scholarly journals Novel Insights for Systemic Inflammation in Sepsis and Hemorrhage

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Bolin Cai ◽  
Edwin A. Deitch ◽  
Luis Ulloa
Keyword(s):  
Inflammatory Responses ◽  
Ethyl Pyruvate ◽  
High Mobility ◽  
Organ Damage ◽  
Experimental Models ◽  
Experimental Sepsis ◽  
Alpha7 Nicotinic Acetylcholine Receptor ◽  
Therapeutic Benefits ◽  
Anti Inflammatory ◽  
Necrosis Factor

The inflammatory responses in sepsis and hemorrhage remain a major cause of death. Clinically, it is generally accepted that shock in sepsis or hemorrhage differs in its mechanisms. However, the recognition of inflammatory cytokines as a common lethal pathway has become consent. Proinflammatory cytokines such as tumor necrosis factor (TNF) or high-mobility group box1 (HMGB1) are fanatically released and cause lethal multiorgan dysfunction. Inhibition of these cytokines can prevent the inflammatory responses and organ damage. In seeking potential anti-inflammatory strategies, we reported that ethyl pyruvate and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonists effectively restrained cytokine production to provide therapeutic benefits in both experimental sepsis and hemorrhage. Here, we review the inflammatory responses and the anti-inflammatory strategies in experimental models of sepsis and hemorrhage, as they may have a consistent inflammatory pathway in spite of their different pathophysiological processes.

scholarly journals Multiple Disruptions of Glial-Neuronal Networks in Epileptogenesis That Follows Prolonged Febrile Seizures

2021 ◽  
Vol 12 ◽  
Author(s):  
Gary P. Brennan ◽  
Megan M. Garcia-Curran ◽  
Katelin P. Patterson ◽  
Renhao Luo ◽  
Tallie Z. Baram
Keyword(s):  
Neuronal Networks ◽  
Day Treatment ◽  
High Mobility ◽  
Febrile Seizures ◽  
Experimental Models ◽  
Normal Brain ◽  
Molecular Signaling ◽  
Rat Pups ◽  
Anti Inflammatory

Background and Rationale: Bi-directional neuronal-glial communication is a critical mediator of normal brain function and is disrupted in the epileptic brain. The potential role of aberrant microglia and astrocyte function during epileptogenesis is important because the mediators involved provide tangible targets for intervention and prevention of epilepsy. Glial activation is intrinsically involved in the generation of childhood febrile seizures (FS), and prolonged FS (febrile status epilepticus, FSE) antecede a proportion of adult temporal lobe epilepsy (TLE). Because TLE is often refractory to treatment and accompanied by significant memory and emotional difficulties, we probed the role of disruptions of glial-neuronal networks in the epileptogenesis that follows experimental FSE (eFSE).Methods: We performed a multi-pronged examination of neuronal-glia communication and the resulting activation of molecular signaling cascades in these cell types following eFSE in immature mice and rats. Specifically, we examined pathways involving cytokines, microRNAs, high mobility group B-1 (HMGB1) and the prostaglandin E2 signaling. We aimed to block epileptogenesis using network-specific interventions as well as via a global anti-inflammatory approach using dexamethasone.Results: (A) eFSE elicited a strong inflammatory response with rapid and sustained upregulation of pro-inflammatory cytokines. (B) Within minutes of the end of the eFSE, HMGB1 translocated from neuronal nuclei to dendrites, en route to the extracellular space and glial Toll-like receptors. Administration of an HMGB1 blocker to eFSE rat pups did not decrease expression of downstream inflammatory cascades and led to unacceptable side effects. (C) Prolonged seizure-like activity caused overall microRNA-124 (miR-124) levels to plunge in hippocampus and release of this microRNA from neurons via extra-cellular vesicles. (D) Within hours of eFSE, structural astrocyte and microglia activation was associated not only with cytokine production, but also with activation of the PGE2 cascade. However, administration of TG6-10-1, a blocker of the PGE2 receptor EP2 had little effect on spike-series provoked by eFSE. (E) In contrast to the failure of selective interventions, a 3-day treatment of eFSE–experiencing rat pups with the broad anti-inflammatory drug dexamethasone attenuated eFSE-provoked pro-epileptogenic EEG changes.Conclusions: eFSE, a provoker of TLE-like epilepsy in rodents leads to multiple and rapid disruptions of interconnected glial-neuronal networks, with a likely important role in epileptogenesis. The intricate, cell-specific and homeostatic interplays among these networks constitute a serious challenge to effective selective interventions that aim to prevent epilepsy. In contrast, a broad suppression of glial-neuronal dysfunction holds promise for mitigating FSE-induced hyperexcitability and epileptogenesis in experimental models and in humans.

scholarly journals Effect of Kramecyne on the Inflammatory Response in Lipopolysaccharide-Stimulated Peritoneal Macrophages

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
E. Sánchez-Miranda ◽  
J. Lemus-Bautista ◽  
S. Pérez ◽  
J. Pérez-Ramos
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Peritoneal Macrophages ◽  
Anti Inflammatory ◽  
Oxide Synthase ◽  
North And South America ◽  
North And South ◽  
Mouse Peritoneal Macrophages ◽  
Necrosis Factor

Kramecyne is a new peroxide, it was isolated fromKrameria cytisoides, methanol extract, and this plant was mostly found in North and South America. This compound showed potent anti-inflammatory activity; however, the mechanisms by which this compound exerts its anti-inflammatory effect are not well understood. In this study, we examined the effects of kramecyne on inflammatory responses in mouse lipopolysaccharide- (LPS-) induced peritoneal macrophages. Our findings indicate that kramecyne inhibits LPS-induced production of tumor necrosis factor (TNF-α) and interleukin- (IL-) 6. During the inflammatory process, levels of cyclooxygenase- (COX-) 2, nitric oxide synthase (iNOS), and nitric oxide (NO) increased in mouse peritoneal macrophages; however, kramecyne suppressed them significantly. These results provide novel insights into the anti-inflammatory actions and support its potential use in the treatment of inflammatory diseases.

scholarly journals Antioxidant and Anti-Inflammatory Potential of Thymoquinone and Lycopene Mitigate the Chlorpyrifos-Induced Toxic Neuropathy

2021 ◽  
Vol 14 (9) ◽  
pp. 940
Author(s):  
Mohamed Aboubakr ◽  
Said M. Elshafae ◽  
Ehab Y. Abdelhiee ◽  
Sabreen E. Fadl ◽  
Ahmed Soliman ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Corn Oil ◽  
Organophosphate Pesticide ◽  
Toxic Neuropathy ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Apoptotic Effects ◽  
Oxidative State ◽  
Necrosis Factor

CPF (chlorpyrifos) is an organophosphate pesticide used in agricultural and veterinary applications. Our experiment aimed to explore the effects of thymoquinone (TQ) and/or lycopene (LP) against CPF-induced neurotoxicity. Wistar rats were categorized into seven groups: first group served as a control (corn oil only); second group, TQ (10 mg/kg); third group, LP (10 mg/kg); fourth group, CPF (10 mg/kg) and deemed as CPF toxic control; fifth group, TQ + CPF; sixth group, (LP + CPF); and seventh group, (TQ + LP + CPF). CPF intoxication inhibited acetylcholinesterase (AchE), decreased glutathione (GSH) content, and increased levels of malondialdehyde (MDA), an oxidative stress biomarker. Furthermore, CPF impaired the activity of antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT) along with enhancement of the level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β. CPF evoked apoptosis in brain tissue. TQ or LP treatment of CPF-intoxicated rats greatly improved AchE activity, oxidative state, inflammatory responses, and cell death. Co-administration of TQ and LP showed better restoration than their sole treatment. In conclusion, TQ or LP supplementation may alleviate CPF-induced neuronal injury, most likely due to TQ or LPs’ antioxidant, anti-inflammatory, and anti-apoptotic effects.

scholarly journals TNF-α as a Therapeutic Target in Acute Pancreatitis — Lessons from Experimental Models

2007 ◽  
Vol 7 ◽  
pp. 431-448 ◽  
Author(s):  
Giuseppe Malleo ◽  
Emanuela Mazzon ◽  
Ajith K. Siriwardena ◽  
Salvatore Cuzzocrea
Keyword(s):  
Acute Pancreatitis ◽  
Tumor Necrosis ◽  
Serum Levels ◽  
Organ Damage ◽  
Experimental Models ◽  
Clinical Applications ◽  
Inclusion Criteria ◽  
Tnf Α ◽  
Considerable Body ◽  
Necrosis Factor

A considerable body of experimental evidence suggests that tumor necrosis factor (TNF)-α plays a major role in several aspects of inflammation and shock. In particular, it is pivotal in many detrimental effects of acute pancreatitis, and it represents a major determinant of the systemic progression and end-organ damage (such as acute lung injury and liver failure) of this pathologic condition. Given the importance of TNF-α in the pathogenesis of acute pancreatitis, investigators have regarded blocking the action of this mediator as an attractive treatment option. Different specific and nonspecific inhibitors have been developed with promising results in animal models, but, on the other hand, no clinical trials have been designed so far. Difficulties in clinical applications may be multifactorial; experimental models are not fully reliable and reproduce at least some aspects of human disease, timing of intervention should be related to changes in TNF-α serum levels, and inclusion criteria should be accurately selected to better define the population most likely to benefit.

scholarly journals Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis

Life ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 57
Author(s):  
Christian Lehmann ◽  
Maral Aali ◽  
Juan Zhou ◽  
Bruce Holbein
Keyword(s):  
Bacterial Pathogens ◽  
Normal Component ◽  
Abdominal Sepsis ◽  
Experimental Models ◽  
Water Soluble ◽  
Iron Chelators ◽  
Therapeutic Benefits ◽  
Anti Inflammatory

Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine—DFO; deferiprone—DFP; and deferasirox—DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis.

scholarly journals Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

2020 ◽  
Author(s):  
Jérôme Hadjadj ◽  
Nader Yatim ◽  
Laura Barnabei ◽  
Aurélien Corneau ◽  
Jeremy Boussier ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
High Risk Population ◽  
Type I ◽  
Interferon Stimulated Genes ◽  
Tnf Α ◽  
Interferon Activity ◽  
Anti Inflammatory ◽  
Global Threat ◽  
Necrosis Factor

AbstractBackgroundCoronavirus disease 2019 (Covid-19) is a major global threat that has already caused more than 100,000 deaths worldwide. It is characterized by distinct patterns of disease progression implying a diverse host immune response. However, the immunological features and molecular mechanisms involved in Covid-19 severity remain so far poorly known.MethodsWe performed an integrated immune analysis that included in-depth phenotypical profiling of immune cells, whole-blood transcriptomic and cytokine quantification on a cohort of fifty Covid19 patients with a spectrum of disease severity. All patient were tested 8 to 12 days following first symptoms and in absence of anti-inflammatory therapy.ResultsA unique phenotype in severe and critically ill patients was identified. It consists in a profoundly impaired interferon (IFN) type I response characterized by a low interferon production and activity, with consequent downregulation of interferon-stimulated genes. This was associated with a persistent blood virus load and an exacerbated inflammatory response that was partially driven by the transcriptional factor NFĸB. It was also characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling as well as increased innate immune chemokines.ConclusionWe propose that type-I IFN deficiency in the blood is a hallmark of severe Covid-19 and could identify and define a high-risk population. Our study provides a rationale for testing IFN administration combined with adapted anti-inflammatory therapy targeting IL-6 or TNF-α in most severe patients. These data also raise concern for utilization of drugs that interfere with the IFN pathway.

scholarly journals BAY 11-7082 Is a Broad-Spectrum Inhibitor with Anti-Inflammatory Activity against Multiple Targets

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Jaehwi Lee ◽  
Man Hee Rhee ◽  
Eunji Kim ◽  
Jae Youl Cho
Keyword(s):  
Inflammatory Responses ◽  
Janus Kinase ◽  
Prostaglandin E ◽  
Activator Protein 1 ◽  
Toll Like Receptor 4 ◽  
Multiple Targets ◽  
Extracellular Signal ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Necrosis Factor

BAY 11-7082 (BAY) is an inhibitor ofκB kinase (IKK) that has pharmacological activities that include anticancer, neuroprotective, and anti-inflammatory effects. In this study, BAY-pharmacological target pathways were further characterized to determine how this compound simultaneously suppresses various responses. Primary and cancerous (RAW264.7 cells) macrophages were activated by lipopolysaccharide, a ligand of toll-like receptor 4. As reported previously, BAY strongly suppressed the production of nitric oxide, prostaglandin E2, and tumor necrosis factor-αand reduced the translocation of p65, major subunit of nuclear factor-κB, and its upstream signaling events such as phosphorylation of IκBα, IKK, and Akt. In addition, BAY also suppressed the translocation and activation of activator protein-1, interferon regulatory factor-3, and signal transducer and activator of transcription-1 by inhibiting the phosphorylation or activation of extracellular signal-related kinase, p38, TANK-binding protein, and Janus kinase-2. These data strongly suggest that BAY is an inhibitor with multiple targets and could serve as a lead compound in developing strong anti-inflammatory drugs with multiple targets in inflammatory responses.

scholarly journals The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases

2018 ◽  
Vol 19 (12) ◽  
pp. 4058 ◽  
Author(s):  
Stella Bernardi ◽  
Annalisa Marcuzzi ◽  
Elisa Piscianz ◽  
Alberto Tommasini ◽  
Bruno Fabris
Keyword(s):  
Lipid Metabolism ◽  
Acute Inflammation ◽  
Metabolic Diseases ◽  
Inflammatory Responses ◽  
Organ Damage ◽  
Lipid Lowering ◽  
Peripheral Tissues ◽  
Obesity Epidemic ◽  
Nutritional Environment ◽  
Anti Inflammatory

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response—and interleukins—had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.

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