Lipopolysaccharide-induced Systemic Inflammation Research Articles

The renoprotective effects of cannabidiol on lipopolysaccharide-induced systemic inflammation model of rats.

Sepsis-induced renal damage poses a significant threat, necessitating effective therapeutic strategies. Cannabidiol (CBD) has beneficial effects on tissues and their functions by exhibiting antioxidant and anti-inflammatory effects. This study investigates the potential protective effects of CBD in mitigating lipopolysaccharide (LPS)-induced renal injury in Wistar Albino rats. Thirty-two Wistar Albino rats were categorized into control, LPS (5mg/kg i.p.), LPS + CBD, and CBD (5mg/kg i.p.) groups. After the experiment, samples were collected for biochemical, genetic, histopathological, and immunohistochemical analyses. Oxidative stress markers as total oxidant status (TOS) and total antioxidant status (TAS), oxidative stress index (OSI), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), immune staining as tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), caspase-3, gene expressions as nuclear factor erythroid 2-related factor 2 (NRF2), C/EBP homologous protein (CHOP), caspase-9, glucose-regulating protein 78 (GRP78), B-cell leukemia/lymphoma 2 (Bcl2), and tissue histology have been examined. The LPS-exposed group exhibited significant renal abnormalities, mitigated by CBD intervention in the LPS + CBD group. CBD reduced immunoexpression scores for TNF-α, caspase-3, and IL-10. Biochemically, CBD induced a positive shift in the oxidative balance, increasing TAS, SOD, and GPx, while decreasing TOS, OSI, and MDA levels. Genetic analyses highlighted CBD's regulatory impact on NRF2, CHOP, caspase-9, GRP78, and Bcl2, providing molecular insights into its protective role against LPS-induced renal damage. This study underscores CBD as a promising protective agent against sepsis-induced renal damage. Our findings could provide valuable insights into potential therapeutic avenues for addressing renal complications in sepsis.

Heterozygous Apex1 deficiency exacerbates lipopolysaccharide-induced systemic inflammation in a murine model

The biological role of apurinic/apyrimidinic endonuclease 1/redox factor-1 (Apex1) in modulating systemic inflammation remains unclear. This study aimed to assess the impact of Apex1 deficiency on systemic inflammation triggered by lipopolysaccharide (LPS) in a murine model. The methods involved transcriptomic analysis and assessments of inflammatory responses in age-matched 8-week-old Apex1+/− and wild-type Apex1+/+ mice, generated using the CRISPR/Cas9 system. Apex1+/− mice displayed no overt changes in body weight, however, Apex1 protein expressions in tissues were significantly reduced compared to wild-type mice. Furthermore, in Apex1+/− mice transcriptomic analysis showed that genes associated with antioxidant pathways were downregulated, and levels of superoxide production, 8-hydroxy-2′-deoxyguanosine (8-OHdG), and malondialdehyde (MDA) were increased. Moreover, hematological analysis showed increased neutrophil levels and a twofold increase in the count of splenic lymphocyte antigen 6 family member G+ (Ly6G+) neutrophils in the Apex1+/− mice compared to those in Apex1+/+ mice. Furthermore, following LPS treatment, the levels of cytokines and chemokines, including interleukin-1β, interleukin-10, tumor necrosis factor-α, and monocyte chemoattractant protein 1, increased in the Apex1+/− mice. The Kaplan-Meier curve showed a significant reduction in the survival rates of Apex1+/− mice treated with LPS compared to those of Apex1+/+ mice. The hepatic and lung injury scores and Ly6G+ neutrophil infiltration levels also increased in Apex1+/− mice after LPS treatment. These results showed that Apex1 deficiency exacerbated the LPS-induced tissue damage in the lung and liver. These findings illustrate that in vivo Apex1 deficiency exacerbates LPS-induced systemic inflammation, tissue damage, and mortality in a murine model, highlighting the crucial role of Apex1 in mitigating inflammatory responses and maintaining a holistic physiological equilibrium.

Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome.

The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5'-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5'-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5'-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.

2,4'-Dihydroxybenzophenone: A Promising Anti-Inflammatory Agent Targeting Toll-like Receptor 4/Myeloid Differentiation Factor 2-Mediated Mitochondrial Reactive Oxygen Species Production during Lipopolysaccharide-Induced Systemic Inflammation.

The biochemical properties of 2,4'-dihydroxybenzophenone (DHP) have not been extensively studied. Therefore, this study aimed to investigate whether DHP could alleviate inflammatory responses induced by lipopolysaccharide (LPS) and endotoxemia. The results indicated that DHP effectively reduced mortality and morphological abnormalities, restored heart rate, and mitigated macrophage and neutrophil recruitment to inflammatory sites in LPS-microinjected zebrafish larvae. Additionally, the expression of pro-inflammatory mediators, including inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12), was significantly reduced in the presence of DHP. In RAW 264.7 macrophages, DHP inhibited the LPS-induced inflammatory response by downregulating pro-inflammatory mediators and decreasing the expression of myeloid differentiation primary response 88 (MyD88), phosphorylation of IL-1 receptor-associated protein kinase-4 (p-IRAK4), and nuclear factor-κB (NF-κB). Molecular docking analysis demonstrated that DHP occupies the hydrophobic pocket of myeloid differentiation factor 2 (MD2) and blocks the dimerization of Toll-like receptor 4 (TLR4). A molecular dynamics simulation confirmed that DHP stably bound to the hydrophobic pocket of MD2. Furthermore, the DHP treatment inhibited mitochondrial reactive oxygen species (mtROS) production during the LPS-induced inflammatory response in both RAW 264.7 macrophages and zebrafish larvae, which was accompanied by stabilizing mitochondrial membrane potential. In conclusion, our study highlights the therapeutic potential of DHP in alleviating LPS-induced inflammation and endotoxemia. The findings suggest that DHP exerts its anti-inflammatory effects by inhibiting the TLR4/MD2 signaling pathway and reducing the level of mtROS production. These results contribute to a better understanding of the biochemical properties of DHP and support its further exploration as a potential therapeutic agent for inflammatory conditions and endotoxemia.

The investigation of the molecular changes during lipopolysaccharide-induced systemic inflammation on rat hippocampus by using FTIR spectroscopy.

The aim of this study is to reveal the molecular changes accompanying the neuronal hyper-excitability during lipopolysaccharide (LPS)-induced systemic inflammation on rat hippocampus using Fourier transform infrared (FTIR) spectroscopy. For this aim, the body temperature of Wistar albino rats administered LPS or saline was recorded by radiotelemetry. The animals were decapitated when their body temperature began to decrease by 0.5°C after LPS treatment and the hippocampi of them were examined by FTIR spectroscopy. The results indicated that systemic inflammation caused lipid peroxidation, an increase in the amounts of lipids, proteins and nucleic acids, a decrease in membrane order, an increase in membrane dynamics and changes in the secondary structure of proteins. Principal component analysis successfully separated control and LPS-treated groups. In conclusion, significant structural, compositional and functional alterations occur in the hippocampus during systemic inflammation and these changes may have specific characteristics which can lead to neuronal hyper-excitability.

Anti-Inflammatory Effects of Idebenone Attenuate LPS-Induced Systemic Inflammatory Diseases by Suppressing NF-κB Activation.

Inflammation is a natural protective process through which the immune system responds to injury, infection, or irritation. However, hyperinflammation or long-term inflammatory responses can cause various inflammatory diseases. Although idebenone was initially developed for the treatment of cognitive impairment and dementia, it is currently used to treat various diseases. However, its anti-inflammatory effects and regulatory functions in inflammatory diseases are yet to be elucidated. Therefore, this study aimed to investigate the anti-inflammatory effects of idebenone in cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation. Murine models of cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation were generated, followed by treatment with various concentrations of idebenone. Additionally, lipopolysaccharide-stimulated macrophages were treated with idebenone to elucidate its anti-inflammatory effects at the cellular level. Idebenone treatment significantly improved survival rate, protected against tissue damage, and decreased the expression of inflammatory enzymes and cytokines in mice models of sepsis and systemic inflammation. Additionally, idebenone treatment suppressed inflammatory responses in macrophages, inhibited the NF-κB signaling pathway, reduced reactive oxygen species and lipid peroxidation, and normalized the activities of antioxidant enzyme. Idebenone possesses potential therapeutic application as a novel anti-inflammatory agent in systemic inflammatory diseases and sepsis.

Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation

Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1β production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1β expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1β maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1β production, providing a potential inflammatory disease target.

Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis

While antibiotics are designed to target bacteria specifically, most are known to affect host cell physiology. Certain classes of antibiotics have been reported to have immunosuppressive effects, but the underlying mechanisms remain elusive. Here, we show that doxycycline, a ribosomal-targeting antibiotic, effectively inhibited both mitochondrial translation and nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated caspase-1 activation and interleukin-1β (IL-1β) production in bone-marrow-derived macrophages (BMDMs). In addition, knockdown of mitochondrial methionyl-tRNA formyltransferase (Mtfmt), which is rate limiting for mitochondrial translation, also resulted in the inhibition of NLRP3 inflammasome-mediated caspase-1 activation and IL-1β secretion. Furthermore, both doxycycline treatment and Mtfmt knockdown blocked the synthesis of mitochondrial DNA (mtDNA) and the generation of oxidized mtDNA (Ox-mtDNA), which serves as a ligand for NLRP3 inflammasome activation. In addition, in vivo results indicated that doxycycline mitigated NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and endometritis. Taken together, the results unveil the antibiotics targeting the mitoribosome have the ability to mitigate NLRP3 inflammasome activation by inhibiting mitochondrial translation and mtDNA synthesis thus opening up new possibilities for the treatment of NLRP3-related diseases.

Lipopolysaccharide triggers exacerbated microglial activation, excessive cytokine release and behavioural disturbances in mice with truncated Fused-in-Sarcoma Protein (FUS)

CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1–359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1–359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1–359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1–359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1–359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression.

Fraxin in Combination with Dexamethasone Attenuates LPS-Induced Liver and Heart Injury and Their Anticytokine Activity in Mice.

Cytokine storm syndrome (CSS) is a major cause of morbidity and mortality in people suffering from hyperinflammatory status, which diverse etiological factors, including pathogens, therapeutic interventions, malignancies, and autoimmune disorders, can instigate. Since there is limited research on the antioxidant properties of fraxin and no studies have investigated its potential as an anticytokine storm agent, it is important to note that most studies have primarily focused on proinflammatory cytokines such as IL-1β, IL-6, and TNFα during cytokine storm. However, little research discusses the role of chemokines, particularly IL-8, during cytokine storms. Therefore, further investigation is warranted into the role of fraxin as an anticytokine storm agent and the involvement of IL-8 in cytokine storms. The present study examines the preventive efficacy of fraxin and the combination of fraxin and dexamethasone (FD) in mitigating lipopolysaccharide-induced systemic inflammation in mice caused by Escherichia coli, 055: B5. Five groups of ten mice were randomly assigned: LPS only group (5 mg/kg, intraperitoneally i.p.), control (normal saline N.S. 1 ml/kg, i.p.), concentrations were selected based on previous literature, fraxin (120 mg/kg, i.p.), dexamethasone (5 mg/kg, i.p.), fraxin + dexamethasone (FD) (60 mg/kg + 2.5 mg/kg, i.p.), administered one hour before LPS injection (5 mg/kg,i.p.), animals were euthanized next day, and interleukin-8 (IL-8) was quantified in serum using an enzyme-linked immunosorbent assay. The liver and heart tissues underwent histopathological analysis to assess morphological changes. For data analysis using ANOVA and Tukey post hoc tests, the Kruskal-Wallis and Mann-Whitney U tests were employed to analyze the histological results. A significant decline in IL-8 levels was recorded in the treatment groups almost to the same degree (p < 0.001), and the percentage of inhibition of IL-8 for fraxin, dexamethasone, and FD was 93%.92.4%, and 93%, respectively, compared to the LPS-only group. Histopathological scores were significantly reduced in liver and heart tissue (P < 0.05). All interventions used in this study significantly reduced interleukin-8 (IL-8) levels and reduced LPS-induced liver and cardiac damage. The combination (FD) did not result in an evident superiority of either agent. More research is required to identify the possible usefulness of these agents in treating hyperinflammatory diseases, such as cytokine storms, in future clinical practice.

Mefloquine targets NLRP3 to reduce lipopolysaccharide-induced systemic inflammation and neural injury.

The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well-known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA-approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide-induced systemic inflammation and Parkinson's disease-like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3-driven diseases and migth expand its clinical use considerably.

Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein

Objective Mitochondrial dysfunction was observed in acute systemic inflammatory conditions such as sepsis and might be involved in sepsis-induced multi-organ failure. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2), also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1), a bi-organellar protein located in the mitochondria and the nucleus, is implicated in cell respiration, survival, and response to tissue hypoxia. Recently, the reduction of the cellular CHCHD2/MNRR1 protein, as part of mitochondrial dysfunction, has been shown to play a role in the amplification of inflammatory cytokines in a murine model of lipopolysaccharide-induced systemic inflammation. The aim of this study was to determine whether the plasma concentration of CHCHD2/MNRR1 changed during human normal pregnancy, spontaneous labor at term, and clinical chorioamnionitis at term. Methods We conducted a cross-sectional study that included the following groups: 1) non-pregnant women (n = 17); 2) normal pregnant women at various gestational ages from the first trimester until term (n = 110); 3) women at term with spontaneous labor (n = 50); and 4) women with clinical chorioamnionitis at term in labor (n = 25). Plasma concentrations of CHCHD2/MNRR1 were assessed by an enzyme-linked immunosorbent assay. Results 1) Pregnant women at term in labor with clinical chorioamnionitis had a significantly higher plasma CHCHD2/MNRR1 concentration than those in labor without chorioamnionitis (p = .003); 2) CHCHD2/MNRR1 is present in the plasma of healthy non-pregnant and normal pregnant women without significant differences in its plasma concentrations between the two groups; 3) there was no correlation between maternal plasma CHCHD2/MNRR1 concentration and gestational age at venipuncture; and 4) plasma CHCHD2/MNRR1 concentration was not significantly different in women at term in spontaneous labor compared to those not in labor. Conclusions CHCHD2/MNRR1 is physiologically present in the plasma of healthy non-pregnant and normal pregnant women, and its concentration does not change with gestational age and parturition at term. However, plasma CHCHD2/MNRR1 is elevated in women at term with clinical chorioamnionitis. CHCHD2/MNRR1, a novel bi-organellar protein located in the mitochondria and the nucleus, is released into maternal plasma during systemic inflammation.

Neuroprotection by Abdominal Ultrasound in Lipopolysaccharide-Induced Systemic Inflammation.

Systemic inflammation is associated with intestinal inflammation and neuroinflammation by imbalancing the gut-brain axis. Low-intensity pulsed ultrasound (LIPUS) has neuroprotective and anti-inflammatory effects. This study explored LIPUS's neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation through transabdominal stimulation. Male C57BL/6J mice were intraperitoneally injected with LPS (0.75 mg/kg) daily for seven days, and abdominal LIPUS was applied to the abdominal area for 15 min/day during the last six days. One day after the last LIPUS treatment, biological samples were collected for microscopic and immunohistochemical analysis. Histological examination showed that LPS administration leads to tissue damage in the colon and brain. Transabdominal LIPUS stimulation attenuated colonic damage, reducing histological score, colonic muscle thickness, and villi shortening. Furthermore, abdominal LIPUS reduced hippocampal microglial activation (labeled by ionized calcium-binding adaptor molecule-1 [Iba-1]) and neuronal cell loss (labeled by microtubule-associated protein 2 [MAP2]). Moreover, abdominal LIPUS attenuated the number of apoptotic cells in the hippocampus and cortex. Altogether, our results indicate that abdominal LIPUS stimulation attenuates LPS-induced colonic inflammation and neuroinflammation. These findings provide new insights into the treatment strategy for neuroinflammation-related brain disorders and may facilitate method development through the gut-brain axis pathway.

Protection of Neuronal Cells from Lipopolysaccharide-Induced Systemic Inflammation by Gossypetin

Systemic inflammation caused by infection, surgery, or injury can lead to cognitive decline. Lipopolysaccharides are known as toll-like receptor 4 ligands, which are common to the cell walls of gram-negative bacteria. Activation of toll-like receptor 4 leads to the production of proinflammatory cytokines that subsequently mediate systemic inflammation. Furthermore, induc¬tion of systemic inflammation by lipopolysaccharide injection in mice can affect the brain, including cognitive functions. To investigate the neuroprotective role of gossypetin in systemic inflammation, a mouse hippocampal cell line (HT22) and mice were challenged with lipopolysaccharide. The increase in proinflammatory cytokines and reactive oxygen species caused by lipopolysaccharide treatment in HT22 cells was decreased by gossypetin treatment. To evaluate the protective function against memory impairment, gossypetin was orally administered to C57BL/6J mice receiving lipopolysaccharide injec¬tion. Lipopolysaccharide-induced memory deficit was observed in lipopolysaccharide-only treated group in Y-maze test. However, the group treated with gossypetin and lipopolysaccharide had a diminution in cognitive impairment. Consistent with the behavioral test results, the proinflammatory cytokines were also relatively downregulated in the gossypetin-treated mouse group. To sum up, gossypetin can be protect the neuron cells from inflammation in vitro and prevent the cognitive impairment in mice in vivo.

Intravenous surfactant protein D inhibits lipopolysaccharide-induced systemic inflammation

BackgroundSurfactant protein D (SP-D) is an innate host defense protein that clears infectious pathogens from the lung and regulates pulmonary host defense cells. SP-D is also detected in lower concentrations in plasma and many other non-pulmonary tissues. Plasma levels of SP-D increase during infection and other proinflammatory states; however, the source and functions of SP-D in the systemic circulation are largely unknown. We hypothesized that systemic SP-D may clear infectious pathogens and regulate host defense cells in extrapulmonary systems. MethodsTo determine if SP-D inhibited inflammation induced by systemic lipopolysaccharide (LPS), E.coli LPS was administered to mice via tail vein injection with and without SP-D and the inflammatory response was measured. ResultsSystemic SP-D has a circulating half-life of 6 h. Systemic IL-6 levels in mice lacking the SP-D gene were similar to wild type mice at baseline but were significantly higher than wild type mice following LPS treatment (38,000 vs 29,900 ng/ml for 20 mg/kg LPS and 100,700 vs 73,700 ng/ml for 40 mg/kg LPS). In addition, treating wild type mice with purified intravenous SP-D inhibited LPS induced secretion of IL-6 and TNFα in a concentration dependent manner. Inhibition of LPS induced inflammation by SP-D correlated with SP-D LPS binding suggesting SP-D mediated inhibition of systemic LPS requires direct SP-D LPS interactions. ConclusionsTaken together, the above results suggest that circulating SP-D decreases systemic inflammation and raise the possibility that a physiological purpose of increasing systemic SP-D levels during infection is to scavenge systemic infectious pathogens and limit inflammation-induced tissue injury.

Time course and mechanistic analysis of human umbilical cord perivascular cell mitigation of lipopolysaccharide-induced systemic and neurological inflammation

Background aimsBecause of their potent immunomodulatory and anti-inflammatory properties, mesenchymal stromal cells are a major focus in the field of stem cell therapy. However, the precise mechanisms underlying this are not entirely understood. Human umbilical cord perivascular cells (HUCPVCs) are a promising cell therapy candidate. This study was designed to evaluate the time course and mechanisms by which HUCPVCs mitigate lipopolysaccharide (LPS)-induced systemic and neurological inflammation in immunocompetent mice. To explore the underlying mechanisms, the authors investigated the biodistribution and fate of HUCPVCs. MethodsMale C57BL/6 mice were randomly allocated to four groups: control, LPS, HUCPVCs or LPS + HUCPVCs. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and cytokine arrays were used to assess changes in pro-inflammatory mediators systemically and in the brain. Depressive-like behavioral changes were evaluated via a forced swim test. Quantum dot (qDot) labeling and immunohistochemistry were used to assess the biodistribution and fate of HUCPVCs and interactions with recipient innate immune cells. ResultsA single intravenously delivered dose of HUCPVCs significantly reduced the systemic inflammation induced by LPS within the first 24 h after administration. HUCPVC treatment abrogated the upregulated expression of pro-inflammatory genes in the hippocampus and cortex and attenuated depressive-like behavior induced by LPS treatment. Biodistribution analysis revealed that HUCPVC-derived qDots rapidly accumulated in the lungs and demonstrated limited in vivo persistence. Furthermore, qDot signals were associated with major recipient innate immune cells and promoted a shift in macrophages toward a regulatory phenotype in the lungs. ConclusionsOverall, this study demonstrates that HUCPVCs can successfully reduce systemic and neurological inflammation induced by LPS within the first 24 h after administration. Biodistribution and fate analyses suggest a critical role for the innate immune system in the HUCPVC-based immunomodulation mechanism.

Cow's microbiome from antepartum to postpartum: A long-term study covering two physiological challenges.

Little is known about the interplay between the ruminant microbiome and the host during challenging events. This long-term study investigated the ruminal and duodenal microbiome and metabolites during calving as an individual challenge and a lipopolysaccharide-induced systemic inflammation as a standardized challenge. Strong inter- and intra-individual microbiome changes were noted during the entire trial period of 168 days and between the 12 sampling time points. Bifidobacterium increased significantly at 3 days after calving. Both challenges increased the intestinal abundance of fiber-associated taxa, e.g., Butyrivibrio and unclassified Ruminococcaceae. NMR analyses of rumen and duodenum samples identified up to 60 metabolites out of which fatty and amino acids, amines, and urea varied in concentrations triggered by the two challenges. Correlation analyses between these parameters indicated a close connection and dependency of the microbiome with its host. It turns out that the combination of phylogenetic with metabolite information supports the understanding of the true scenario in the forestomach system. The individual stages of the production cycle in dairy cows reveal specific criteria for the interaction pattern between microbial functions and host responses.

RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth

An acute inflammatory response needs to be properly regulated to promote the elimination of pathogens and prevent the risk of tumorigenesis, but the relevant regulatory mechanism has not been fully elucidated. Here, we report that Ras guanine nucleotide-releasing protein 1 (RasGRP1) is a bifunctional regulator that promotes acute inflammation and inhibits inflammation-associated cancer. At the mRNA level, Rasgrp1 activates the inflammatory response by functioning as a competing endogenous RNA to specifically promote IL-6 expression by sponging let-7a. In vivo overexpression of the Rasgrp1 3’ untranslated region enhances lipopolysaccharide-induced systemic inflammation and dextran sulphate sodium-induced colitis in Il6+/+ mice but not in Il6-/- mice. At the protein level, RasGRP1 overexpression significantly inhibits the tumour-promoting effect of IL-6 in hepatocellular carcinoma progenitor cell-like spheroids. Examination of the EGFR signalling pathway shows that RasGRP1 inhibits inflammation-associated cancer cell growth by disrupting the EGFR-SOS1-Ras-AKT signalling pathway. Tumour patients with high RasGRP1 expression have better clinical outcomes than those with low RasGRP1 expression. Considering that acute inflammation rarely leads to tumorigenesis, this study suggests that RasGRP1 may be an important bifunctional regulator of the acute inflammatory response and tumour growth.

Structural Characterization and In Vivo Anti-Inflammatory Activity of Fucoidan from Cystoseira crinita (Desf.) Borry.

The aim of this study was to evaluate the effects of fucoidan isolated from C. crinita on histamine-induced paw inflammation in rats, and on the serum levels of TNF-α, IL-1β, IL-6, and IL-10 in rats during systemic inflammation response. The levels of TNF-α in a model of acute peritonitis in rats were also investigated. The isolated crude fucoidan was identified as a sulfated xylogalactofucan with high, medium, and low molecular weight fractions and a content of fucose of 39.74%, xylose of 20.75%, and galactose of 15.51%. Fucoidan from C. crinita showed better anti-inflammatory effects in the rat paw edema model, and this effect was present during all stages of the experiment. When compared to controls, a commercial fucoidan from F. vesiculosus, the results also displayed anti-inflammatory activity on the 60th, 90th, and 120th minute of the experiment. A significant decrease in serum levels of IL-1β in rats treated with both doses of C. crinita fucoidan was observed in comparison to controls, whereas TNF-α concentrations were reduced only in the group treated with fucoidan from C. crinita at the dose of 25 mg/kg bw. In the model of carrageenan-induced peritonitis, we observed a tendency of decrease in the levels of the pro-inflammatory cytokine TNF-α in peritoneal fluid after a single dose of C. crinita fucoidan, but this did not reach the statistical significance margin. Single doses of C. crinita fucoidan did not alter serum levels of the anti-inflammatory cytokine IL-10 in animals with lipopolysaccharide-induced systemic inflammation.

Effects of lipopolysaccharide-induced systemic inflammation and fatigue on cognitive effort expenditure

Effects of lipopolysaccharide-induced systemic inflammation and fatigue on cognitive effort expenditure