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Serum-derived bovine immunoglobulin (SBI) prevents translocation and inflammation via direct binding of microbial components. Recently, SBI also displayed potential benefits through gut microbiome modulation. To confirm and expand upon these preliminary findings, SBI digestion and colonic fermentation were investigated using the clinically predictive ex vivo SIFR® technology (for 24 human adults) that was, for the first time, combined with host cells (epithelial/immune (Caco-2/THP-1) cells). SBI (human equivalent dose (HED) = 2 and 5 g/day) and the reference prebiotic inulin (IN; HED = 2 g/day) significantly promoted gut barrier integrity and did so more profoundly than a dietary protein (DP), especially upon LPS-induced inflammation. SBI also specifically lowered inflammatory markers (TNF-α and CXCL10). SBI and IN both enhanced SCFA (acetate/propionate/butyrate) via specific gut microbes, while SBI specifically stimulated valerate/bCFA and indole-3-propionic acid (health-promoting tryptophan metabolite). Finally, owing to the high-powered cohort (n = 24), treatment effects could be stratified based on initial microbiota composition: IN exclusively stimulated (acetate/non-gas producing) Bifidobacteriaceae for subjects classifying as Bacteroides/Firmicutes-enterotype donors, coinciding with high acetate/low gas production and thus likely better tolerability of IN. Altogether, this study strongly suggests gut microbiome modulation as a mechanism by which SBI promotes health. Moreover, the SIFR® technology was shown to be a powerful tool to stratify treatment responses and support future personalized nutrition approaches. [ABSTRACT FROM AUTHOR]

Despite many advances in infection control practices, including prophylactic antibiotics, surgical site infections (SSIs) remain a significant cause of morbidity, prolonged hospitalization, and death worldwide. Our innate immune system possesses a multitude of powerful antimicrobial strategies which make it highly effective in combating bacterial, fungal, and viral infections. However, pathogens use various stealth mechanisms to avoid the innate immune system, which in turn buy them time to colonize wounds and damage tissues at surgical sites. We hypothesized that immunomodulators that can jumpstart and activate innate immune responses at surgical sites, would likely reduce infection at surgical sites. We used three immunomodulators; fMLP (formyl-Methionine-Lysine-Proline), CCL3 (MIP-1α), and LPS (Lipopolysaccharide), based on their documented ability to elicit strong inflammatory responses; in a surgical wound infection model with Pseudomonas aeruginosa to evaluate our hypothesis. Our data indicate that one-time topical treatment with these immunomodulators at low doses significantly increased proinflammatory responses in infected and uninfected surgical wounds and were as effective, (or even better), than a potent prophylactic antibiotic (Tobramycin) in reducing P. aeruginosa infection in wounds. Our data further show that immunomodulators did not have adverse effects on tissue repair and wound healing processes. Rather, they enhanced healing in both infected and uninfected wounds. Collectively, our data demonstrate that harnessing the power of the innate immune system by immunomodulators can significantly boost infection control and potentially stimulate healing. We propose that topical treatment with these immunomodulators at the time of surgery may have therapeutic potential in combating SSI, alone or in combination with prophylactic antibiotics.

• Comparison of cross-protection after deletion of LPS synthesis-related genes. • LPS-deficient strains induced mucosal, humoral and cellular immune responses. • The double deletion strain of rfbB and rffG provides partial protection against heterologous serotypes. Interference with the normal synthesis of LPS was shown to enhance immune responses to conserved outer membrane proteins. In the present study, we have constructed three vaccine candidates by deleting four genes (rfaL , rfbB , rffG and wzy) associated with LPS synthesis in the wild-type strain UK-1. Virulence assessment showed that after oral immunization of BALB/c mice, all mutant strains were attenuated and had significantly reduced ability to colonize host tissues compared to the wild-type strain. In addition, all three vaccine candidates induced elevated humoral, mucosal and cellular immune responses against S. Typhimurium and S. Choleraesuis OMPs compared to the PBS-treated group. Finally, immunization of mice with the rSC0136 vaccine candidate strain provided 100 % and 40 % protection against S. Typhimurium and S. Choleraesuis challenge, respectively. These results suggest that the deletion of LPS synthesis-related genes may be an effective strategy against homologous serotypes, but provides only partial protection against heterologous serotypes. [ABSTRACT FROM AUTHOR]

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Disease outbreaks are a common problem in aquaculture, with serious economic consequences to the sector. Some of the most important bacterial diseases affecting aquaculture are caused by Gram-negative bacteria including Vibrio spp. (vibriosis), Photobacterium damselae (photobacteriosis), Aeromonas spp. (furunculosis; haemorrhagic septicaemia) or Tenacibaculum maritimum (tenacibaculosis). Lipopolysaccharides (LPS) are important components of the outer membrane of Gram-negative bacteria and have been linked to strong immunogenic responses in terrestrial vertebrates, playing a role in disease development. To evaluate LPS effects in fish, we used a hot-phenol procedure to extract LPS from common fish pathogens. A. hydrophila, V. harveyi, T. maritimum and P. damselae purified LPS were tested at different concentrations (50, 100, 250 and 500 µg mL−1) at 3 days post-fertilisation (dpf) Danio rerio larvae, for 5 days. While P. damselae LPS did not cause any mortality under all concentrations tested, A. hydrophila LPS induced 15.5% and V. harveyi LPS induced 58.3% of zebrafish larvae mortality at 500 µg mL−1. LPS from T. maritimum was revealed to be the deadliest, with a zebrafish larvae mortality percentage of 80.6%. Analysis of LPS separated by gel electrophoresis revealed differences in the overall LPS structure between the bacterial species analysed that might be the basis for the different mortalities observed. [ABSTRACT FROM AUTHOR]

Lipopolysaccharides are a type of polysaccharide mainly present in the bacterial outer membrane of Gram-negative bacteria. Recent studies have revealed that lipopolysaccharides contribute to the immune response of the host by functioning as a cancer antigen. We retrospectively recruited 198 patients with gastric cancer who underwent surgery. The presence of lipopolysaccharides was determined using immunohistochemical staining, with the intensity score indicating positivity. The relationship between lipopolysaccharides and CD8, PD-L1, TGFBI (a representative downstream gene of TGF-β signaling), wnt3a, and E-cadherin (epithelial–mesenchymal transition marker) was also investigated. Thereafter, we identified 20 patients with advanced gastric cancer receiving nivolumab and investigated the relationship between lipopolysaccharides and nivolumab sensitivity. After staining for lipopolysaccharides in the nucleus of cancer cells, 150 negative (75.8%) and 48 positive cases (24.2%) were found. The lipopolysaccharide-positive group showed increased cancer stromal TGFBI expression (p < 0.0001) and PD-L1 expression in cancer cells (p = 0.0029). Lipopolysaccharide positivity was significantly correlated with increased wnt3a signaling (p = 0.0028) and decreased E-cadherin expression (p = 0.0055); however, no significant correlation was found between lipopolysaccharide expression and overall survival rate (p = 0.71). In contrast, high TGFBI expression in the presence of LPS was associated with a worse prognosis than that in the absence of LPS (p = 0.049). Among cases receiving nivolumab, the lipopolysaccharide-negative and -positive groups had disease control rates of 66.7% and 11.8%, respectively (p = 0.088). Lipopolysaccharide positivity was associated with wnt3a, TGF-β signaling, and epithelial–mesenchymal transition and was considered to tend to promote therapeutic resistance to nivolumab. [ABSTRACT FROM AUTHOR]

Background: Inflammation is known to be an essential driver of various types of cancer. An increasing number of studies have suggested that the occurrence and development of colorectal cancer (CRC) are linked to the inflammatory microenvironment of the intestine. This assumption is further supported by the fact that patients with inflammatory bowel disease (IBD) are more likely to develop CRC. Multiple studies in mice and humans have shown that preoperative systemic inflammatory response is predictive of cancer recurrence after potentially curative resection. Lipopolysaccharides (LPS) are membrane surface markers of gram-negative bacteria, which induce gut barrier dysfunction and inflammation and might be significantly involved in the occurrence and development of CRC. Methods: A selective literature search was conducted in Medline and PubMed, using the terms "Colorectal Cancer", "Gut Barrier", "Lipopolysaccharides", and "Inflammation". Results: Disruption of intestinal homeostasis, including gut barrier dysfunction, is linked to increased LPS levels and is a critical factor for chronic inflammation. LPS can activate the diverse nuclear factor-κB (NF-κB) pathway via Toll-like receptors 4 (TLR4) to promote the inflammatory response, which aggravates gut barrier dysfunction and encourages CRC development. An intact gut barrier prevents antigens and bacteria from crossing the intestinal endothelial layer and entering circulation. In contrast, a damaged gut barrier triggers inflammatory responses and increases susceptibility to CRC. Thus, targeting LPS and the gut barrier might be a promising novel therapeutic approach for additional treatment of CRC. Conclusion: Gut barrier dysfuction and bacterial LPS seem to play an important role in the pathogenesis and disease progression of colorectal cancer and therefore require further investigation. [ABSTRACT FROM AUTHOR]

Dietary intervention in the treatment of ulcerative colitis involves, among other things, modifications in fatty acid content and/or profile. For example, replacing saturated long chain fatty acids with medium chain fatty acids (MCFAs) has been reported to ameliorate inflammation. The Black Soldier Fly Larvae's (BSFL) oil is considered a sustainable dietary ingredient rich in the MCFA C12:0; however, its effect on inflammatory-related conditions has not been studied until now. Thus, the present study aimed to investigate the anti-inflammatory activity of BSFL oil in comparison to C12:0 using TLR4- or TLR2-activated THP-1 and J774A.1 cell lines and to assess its putative protective effect against dextran sulfate sodium (DSS)-induced acute colitis in mice. BSFL oil and C12:0 suppressed proinflammatory cytokines release in LPS-stimulated macrophages; however, only BSFL oil exerted anti-inflammatory activity in Pam3CSK4-stimulated macrophages. Transcriptome analysis provided insight into the possible role of BSFL oil in immunometabolism switch, involving mTOR signaling and an increase in PPAR target genes promoting fatty acid oxidation, exhibiting a discrepant mode of action compared to C12:0 treatment, which mainly affected cholesterol biosynthesis pathways. Additionally, we identified anti-inflammatory eicosanoids, oxylipins, and isoprenoids in the BSFL oil that may contribute to an orchestrated anti-inflammatory response. In vivo, a BSFL oil-enriched diet (20%) ameliorated the clinical signs of colitis, as indicated by improved body weight recovery, reduced colon shortening, reduced splenomegaly, and an earlier phase of secretory IgA response. These results indicate the novel beneficial use of BSFL oil as a modulator of inflammation. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the effects of toll-like receptor 4 (TLR4) deletion on high fat diet-induced aortic stiffness and gut microbiota alterations. We hypothesized that a high fat diet would result in perturbation of the gutmicrobiota in both control and TLR4 knockout mice (TLR4-/-), but that the absence of TLR4 signaling would protect mice from downstream vascular consequences of the high fat diet. Male controlmice (CON, n=12) and TLR4-/- mice (KO, n=12) were fed either a standard low-fat diet (SD) or a high fat diet (HFD) (60% kcals from fat) for 6 months, after which timemeasurements of aortic stiffness (via pulse wave velocity [aPWV]) and gutmicrobiota composition (16S rRNA sequencing) were determined. Compared to the SD, HFD reduced microbial variability, promoted perturbation of the gut microbiota, and increased intestinal permeability in both CON and KO mice, with no effect of genotype. This increased intestinal permeability in HFD mice was accompanied by increases in plasma lipopolysaccharide binding protein (LBP) levels, an indicator of circulating endotoxin (p<0.05 for all comparisons between HFD and SD groups). aPWV was increased in CON+HFD mice (CON +HFD vs CON+SD: 525.4 ± 16.5 cm/sec vs. 455.2 ± 16.5 cm/sec; p<0.05), whereas KO+HFD mice displayed partial protection from HFD-induced arterial stiffening (KO+HFD vs. CON+SD: 488.2 ± 16.6 cm/sec vs. 455.2 ± 16.5 cm/sec; p=0.8) (KO +HFD vs. CON+HFD: 488.2 ± 16.6 cm/sec vs. 525.4 ± 16.5 cm/sec; p=0.1). In summary, TLR4 KO mice are not protected from deleterious alterations in gut microbial composition or intestinal permeability following a HFD, but are partially protected fromthe downstreamarterial stiffening, suggesting that TLR4 signaling is not required for HFD-mediated intestinal disturbances, but is an important determinant of downstream vascular consequences. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the effects of toll-like receptor 4 (TLR4) deletion on high fat diet-induced aortic stiffness and gut microbiota alterations. We hypothesized that a high fat diet would result in perturbation of the gut microbiota in both control and TLR4 knockout mice (TLR4-/-), but that the absence of TLR4 signaling would protect mice from downstream vascular consequences of the high fat diet. Male control mice (CON, n=12) and TLR4-/- mice (KO, n=12) were fed either a standard low-fat diet (SD) or a high fat diet (HFD) (60% kcals from fat) for 6 months, after which time measurements of aortic stiffness (via pulse wave velocity [aPWV]) and gut microbiota composition (16S rRNA sequencing) were determined. Compared to the SD, HFD reduced microbial variability, promoted perturbation of the gut microbiota, and increased intestinal permeability in both CON and KO mice, with no effect of genotype. This increased intestinal permeability in HFD mice was accompanied by increases in plasma lipopolysaccharide binding protein (LBP) levels, an indicator of circulating endotoxin (p

IntroductionObesity is a growing health problem among young people worldwide and is associated with gut conditions. This study aimed to explore the relationship between obesity, intestinal microbiota, fecal short-chain fatty acids (SCFAs), and lipopolysaccharide (LPS) in young college students.Methods16S rRNA gene sequences, SCFA and LPS contents, and obesity status were analyzed in 68 young college students (20-25 years old).ResultsThere were significant differences in intestinal microbial beta diversity among students with different body mass index (BMI). The abundance and proportion of Firmicutes and Bacteroides had no significant correlation with BMI. The contents of butyric acid and valeric acid in the feces of obese students were low, and the content of SCFAs had no significant correlation with BMI and LPS. The content of LPS in the feces of obese people was significantly higher than that in healthy people, and there was a significant positive correlation between LPS content and BMI.ConclusionIn general, there was a correlation between intestinal microbiota, SCFA, LPS, and BMI in young college students. Our results may enrich the understanding of the relationship between intestinal conditions and obesity and contribute to the study of obesity in young college students

This study investigated the role of neuroinflammation in a lipopolysaccharides (LPS)-induced cognitive dysfunction model in rats using an antioxidant, α-glycosyl isoquercitrin (AGIQ). Six-week-old rats were dietary treated with 0.5% (w/w) AGIQ for 38 days, and LPS at 1 mg/kg body weight was administered intraperitoneally once daily on Days 8 and 10. On Day 11, LPS alone increased or tended to increase interleukin-1β and tumor necrosis factor-a in the hippocampus and cerebral cortex. Immu-nohistochemically, LPS alone increased the number of Iba1+ and CD68+ microglia, and GFAP+ astrocytes in the hilus of the hippocampal dentate gyrus (DG). AGIQ treatment decreased or tended to decrease brain proinflammatory cytokine levels and the number of CD68+ microglia in the DG hilus. In the contextual fear conditioning test during Day 34 and Day 38, LPS alone impaired fear memory acquisition, and AGIQ tended to recover this impairment. On Day 38, LPS alone decreased the number of DCX+ cells in the neurogenic niche, and AGIQ increased the numbers of PCNA+ cells in the subgranular zone and CALB2+ hilar interneurons. Additionally, LPS alone decreased or tended to decrease the number of synaptic plasticity-related FOS+ and COX2+ granule cells and AGIQ recovered them. The results suggest that LPS administration induced acute neuroinflammation and subsequent impairment of fear memory acquisition caused by suppressed synaptic plasticity of newborn granule cells following disruptive neurogene-sis. In contrast, AGIQ exhibited anti-inflammatory effects and ameliorated LPS-induced adverse effects. These results suggest that neuroinflammation is a key factor in the development of LPS-induced impairment of fear memory acquisition. [ABSTRACT FROM AUTHOR]

Second- and third-line treatments of patients with antibiotic-resistant infections can have serious side effects, such as organ failure with prolonged care and recovery. As clinical practices such as cancer therapies, chronic disease treatment, and organ transplantation rely on the ability of available antibiotics to fight infection, the increased resistance of microbial pathogens presents a multifaceted, serious public health concern worldwide. The pipeline of traditional antibiotics is exhausted and unable to overcome the continuously developing multi-drug resistance. To that end, the widely observed limitation of clinically utilized antibiotics has prompted researchers to find a clinically relevant alternate antimicrobial strategy. In recent decades, the discovery of antimicrobial peptides (AMPs) as an excellent candidate to overcome antibiotic resistance has received further attention, particularly from scientists, health professionals, and the pharmaceutical industry. Effective AMPs are characterized by a broad spectrum of antimicrobial activities, high pathogen specificity, and low toxicity. In addition to their antimicrobial activity, AMPs have been found to be involved in a variety of biological functions, including immune regulation, angiogenesis, wound healing, and antitumor activity. This review provides a current overview of the structure, molecular action, and therapeutic potential of AMPs. [ABSTRACT FROM AUTHOR]

We investigated the effect of lipopolysaccharide (LPS)‐induced maternal immune activation used as a model for producing neurodevelopmental disorders on hippocampal neurogenesis and behaviors in rat offspring by exploring the antioxidant effects of alpha‐glycosyl isoquercitrin (AGIQ). Pregnant Sprague–Dawley rats were intraperitoneally injected with LPS (50 μg/kg body weight) at gestational days 15 and 16. AGIQ was administered in the diet to dams at 0.5% (w/w) from gestational day 10 until weaning at postnatal day 21 and then to offspring until adulthood at postnatal day 77. During postnatal life, offspring of LPS‐injected animals did not show neuroinflammation or oxidative stress in the brain. At weaning, LPS decreased the numbers of type‐2b neural progenitor cells (NPCs) and PCNA+ proliferating cells in the subgranular zone, FOS‐expressing granule cells, and GAD67+ hilar interneurons in the dentate gyrus. In adulthood, LPS decreased type‐1 neural stem cells, type‐2a NPCs, and GAD67+ hilar interneurons, and downregulated Dpysl3, Sst, Fos, Mapk1, Mapk3, Grin2a, Grin2b, Bdnf, and Ntrk2. In adults, LPS suppressed locomotor activity in the open field test and suppressed fear memory acquisition and fear extinction learning in the contextual fear conditioning test. These results indicate that mid‐gestation LPS injections disrupt programming of normal neurodevelopment resulting in progressive suppression of hippocampal neurogenesis and synaptic plasticity of newborn granule cells by suppressing GABAergic and glutamatergic neurotransmitter signals and BDNF/TrkB signaling to result in adult‐stage behavioral deficits. AGIQ ameliorated most aberrations in hippocampal neurogenesis and synaptic plasticity, as well as behavioral deficits. Effective amelioration by continuous AGIQ treatment starting before LPS injections may reflect both anti‐inflammatory and anti‐oxidative stress effects during gestation and neuroprotective effects of continuous exposure through adulthood. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) proved to be an important tool, not only in the induction of neuroinflammatory models, but also in demonstrating the behavioral and cognitive consequences of endotoxemia. Curcumin, in its native form, has proven to be a worthy candidate for further development as it protects the dopaminergic neurons against LPS-induced neurotoxicity. However, it remains hindered by its poor bioavailability. In this study we aim to explore the possible molecular mechanism of LPS-induced neurotoxicity and the possible protective effects of orally supplemented nanocurcumin. Thirty-six adult male Wistar rats weighing 170–175 g were divided into six groups and treated with single I.P. (intra-peritoneal) dose of LPS (sigma and extracted; separately) (5 mg/kg BW) plus daily oral nanocurcumin (15 mg/kg BW). The rats were followed for 7 days after the LPS injection and nanocurcumin supplementations daily via oral gavage. After scarification, the levels of neurotransmitters, antioxidants, and amyloidogenesis markers were assessed in brain tissues. Nanocurcumin showed adequate antioxidant and neuroprotective effects, rescuing the rats which had been injected intraperitoneally with LPS endotoxin. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has long posed challenges in clinical practice, lacking established preventive and therapeutic approaches. Lianhua Qingke (LHQK), a patented traditional Chinese medicine (TCM), has been found to have anti-inflammatory effects for ameliorating ALI/ARDS induced by lipopolysaccharide (LPS). This study aimed to investigate the effects and potential mechanisms of LHQK on endothelial protection in LPS-induced ALI/ARDS in vivo and in LPS-induced human pulmonary microvascular endothelial cells (HPMECs) injury in vitro., Methods: In the animal experiment, we induced an ALI/ARDS model by intratracheal injection of LPS (5 mg/mL). LHQK (3.7 g/kg/d for low dose and 7.4 g/kg/d for high dose) or dexamethasone (DEX) (5 mg/kg/d) was administered to mice 3 days prior to LPS treatment. In the in vitro experiments, HPMECs were pretreated with LHQK at concentrations of 125 and 250 µg/mL for 2 hours before being stimulated with LPS (10 µg/mL). We employed lung function test, measurement of lung index, hematoxylin and eosin (H&E) staining, bronchoalveolar lavage fluid (BALF) cell counts, and inflammatory cytokine levels to assess the therapeutic effect of LHQK. Additionally, the extravasation assay of fluorescein isothiocyanate-dextran (FITC-dextran) dye and the transmembrane electrical resistance (TEER) assay were used to evaluate endothelial barrier. Barrier integrity and relevant protein validation were assessed using immunofluorescence (IF) and Western blot analyses. Furthermore, network pharmacology analysis and cellular level screening were employed to predict and screen the active ingredients of LHQK., Results: Compared to the LPS group, LHQK significantly improved lung function, mitigated lung pathological injuries, reduced inflammatory cells and inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6] levels in BALF, and inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), attenuated LPS-induced pulmonary oedema and FITC-dextran permeability, and enhanced the expression of vascular endothelial-cadherin (VE-cadherin) and occludin. In vitro , LHQK attenuated LPS-induced HPMECs injury by elevating TEER values and enhancing VE-cadherin and occludin protein levels. Finally, network pharmacology analysis and cellular level validation identified potential active ingredients of LHQK., Conclusions: In summary, LHQK can mitigate LPS-induced inflammatory infiltration, pulmonary edema, and pulmonary vascular endothelial barrier dysfunction in the context of ALI/ARDS. This is achieved by decreasing the levels of VCAM-1, and increasing the expression levels of barrier-associated junctions, such as VE-cadherin and occludin. Consequently, LHQK exhibits promising therapeutic potential in preventing the progression of ALI/ARDS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-700/coif). Z.J. is the spouse of Ms. Rui Wu, who holds shares and serves as a director of Shijiazhuang Yiling Pharmaceutical Co., Ltd. Z.J. reports affiliated to Hebei Yiling Hospital, a non-profit medical institution, which is two completely independent legal entities with Shijiazhuang Yiling Pharmaceutical Co., Ltd. He has fully disclosed these interests to the research committee and have developed an approved plan to manage any potential conflicts that may arise from such an arrangement and ensure the research results being scientific, objective and authoritative. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Abstract Background Neuroinflammatory response is considered to be a high-risk factor for cognitive impairments in the brain. Lipopolysaccharides (LPS) is an endotoxin that induces acute inflammatory responses in injected bodies. However, the molecular mechanisms underlying LPS-associated cognitive impairments still remain unclear. Methods Here, primary hippocampal neurons were treated with LPS, and western blotting and immunofluorescence were used to investigate whether LPS induces neurons damage. At the same time, SD rats were injected with LPS (830 μg/Kg) intraperitoneally, and Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, and molecular biology technology was used to assess the NF-κB pathway, while ELISA was used to detect inflammatory factors. In addition, metformin was used to treat primary hippocampal neurons, and intraventricularly administered to SD rats. The same molecular technics, behavioral and electrophysiological tests were used to examine whether metformin could alleviate the LPS-associated neuronal damage, as well as synaptic plasticity, and behavioral alterations in SD rats. Results Altogether, neuronal damage were observed in primary hippocampal neurons after LPS intervention, which were alleviated by metformin treatment. At the same time, LPS injection in rat triggers cognitive impairment through activation of NF-κB signaling pathway, and metformin administration alleviates the LPS-induced memory dysfunction and improves synaptic plasticity. Conclusion These findings highlight a novel pathogenic mechanism of LPS-related cognitive impairments through activation of NF-κB signaling pathway, and accumulation of inflammatory mediators, which induces neuronal pathologic changes and cognitive impairments. However, metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway.

Besides the roles in regulating immune responses, recent studies have also suggested a pivotal role of Toll-like receptors (TLRs) in lipid metabolism. Previously we reported that graphene oxide (GO) suppresses TLR signaling pathways. In this study, we further investigated the in vivo toxicity of GO in zebrafish larvae via TLRs. Zebrafish embryos (5 h post fertilization; hpf) were exposed to 0.01, 0.1, 1 or 10 mg/L GO for up to 5 days, and the results revealed that GO induced developmental toxicity, in the form of delayed hatching time and increased deformity, mortality and heart rate; blood flow and linear velocity, however, remained unchanged. Meanwhile, the locomotor activities of larvae were also increased with GO exposure. As the possible mechanism for these effects, GO exposure significantly decreased TLR1, TLR4 and TLR5 expression, leading to suppressed expression of immune genes, including interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor α (TNFα). Furthermore, the expression of perilipin 2 (PLIN2) was also decreased, which consequently led to decreased lipid droplet (LD) staining and triglyceride (TG) content. Interestingly, GO-induced deformity was significantly increased by TLR2/TLR4 agonist lipopolysaccharides (LPS), but less effectively promoted by TLR3 agonist poly inosinic: cytidylic acid (IC). The results from this study suggested that GO exposure induces developmental toxicity to zebrafish larvae via the suppression of TLR signaling pathways, likely due to immune inhibition and dysfunction of LD biogenesis.

Disease outbreaks are a common problem in aquaculture, with serious economic consequences to the sector. Some of the most important bacterial diseases affecting aquaculture are caused by Gram-negative bacteria including Vibrio spp. (vibriosis), Photobacterium damselae (photobacteriosis), Aeromonas spp. (furunculosis; haemorrhagic septicaemia) or Tenacibaculum maritimum (tenacibaculosis). Lipopolysaccharides (LPS) are important components of the outer membrane of Gram-negative bacteria and have been linked to strong immunogenic responses in terrestrial vertebrates, playing a role in disease development. To evaluate LPS effects in fish, we used a hot-phenol procedure to extract LPS from common fish pathogens. A. hydrophila, V. harveyi, T. maritimum and P. damselae purified LPS were tested at different concentrations (50, 100, 250 and 500 µg mL−1) at 3 days post-fertilisation (dpf) Danio rerio larvae, for 5 days. While P. damselae LPS did not cause any mortality under all concentrations tested, A. hydrophila LPS induced 15.5% and V. harveyi LPS induced 58.3% of zebrafish larvae mortality at 500 µg mL−1. LPS from T. maritimum was revealed to be the deadliest, with a zebrafish larvae mortality percentage of 80.6%. Analysis of LPS separated by gel electrophoresis revealed differences in the overall LPS structure between the bacterial species analysed that might be the basis for the different mortalities observed.

Abstract Background Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. Methods The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. Results Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. Conclusions Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. Trial registration This study is based on a study registered at ClinicalTrials.gov, NCT03392701 . Registered 21 December 2017.

In this study, we examined the role of the lipopolysaccharide (LPS) core of Rhizobium etli in facilitating the adsorption and infection of phages with broad host range. When the plasmid-encoded LPS biosynthesis genes, wreU and wreV , were disrupted, distinct and contrasting effects on phage infection were observed. The wreU mutant strains exhibited wild-type adsorption and infection properties, whereas the wreV mutant demonstrated resistance to phage infection, but retained the capacity to adsorb phages. Complementation of the wreV mutant strains with a recombinant plasmid containing the wreU and wreV , restored the susceptibility to the phages. However, the presence of this recombinant plasmid in a strain devoid of the native lps -encoding plasmid was insufficient to restore phage susceptibility. These results suggest that the absence of wreV impedes the proper assembly of the complete LPS core, potentially affecting the formation of UDP-KdgNAg or KDO precursors for the O-antigen. In addition, a protein not yet identified, but residing in the native lps -encoding plasmid, may be necessary for complete phage infection. [ABSTRACT FROM AUTHOR]

Background: Extra virgin olive oil (EVOO) improves post-prandial glycemia, but the underlying mechanism has not been fully elucidated. We tested the hypothesis that EVOO improves post-prandial glycemia by reducing gut permeability-derived low-grade endotoxemia. Methods: Serum levels of lipopolysaccharides (LPS), zonulin, a marker of gut permeability, glucose, insulin and glucagon-like peptide 1 (GLP1) were measured in 20 patients with impaired fasting glucose (IFG) and 20 healthy subjects (HS) matched for sex and age. The same variables were measured in IFG patients (n = 20) and HS (n = 20) before and after a Mediterranean diet with 10 g EVOO added or not (n = 20) or in IFG patients (n = 20) before and after intake of 40 g chocolate with EVOO added or not. Results: Compared to HS, IFG had higher levels of LPS and zonulin. In HS, meal intake was associated with a significant increase of blood glucose, insulin, and GLP1 with no changes of blood LPS and zonulin. Two hours after a meal intake containing EVOO, IFG patients showed a less significant increase of blood glucose, a more marked increase of blood insulin and GLP1 and a significant reduction of LPS and zonulin compared to IFG patients not given EVOO. Correlation analysis showed that LPS directly correlated with blood glucose and zonulin and inversely with blood insulin. Similar findings were detected in IFG patients given a chocolate added or without EVOO. Conclusion: Addition of EVOO to a Mediterranean diet or chocolate improves gut permeability and low-grade endotoxemia. [ABSTRACT FROM AUTHOR]

Background: The availability of glucose in tissue has a role in macrophages polarisation into an inflammatory phenotype. The overnutrition condition such as hyperglycaemia induces macrophage infiltration especially the inflammatory macrophages. The aim of this study was to analyse the effect of hyperglycaemia condition on cytokines production by human monocytes-derived macrophages.Materials and Methods: Monocyte cells obtained from peripheral blood mononuclear cells isolation from donors were incubated for 6 days in 37°C, 5% CO2. On day 4, the stimulating factors such as lipopolysaccharide (LPS) and interferon gamma were added to activate monocytes into macrophages. Then, on day 6, two doses of glucose; either normal or high doses along with low or high dose of LPS were given for 24 h, followed by collecting the culture media and cells then stored at -80°C until assayed.Results: There was a significant difference in tumour necrosis factor alpha (TNF-a) levels among groups, with highest level found in group with high-dose glucose plus high-dose LPS. However, the concentration of interleukin-6 (IL-6) among groups was not significantly different.Conclusions: Macrophages treated with high-dose glucose plus high-dose LPS significantly increased production of TNF-a, but not of IL-6. [ABSTRACT FROM AUTHOR]

Lung diseases are common health problems in many countries. The dysfunction of bronchial epithelial cells is important for the development of lung diseases. Recent progress reveals that inflammasome is the fundamental mechanism of epithelial activation. Here, we report the protective effect of doxofylline, a theophylline derivative agent, on lipopolysaccharides (LPS)-induced inflammatory response in bronchial epithelial cells. The presence of doxofylline reduces LPS-induced production of NO and PGE2. Doxofylline also inhibits LPS-induced production of mitochondrial ROS. Mechanistically, we show that doxofylline suppresses the expression of NOX4 induced by LPS. Doxofylline inhibits LPS-induced NLRP3-TXNIP inflammasome activation as revealed by its inhibitive effect on NLRP3, caspase 1 (P10 unit), and TXNIP induction as well as weakened induction of IL-1β and IL-18. Furthermore, we show that doxofylline ameliorates LPS-induced Sirtuin 1 (SIRT1) reduction. The silencing of SIRT1 abolishes the inhibitory effect of doxofylline on NLRP3 inflammasome activation. Collectively, our study demonstrates that doxofylline mitigates epithelial inflammation via amelioration of multiple cellular pathways, including NLRP3-TXNIP inflammasome activation.

Background: Neuroinflammatory response is considered to be a high-risk factor for cognitive impairments in the brain. Lipopolysaccharides (LPS) is an endotoxin that induces acute inflammatory responses in injected bodies. However, the molecular mechanisms underlying LPS-associated cognitive impairments still remain unclear.Methods: Here, primary hippocampal neurons were treated with LPS, and western blotting and immunofluorescence were used to investigate whether LPS induces neurons damage. At the same time, SD rats were injected with LPS (830 μg/Kg) intraperitoneally, and Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, and molecular biology technology was used to assess the NF-κB pathway, while ELISA was used to detect inflammatory factors. In addition, metformin was used to treat primary hippocampal neurons, and intraventricularly administered to SD rats. The same molecular technics, behavioral and electrophysiological tests were used to examine whether metformin could alleviate the LPS-associated neuronal damage, as well as synaptic plasticity, and behavioral alterations in SD rats.Results: Altogether, neuronal damage were observed in primary hippocampal neurons after LPS intervention, which were alleviated by metformin treatment. At the same time, LPS injection in rat triggers cognitive impairment through activation of NF-κB signaling pathway, and metformin administration alleviates the LPS-induced memory dysfunction and improves synaptic plasticity.Conclusion: These findings highlight a novel pathogenic mechanism of LPS-related cognitive impairments through activation of NF-κB signaling pathway, and accumulation of inflammatory mediators, which induces neuronal pathologic changes and cognitive impairments. However, metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway. [ABSTRACT FROM AUTHOR]

During the last years, infections have become a global health emergency, where the appearance of bacteria highly resistant to traditional antibiotics have set off an alarm worldwide. Moreover, the increased incidence and mortality resulting from its aggravated states, sepsis, and septic shock, have been observed with growing concern. In this context, knowing the need for a new concept for treatment, peptides such as antimicrobial peptides (AMP) and host defense peptides (HDP), have started to show interesting properties in the development of new antimicrobial agents and host response modulatory therapies. Nevertheless, since it is a well-known fact that a peptide-based drug development is a long process that consumes a significant number of resources, recent approaches that tend to mitigate these obstacles, have included the implementation of novel in silico strategies for the optimization of naturally occurring AMP and HDP. In this review, we analyze these strategies that seek to improve not only peptide design, but also production, by including the incorporation of computational biology techniques such as molecular dynamics. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) proved to be an important tool, not only in the induction of neuroinflammatory models, but also in demonstrating the behavioral and cognitive consequences of endotoxemia. Curcumin, in its native form, has proven to be a worthy candidate for further development as it protects the dopaminergic neurons against LPS-induced neurotoxicity. However, it remains hindered by its poor bioavailability. In this study we aim to explore the possible molecular mechanism of LPS-induced neurotoxicity and the possible protective effects of orally supplemented nanocurcumin. Thirty-six adult male Wistar rats weighing 170–175 g were divided into six groups and treated with single I.P. (intra-peritoneal) dose of LPS (sigma and extracted; separately) (5 mg/kg BW) plus daily oral nanocurcumin (15 mg/kg BW). The rats were followed for 7 days after the LPS injection and nanocurcumin supplementations daily via oral gavage. After scarification, the levels of neurotransmitters, antioxidants, and amyloidogenesis markers were assessed in brain tissues. Nanocurcumin showed adequate antioxidant and neuroprotective effects, rescuing the rats which had been injected intraperitoneally with LPS endotoxin.

Second- and third-line treatments of patients with antibiotic-resistant infections can have serious side effects, such as organ failure with prolonged care and recovery. As clinical practices such as cancer therapies, chronic disease treatment, and organ transplantation rely on the ability of available antibiotics to fight infection, the increased resistance of microbial pathogens presents a multifaceted, serious public health concern worldwide. The pipeline of traditional antibiotics is exhausted and unable to overcome the continuously developing multi-drug resistance. To that end, the widely observed limitation of clinically utilized antibiotics has prompted researchers to find a clinically relevant alternate antimicrobial strategy. In recent decades, the discovery of antimicrobial peptides (AMPs) as an excellent candidate to overcome antibiotic resistance has received further attention, particularly from scientists, health professionals, and the pharmaceutical industry. Effective AMPs are characterized by a broad spectrum of antimicrobial activities, high pathogen specificity, and low toxicity. In addition to their antimicrobial activity, AMPs have been found to be involved in a variety of biological functions, including immune regulation, angiogenesis, wound healing, and antitumor activity. This review provides a current overview of the structure, molecular action, and therapeutic potential of AMPs.

Brucella is a facultatively intracellular bacterial pathogen and the cause of worldwide zoonotic infections, infamous for its ability to evade the immune system and persist chronically within host cells. Despite the frequent association with attenuation in other Gram-negative bacteria, a rough lipopolysaccharide phenotype is retained by Brucella canis and Brucella ovis, which remain fully virulent in their natural canine and ovine hosts, respectively. While these natural rough strains lack the O-polysaccharide they, like their smooth counterparts, are able to evade and manipulate the host immune system by exhibiting low endotoxic activity, resisting destruction by complement and antimicrobial peptides, entering and trafficking within host cells along a similar pathway, and interfering with MHC-II antigen presentation. B. canis and B. ovis appear to have compensated for their roughness by alterations to their outer membrane, especially in regards to outer membrane proteins. B. canis, in particular, also shows evidence of being less proinflammatory in vivo, suggesting that the rough phenotype may be associated with an enhanced level of stealth that could allow these pathogens to persist for longer periods of time undetected. Nevertheless, much additional work is required to understand the correlates of immune protection against the natural rough Brucella spp., a critical step toward development of much-needed vaccines. This review will highlight the significance of rough lipopolysaccharide in the context of both natural disease and host–pathogen interactions with an emphasis on natural rough Brucella spp. and the implications for vaccine development.

Background LPS-type endotoxins, naturally found in the gut microbiota, are recognized as triggers of inflammation and emerge as detrimental factors of healthy aging. Nutrition represents a promising strategy to reduce LPS burden, yet little is known about the relation of diet to circulating LPS concentrations. Objective The aim was to evaluate the associations between food groups, dietary patterns, and circulating 3-hydroxy fatty acids (3-OH FAs), a proxy of LPS burden. Methods In a cross-sectional study of 698 French older community-dwelling individuals, 3-OH FA concentrations were measured by LC–tandem MS. Dietary patterns were determined using food-frequency questionnaires. Adherence to a Mediterranean-type diet was computed according to the consumption of 8 food groups (fruits, vegetables, legumes, cereals, fish, olive oil, meat, and dairy products) and alcohol intake (range: 0, low adherence, to 18, high adherence). Three a posteriori dietary patterns were derived from factor analysis: complex carbohydrate (rich in rice, pasta, eggs, poultry, and potatoes), traditional (rich in alcohol, meat, processed meats–cold cuts, and legumes), and prudent (rich in vegetables and fruits and low in cookies) diets. Linear regression models were applied. Results The frequency of consumption of each food group was not associated with 3-OH FA concentrations. Greater adherence to both the Mediterranean diet and the prudent diet were associated with lower circulating 3-OH FAs (β [95% CI] for each additional point of score: −0.12 [−0.22, −0.01] and −0.27 [−0.48, −0.07], respectively). In contrast, greater adherence to the traditional diet was associated with higher concentration of 3-OH FAs (β [95% CI] 0.22 [0.001, 0.46]). The adherence to the complex-carbohydrate diet was not associated with 3-OH FA concentrations. Conclusions Based on 2 complementary approaches, the identified plant-based dietary patterns were associated with lower 3-OH FA concentrations, and thus a lower LPS burden, which is considered a potent trigger of inflammatory response. [ABSTRACT FROM AUTHOR]

Background: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects.Methods: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18-40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models.Results: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP.Conclusions: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway.Trial Registration: This study is based on a study registered at ClinicalTrials.gov, NCT03392701 . Registered 21 December 2017. [ABSTRACT FROM AUTHOR]

Brucella is a facultatively intracellular bacterial pathogen and the cause of worldwide zoonotic infections, infamous for its ability to evade the immune system and persist chronically within host cells. Despite the frequent association with attenuation in other Gram-negative bacteria, a rough lipopolysaccharide phenotype is retained by Brucella canis and Brucella ovis , which remain fully virulent in their natural canine and ovine hosts, respectively. While these natural rough strains lack the O-polysaccharide they, like their smooth counterparts, are able to evade and manipulate the host immune system by exhibiting low endotoxic activity, resisting destruction by complement and antimicrobial peptides, entering and trafficking within host cells along a similar pathway, and interfering with MHC-II antigen presentation. B. canis and B. ovis appear to have compensated for their roughness by alterations to their outer membrane, especially in regards to outer membrane proteins. B. canis , in particular, also shows evidence of being less proinflammatory in vivo , suggesting that the rough phenotype may be associated with an enhanced level of stealth that could allow these pathogens to persist for longer periods of time undetected. Nevertheless, much additional work is required to understand the correlates of immune protection against the natural rough Brucella spp., a critical step toward development of much-needed vaccines. This review will highlight the significance of rough lipopolysaccharide in the context of both natural disease and host–pathogen interactions with an emphasis on natural rough Brucella spp. and the implications for vaccine development. [ABSTRACT FROM AUTHOR]

• B. fragilis LPS suppresses cytokine production induced by E. coli LPS or feces. • B. fragilis LPS causes less arthritis in CAIA model mice compared to E. coli LPS. • Pretreatment or coadministration of B. fragilis LPS suppress developing arthritis. It has been reported that patients with rheumatoid arthritis (RA) have significantly less bacteria belonging to the Bacteroides group in their microbiota. We speculate that inhibition of cytokine production is impaired in patients with RA owing to their low levels of intestinal bacteria belonging to the Bacteroidetes group. Here we investigated the effect of Bacteroides fragilis lipopolysaccharide (B-LPS) on cytokine production in vitro and on the development of collagen antibody-induced arthritis (CAIA) in DBA/1 mice, an animal model of RA. in vitro culture experiments showed that Escherichia coli LPS (E-LPS)-induced cytokine production from THP-1 monocytic cells and peripheral blood mononuclear cells was significantly suppressed by B-LPS in a dose-dependent manner. A decrease in TNF-α and IL-1β production was also observed in LPS-tolerized macrophages induced by B-LPS at concentrations equal to and higher than that of E-LPS. Similar results were obtained when autoclaved feces were used to induce cytokine production instead of E-LPS. In in vivo experiments using CAIA models, B-LPS had no adverse effects even when administered at 10 times the concentration of E-LPS, which elicits severe arthritis. In addition, simultaneous administration of high dose B-LPS with E-LPS or administration of B-LPS prior to E-LPS significantly suppressed arthritis development in CAIA model animals when compared with administration of E-LPS alone. These results suggest that increasing certain bacterial groups such as Bacteroides is an effective strategy for preventing arthritis development in patients with RA. [ABSTRACT FROM AUTHOR]

Hepatitis is a condition that can be self-limiting or can progress to fibrosis (scarring), cirrhosis, or liver cancer. These days, gut microbiota becomes an important part of our immune system, which is important for disease progression or recovery. Translocation of gut microbial and metabolic products causes intestinal inflammation by modulating immune cells leading to impairment of the primary barrier. But there are limited studies discussing pathogenesis and management of hepatitis with gut microbiota. In this review, we have discussed the role of gut microbiota in pathogenesis and management of various hepatitis, especially hepatitis B and C. We have discussed the role of bacterial products, LPS-TLR4 pathway, and unmethylated CpG DNA, which ultimately affects downstream NF-kB signaling in hepatitis. Finally, we have discussed the role of fecal microbiota transplantation in the management of hepatitis.

Bacterial lipopolysaccharides (LPS) are important bio-medical structures, playing a major role in the interaction with human immune systems. Their core regions, containing multiple units of l-glycero-d-manno heptoses (l,d-heptose), are highly conserved structurally (with O3 and O7 glycosidic bonds), making them an epitope of high interest for the potential development of new antibiotics and vaccines. Research in this field has always been restricted by the limited availability of the parent l,d-heptose as well as its biochemical epimeric precursor d-glycero-d-manno heptose (d,d-heptose). This problem of availability has recently been solved by us, through a rapid and efficient practical synthesis of l,d-manno-heptose peracetate demonstrated at scale. Herein we report an optimized, technically simple and versatile synthetic strategy for the differentiation of both the l-glycero and d-glycero-d-manno heptose scaffolds. Our approach is based on an orthoester methodology for the differentiation of all three positions of the sugar core using a O6, O7-tetraisopropyl disiloxyl (TIPDS) protecting group for the exocyclic positions. Furthermore, the regioselective opening toward 7-OH acceptors (6O-FTIPDS ethers) differentiates the exocyclic diol which has been demonstrated with a broader set of substrates and for both manno-heptoses for the first time.

Abstract Background Because antibiotic use in livestock is assumed to contribute to the emerging public health crisis of antibiotic resistance, alternatives are required. Phytogenic additives are extensively studied due to their antibiotic properties. Components of Agrimonia species have been reported as candidate antimicrobials that possess antioxidative and anti-inflammatory properties. We studied the impact of Agrimonia procera (AP) on the growth of selected strains of gut bacteria, the effect of AP on the mRNA abundance of genes involved in inflammation and bacterial defense in a colon carcinoma cell line, the effect of AP in piglets challenged with lipopolysaccharides, and the effect of AP on the growth performance of healthy piglets. Results The in vitro growth rate of different bacteria strains was negatively affected by AP, especially in Pediococcus pentosaceus and all tested E. coli strains. Stimulation of Caco-2 cells with TNFα resulted in elevated mRNA expression of CXCL1, IL-8 and GPX2. After pretreatment of cells with AP, stimulation of Caco-2 cells with TNFα still resulted in elevated mRNA expression of CXCL1 and IL-8 at all measured points in time. However, mRNA expression in AP-pretreated cells was lower after 6 h and 24 h. In addition, expression of DEFB1 and GPX2 was significantly elevated after TNFα stimulation. In vivo, application of lipopolysaccharides induced significantly increased animal body temperatures. Piglets pretreated with AP prior to lipopolysaccharide application showed a faster and larger increase in body temperature than controls. In addition, piglets pretreated with AP appeared to release more TNFα than controls. In healthy piglets, AP treatment had no impact on growth performance parameters. Fecal dry matter and total plasma antioxidant capacity tended to be higher in piglets treated with AP than in control piglets (P = 0.055 and P = 0.087, respectively). Conclusions AP has antimicrobial effects in vitro and stimulated the expression of proinflammatory cytokines in Caco-2 cells. The additive had no effect on growth in healthy piglets but increased the immune response in LPS-treated animals. In addition, AP appeared to have antioxidative effects in vivo. Therefore, AP merits testing as a future alternative to antibiotics in animal husbandry.

Background/Aims: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. Methods: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. Results: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. Conclusion: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade.

Lung diseases are common health problems in many countries. The dysfunction of bronchial epithelial cells is important for the development of lung diseases. Recent progress reveals that inflammasome is the fundamental mechanism of epithelial activation. Here, we report the protective effect of doxofylline, a theophylline derivative agent, on lipopolysaccharides (LPS)-induced inflammatory response in bronchial epithelial cells. The presence of doxofylline reduces LPS-induced production of NO and PGE2. Doxofylline also inhibits LPS-induced production of mitochondrial ROS. Mechanistically, we show that doxofylline suppresses the expression of NOX4 induced by LPS. Doxofylline inhibits LPS-induced NLRP3-TXNIP inflammasome activation as revealed by its inhibitive effect on NLRP3, caspase 1 (P10 unit), and TXNIP induction as well as weakened induction of IL-1β and IL-18. Furthermore, we show that doxofylline ameliorates LPS-induced Sirtuin 1 (SIRT1) reduction. The silencing of SIRT1 abolishes the inhibitory effect of doxofylline on NLRP3 inflammasome activation. Collectively, our study demonstrates that doxofylline mitigates epithelial inflammation via amelioration of multiple cellular pathways, including NLRP3-TXNIP inflammasome activation. [ABSTRACT FROM AUTHOR]

Hepatitis is a condition that can be self-limiting or can progress to fibrosis (scarring), cirrhosis, or liver cancer. These days, gut microbiota becomes an important part of our immune system, which is important for disease progression or recovery. Translocation of gut microbial and metabolic products causes intestinal inflammation by modulating immune cells leading to impairment of the primary barrier. But there are limited studies discussing pathogenesis and management of hepatitis with gut microbiota. In this review, we have discussed the role of gut microbiota in pathogenesis and management of various hepatitis, especially hepatitis B and C. We have discussed the role of bacterial products, LPS-TLR4 pathway, and unmethylated CpG DNA, which ultimately affects downstream NF-kB signaling in hepatitis. Finally, we have discussed the role of fecal microbiota transplantation in the management of hepatitis. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, often pose a serious risk not only when delivered in the bloodstream but also in air, the environment and several industrial fields such as pharmaceutics or food. LPS is constituted of three regions; the O-specific chain, the core region and the lipid A, which is the responsible segment of the toxicity. Previous literature dealt with the study of lipid A, its potential ligands as well as the mechanisms of Lipid A interactions that, among other applications, establish the basis for detection methods such as Limulus Amebocyte Lysate (LAL) assays and emerging biosensoring techniques. However, quantifying LPS binding affinity is an urgent need that still requires thorough studies. In this context, this work reviews the molecules that bind LPS, highlighting quantitative affinity parameters. Moreover, state of the art methods to analyze the affinity and kinetics of lipid-ligand interactions are also reviewed and different techniques have been briefly described. Thus, first, we review existing information on LPS ligands, classifying them into three main groups and targeting the comparison of molecules in terms of their interaction affinities and, second, we establish the basis for further research aimed at the development of effective methods for LPS detection and removal. [ABSTRACT FROM AUTHOR]

Abstract Background Recent evidence has suggested that peripheral inflammatory responses induced by lipopolysaccharides (LPS) play an important role in neuropsychiatric dysfunction in rodents. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, has been proposed to be a key mediator in a variety of behavioral dysfunction induced by LPS in mice. Thus, inhibition of IL-1β may have a therapeutic benefit in the treatment of neuropsychiatric disorders. However, the precise underlying mechanism of knock-down of IL-1β in repairing behavioral changes by LPS remains unclear. Methods The mice were treated with either IL-1β shRNA lentivirus or non-silencing shRNA control (NS shRNA) lentivirus by microinjection into the dentate gyrus (DG) regions of the hippocampus. After 7 days of recovery, LPS (1 mg/kg, i.p.) or saline was administered. The behavioral task for memory deficits was conducted in mice by the novel object recognition test (NORT), the anxiety-like behaviors were evaluated by the elevated zero maze (EZM), and the depression-like behaviors were examined by the sucrose preference test (SPT) and the forced swimming test (FST). Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase 1 (HO1), IL-1β, tumor necrosis factor (TNF-α), neuropeptide VGF (non-acronymic), and brain-derived neurotrophic factor (BDNF) were assayed. Results Our results demonstrated that IL-1β knock-down in the hippocampus significantly attenuated the memory deficits and anxiety- and depression-like behaviors induced by LPS in mice. In addition, IL-1β knock-down ameliorated the oxidative and neuroinflammatory responses and abolished the downregulation of VGF and BDNF induced by LPS. Conclusions Collectively, our findings suggest that IL-1β is necessary for the oxidative and neuroinflammatory responses produced by LPS and offers a novel drug target in the IL-1β/oxidative/neuroinflammatory/neurotrophic pathway for treating neuropsychiatric disorders that are closely associated with neuroinflammation, oxidative stress, and the downregulation of VGF and BDNF.

Conformationally constrained peptidomimetics have been developed to mimic interfacial epitopes and target a wide selection of protein-protein interactions. ß-Hairpin mimetics based on constrained macrocyclic peptides have provided access to excellent structural mimics of ß-hairpin epitopes and found applications as interaction inhibitors in many areas of biology and medicinal chemistry. Recently, ß-hairpin peptidomimetics and naturally occurring ß-hairpin-shaped peptides have also been discovered with potent antimicrobial activity and novel mechanisms of action, targeting essential outer membrane protein (OMP) complexes in Gram-negative bacteria. This includes the Lpt complex, required for transporting LPS to the cell surface during OM biogenesis and the BAM complex that folds OMPs and inserts them into the OM bilayer. The Lpt complex is a macromolecular superstructure comprising seven different proteins (LptA-LptG) that spans the entire bacterial cell envelope, whereas the BAM complex is a folding machine comprising a ß-barrel OMP (BamA) and four different lipoproteins (BamB-BamE). Folded synthetic and natural ß-hairpin-shaped peptides appear well-suited for interacting with proteins within the Lpt and BAM complexes that are rich in ß-structure. Recent progress in identifying antibiotics targeting these complexes are reviewed here. Already a clinical candidate has been developed (murepavadin) that targets LptD, with potent antimicrobial activity specifically against pseudmonads. The ability of folded synthetic ß-hairpin epitope mimetics to interact with ß-barrel and ß-jellyroll domains in the Lpt and Bam complexes represent new avenues for antibiotic discovery, which may lead to the development of much needed new antimicrobials to combat the rise of drug-resistant pathogenic Gram-negative bacteria.

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Highlights • H4R expression increased in a rat model of lipopolysaccharide (LPS)-induced CNS inflammation. • Overexpression of H4R in microglial HAPI cells decreased the production of proinflammatory cytokines following LPS stimulation. • Knockdown of H4R enhanced proliferation and migration in LPS-treated microglia. • An interaction between H4R and tumor necrosis factor receptor-associated factor 6 (TRAF6) was observed in microglia. Abstract Microglia, the resident immune cells of the central nervous system (CNS), are activated at the beginning of the inflammatory response and induce detrimental neuroinflammation by producing excessive pro-inflammatory cytokines. Nuclear factor kappa B (NF-κB) signaling facilitates the onset of microglia activation. However, the molecular mechanisms underlying the negative regulation of NF-κB remain to be fully elucidated. In the present study, our results indicated that H4R expression increased in a rat model of lipopolysaccharide (LPS)-induced CNS inflammation. Knockdown of H4R in microglia HAPI cells enhanced the production of cytokines following LPS stimulation. Co-immunoprecipitation experiments further revealed an interaction between H4R and tumor necrosis factor receptor-associated factor 6 (TRAF6) in microglia, which was verified both in vivo and in vitro. Our experimental results support our hypothesis that H4R interacts with TRAF6 to inhibit the release of inflammatory cytokines in LPS-induced microglia cells by decreasing TRAF6-mediated ubiquitination of K63. These findings provide theoretical and experimental evidence regarding the role of H4R in the microglia inflammatory response, which may aid in the development of novel treatments for inflammation. [ABSTRACT FROM AUTHOR]

Herein, we report the total synthesis of the trisaccharide repeating unit of the O-antigen of Actinobacillus actinomycetemcomitans serotype f. The trisaccharide comprising of α-(1–2) and α-(1–3)-linked L-rhamnopyranosides backbone with the latter rhamnose containing a branching N- acetyl- d -galactosaminopyranoside at the C2–O via a β-glycosidic bond was synthesized by two methods. Initially, the protected trisaccharide has been synthesized by step-wise assembly of the monosaccharide building blocks and subsequently the former was synthesized by the one-pot assembly of the latter components. The synthesized trisaccharide contains an aminoethyl linker appended as an O-glycoside at the reducing end, thereby providing scope for further conjugation for different applications. [Display omitted] • Concise step-wise synthesis of the trisaccharide repeating unit. • One-pot synthesis of the trisaccharide repeating unit. • Synthesis of conjugation-ready trisaccharide unit. [ABSTRACT FROM AUTHOR]

This study compared the effects of embryonic and neonatal lipopolysaccharides (LPS) exposure (E-LPS and N-LPS) on oligodendrocyte (OL) differentiation in the hippocampus of male rats and explored the protective effect of the antioxidant alpha-glycosyl isoquercitrin (AGIQ). Using SD rats, LPS exposure occurred either intraperitoneally in dams between gestational days 15 and 16 (50 µg/kg body weight/time) or in male pups on postnatal day (PND) 3 (1 mg/kg body weight). Under both regimens, AGIQ at 0.5% (w/w) was supplemented, to dams from the gestation period (before LPS exposure) until weaning on PND 21 and to male offspring from weaning until PND 77 (adulthood). Compared with a control treatment, E-LPS treatment resulted in fewer NG2+ OL progenitor cells (OPCs) and an upregulation of Tcf4 at PND 6; by PND 21, low NG2+ OPC number persisted, but OLIG2+ OL lineage cells increased, while CNPase+ mature OLs counts were unchanged. By contrast, N-LPS treatment resulted in fewer OLIG2+ cells and an upregulation of Bmp4 at PND 6; by PND 21, NG2+ OPCs decreased, while GFAP+ astrocytes increased at both PND 6 and 21. After N-LPS treatment, Kl and Yy1 were downregulated and there were fewer Klotho+ and CNPase+ cells at PND 21. Results suggest that E-LPS treatment facilitates OPC differentiation into pre- and immature OLs until weaning, while N-LPS treatment suppresses OPC differentiation into mature OLs but facilitates astrocyte generation; however, these changes spontaneously recovered by adulthood under both regimens. AGIQ treatment ameliorated the effects of LPS treatment of both regimens, suggesting that LPS-induced disruption of OPC/OL differentiation occurs via neuroinflammation. • E-LPS suggested to cause OPC differentiation into pre- and immature OLs until weaning. • N-LPS might suppress OL differentiation but facilitate astrocyte generation. • Observed changes spontaneously recovered by adulthood under both exposure regimens. • AGIQ treatment ameliorated the effects of LPS treatment in both regimens. • Neuroinflammation might cause LPS-induced disruption of OPC/OL differentiation. [ABSTRACT FROM AUTHOR]

Background/Aims: Although acute lung injury (ALI) is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. Methods: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV) carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS) to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus-mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. Results: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFα, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. Conclusion: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI.