorders. Full article