Extreme Inflammatory Response Research Articles

Polystyrene nanoplastic and engine oil synergistically intensify toxicity in Nile tilapia, Oreochromis niloticus

Polystyrene nanoplastic (PS-NPs) and Engine oil (EO) pose multiple ecotoxic effects with increasing threat to fish ecosystems. The current study investigated the toxicity of 15 days exposure to PS-NPs and / or EO to explore their combined synergistic effects on Nile tilapia, Oreochromis niloticus (O. niloticus). Hematobiochemical parameters, proinflammatory cytokines, and oxidative stress biomarkers as well as histological alterations were evaluated. The experimental design contained 120 acclimated Nile tilapia distributed into four groups, control, PS-NPs (5 mg/L), EO (1%) and their combination (PS-NPs + EO). After 15-days of exposure, blood and tissue samples were collected from all fish experimental groups. Results indicated that Nile tilapia exposed to PS-NPs and / or EO revealed a significant decrease in almost all the measured hematological parameters in comparison to the control, whereas WBCs and lymphocyte counts were significantly increased in the combined group only. Results clarified that the combined PS-NPs + EO group showed the maximum decrease in RBCs, Hb, MCH and MCHC, and showed the maximum significant rise in interleukin-1β (IL-1β), and interleukin-6 (IL-6) in comparison to all other exposed groups. Meanwhile, total antioxidant capacity (TAC) showed a significant (p < 0.05) decline only in the combination group, whereas reduced glutathione (GSH) showed a significant decline in all exposed groups in comparison to the control. Both malondialdehyde (MDA) and aspartate aminotransferase (AST) showed a significant elevation only in the combination group. Uric acid showed the maximum elevation in the combination group than all other groups, whereas creatinine showed significant elevation in the EO and combination group when compared to the control. Furthermore, the present experiment proved that exposure to these toxicants either individually or in combination is accompanied by pronounced histomorpholgical damage characterized by severe necrosis and hemorrhage of the vital organs of Nile tilapia, additionally extensively inflammatory conditions with leucocytes infiltration. We concluded that combination exposure to both PS-NPs and EO caused severe anemia, extreme inflammatory response, oxidative stress, and lipid peroxidation effects, thus they can synergize with each other to intensify toxicity in fish.

AI-driven Discovery of Celecoxib and Dexamethasone for Exploring their Mode of Action as Human Interleukin (IL-6) Inhibitors to Treat COVID-19-induced Cytokine Storm in Humans.

In the case of COVID-19 patients, it has been observed that the immune system of the infected person exhibits an extreme inflammatory response known as cytokine release syndrome (CRS) where the inflammatory cytokines are swiftly produced in quite large amounts in response to infective stimuli. Numerous case studies of COVID-19 patients with severe symptoms have documented the presence of higher plasma concentrations of human interleukin-6 (IL-6), which suggests that IL-6 is a crucial factor in the pathophysiology of the disease. In order to prevent CRS in COVID-19 patients, the drugs that can exhibit binding interactions with IL-6 and block the signaling pathways to decrease the IL-6 activity may be repurposed. This research work focused on molecular docking-based screening of the drugs celecoxib (CXB) and dexamethasone (DME) to explore their potential to interact with the binding sites of IL-6 protein and reduce the hyper-activation of IL-6 in the infected personnel. Both of the drugs were observed to bind with the IL-6 (IL-6 receptor alpha chain) and IL-6Rα receptor with the respective affinities of -7.3 kcal/mol and -6.3 kcal/mol, respectively, for CXB and DME. Moreover, various types of binding interactions of the drugs with the target proteins were also observed in the docking studies. The dynamic behaviors of IL-6/IL-6Rα in complex with the drugs were also explored through molecular dynamics simulation analysis. The results indicated significant stabilities of the acquired drug-protein complexes up to 100 ns. The findings of this study have suggested the potential of the drugs studied to be utilized as antagonists for countering CRS in COVID-19 ailment. This study presents the studied drugs as promising candidates both for the clinical and pre-clinical treatment of COVID-19.

Pyroptosis: the potential eye of the storm in adult-onset Still's disease.

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1β (IL-1β) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1β and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.

Use of cardiopulmonary bypass is associated with chronic postsurgical pain among patients undergoing coronary artery bypass graft surgery: follow-up of a randomized, clinical trial.

Chronic postsurgical pain (CPSP) worsens patients' mortality, morbidity, and quality of life. Cardiopulmonary bypass is mandatory for cardiac surgery, but it induces intense inflammation. The presence of inflammation is a crucial part of pain sensitization. An extreme inflammatory response due to cardiopulmonary bypass might cause a high prevalence of CPSP after cardiac surgery. We hypothesized that the prevalence and severity of CPSP are higher in patients after on-pump coronary artery bypass graft (CABG) surgery than in those after off-pump CABG surgery. This prospective, observational study was performed on a cohort from a randomized trial (on-pump CABG: 81 patients, off-pump CABG: 86 patients). A questionnaire about the severity of surgical wound pain that evaluated pain with the numerical rating scale (NRS) was filled out by the patients. NRS responses for current pain, peak pain in the last 4weeks, and average pain in the last 4weeks were evaluated. The main outcomes were the severity of CPSP as evaluated using the NRS and the prevalence of CPSP. CPSP was defined as pain with an NRS score > 0. Differences in severity between groups were analyzed using multivariate ordinal logistic regression models adjusted for age and sex, and differences in prevalence between groups were analyzed using multivariate logistic regression models adjusted for age and sex. The questionnaire return rate was 77.0%. During a median follow-up of 17years, 26 patients complained of CPSP (on-pump CABG: 20 patients, off-pump CABG: 6 patients). Ordinal logistic regression showed that the NRS response for current pain (odds ratio [OR] 2.34; 95% CI 1.12-4.92; P = 0.024) and the NRS response for peak pain in the last 4weeks (OR 2.71; 95% CI 1.35-5.42; P = 0.005) were significantly higher in patients who underwent on-pump CABG surgery than in those who underwent off-pump CABG. Logistic regression showed that on-pump CABG surgery was an independent predictor of CPSP (OR 2.59; 95% CI 1.06-6.31; P = 0.036). The prevalence and severity of CPSP are higher in patients with on-pump CABG surgery than in those with off-pump CABG surgery.

Glycomic Analysis Reveals a Conserved Response to Bacterial Sepsis Induced by Different Bacterial Pathogens.

Sepsis is an extreme inflammatory response to infection that occurs in the bloodstream and causes damage throughout the body. Glycosylation is known to play a role in immunity and inflammation, but the role of glycans in sepsis is not well-defined. Herein, we profiled the serum glycomes of experimental mouse sepsis models to identify changes induced by 4 different clinical bacterial pathogens (Gram-positive: Streptococcus pneumoniae and Staphylococcus aureus, Gram-negative: Escherichia coli and Salmonella Typhimurium) using our lectin microarray technology. We observed global shifts in the blood sera glycome that were conserved across all four species, regardless of whether they were Gram positive or negative. Bisecting GlcNAc was decreased upon sepsis and a strong increase in core 1/3 O-glycans was observed. Lectin blot analysis revealed a high molecular weight protein induced in sepsis by all four bacteria as the major cause of the core 1/3 O-glycan shift. Analysis of this band by mass spectrometry identified interalpha-trypsin inhibitor heavy chains (ITIHs) and fibronectin, both of which are associated with human sepsis. Shifts in the glycosylation of these proteins were observed. Overall, our work points toward a common mechanism for bacterially induced sepsis, marked by conserved changes in the glycome.

Inflammatory response of stem cell secreting conditioned media in SH-SY5Y cell line

Mesenchymal stem cells (MSCs) are reported to secrete anti-inflammatory cytokines and growth factors, which makes MSCs a promising candidate in the treatment of various neurodegenerative diseases. SH-SY5Y show extreme inflammatory response under LPS and an inadequate inflammatory response when treated with Wharton's jelly, conditioned media. This study mainly focuses on the inflammatory (pro and anti-inflammatory) response of SH-SY5Y by gene expression study. SH-SY5Y cell line used for cell culture and RT- q PCR was done with 5 different primers. In this article, lipopolysaccharides (LPS) show a significant result in pro-inflammatory and pro-apoptotic. In this article, we focus on the therapeutic approach of stem cells, which reduce inflammation by secreting stem cell factors to cure various neurodegenerative diseases.

Fermented soybean meal extract improves oxidative stress factors in the lung of inflammation/infection animal model

ContextFermented soybean products have been used in various ways, and more research is being conducted on them to reveal their benefit.ObjectiveThe objective of this study was to evaluate the antioxidative activity of fermented soybean meal extract by Lactobacillus plantarum in vitro and in vivo tests.Materials and methodsA Lactobacillus plantarum strain RM10 was selected through plate and fermentation experiment, which increased the degree of protein hydrolysis (1.015 μg/mL) and antioxidant activity in soybean meal fermented by selected bacteria (FSBM). In vivo study was done on septic rats as an inflammation/infection model, and then the trial groups were treated with different concentrations of fermented soybean meal extracts (FSBM, 5, 10, and 20%).ResultsDPPH radical-scavenging and ferrozine ion-chelating activity enhanced (P < 0.05) after fermentation of soybean meal compared to control group. Reduced (P < 0.05) expression of inflammatory genes and enzymes was detected in the lungs of rats treated with fermented soybean meal extract.Discussion and conclusionsThese results demonstrated that a diet containing fermented soybean meal extract improved extreme inflammatory response in an infectious disease like sepsis by reducing inflammatory factors.

The management of herpes labialis, oral thrush and angular cheilitis in cases of oral diabetes

Background: As reported in several studies, prolonged or uncontrolled cases of diabetes mellitus (DM) may induce a more extreme inflammatory response. Mucosal lesions can be observed in patients who present this systemic condition. Purpose: The purpose of this study was to elaborate the management of herpes labialis, oral thrush and angular cheilitis as oral manifestations of diabetes. Case: A 49-year-old male complained of having experienced painful lip ulceration for the preceding seven days. The anamnesis of the patient revealed that, prior to lip ulceration, he had experienced high fever and malaise in addition to frequent urination at night and a tingling sensation in the toes and fingertips on waking. Case management: The patient was referred to undergo blood count, fasting blood glucose and oral glucose tolerance tests. The blood test result confirmed the patient to be suffering from DM and anemia. The immunocompromised condition of the patient prompted the occurrence of herpes labialis, oral thrush and angular cheilitis. Conclusion: Multidisciplinary treatment for herpes labialis resulting in oral candidiasis in DM patients is indispensable. Concurrent infection with HSV and candidiasis necessitates a more prolonged healing process. Consequently, it is a essential to treat the hyperglycemia which induces an immunocompromised state in diabetic patients.

Early Sepsis Detection with Deep Learning on EHR Event Sequences

Background: Sepsis is a clinical condition involving an extreme inflammatory response to an infection, and is associated with high morbidity and mortality. Without intervention, this response can progress to septic shock, organ failure and death. Every hour that treatment is delayed mortality increases. Early identification of sepsis is therefore important for a positive outcome.&#x0D; Methods: We constructed predictive models for sepsis detection and performed a register-based cohort study on patients from four Danish municipalities. We used event-sequences of raw electronic health record (EHR) data from 2013 to 2017, where each event consists of three elements: a timestamp, an event category (e.g. medication code), and a value. In total, we consider 25.622 positive (SIRS criteria) sequences and 25.622 negative sequences with a total of 112 million events distributed across 64 different hospital units. The number of potential predictor variables in raw EHR data easily exceeds 10.000 and can be challenging for predictive modeling due to this large volume of sparse, heterogeneous events. Traditional approaches have dealt with this complexity by curating a limited number of variables of importance; a labor-intensive process that may discard a vast majority of information. In contrast, we consider a deep learning system constructed as a combination of a convolutional neural network (CNN) and long short-term memory (LSTM) network. Importantly, our system learns representations of the key factors and interactions from the raw event sequence data itself.&#x0D; Results: Our model predicts sepsis with an AUROC score of 0.8678, at 11 hours before actual treatment was started, outperforming all currently deployed approaches. At other prediction times, the model yields following AUROC scores. 15 min: 0.9058, 3 hours: 0.8803, 24 hours: 0.8073.&#x0D; Conclusion: We have presented a novel approach for early detection of sepsis that has more true positives and fewer false negatives than existing alarm systems without introducing domain knowledge into the model. Importantly, the model does not require changes in the daily workflow of healthcare professionals at hospitals, as the model is based on data that is routinely captured in the EHR. This also enables real-time prediction, as healthcare professionals enters the raw events in the EHR.

The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection.

BackgroundHighly pathogenic influenza viruses cause high levels of morbidity, including excessive infiltration of leukocytes into the lungs, high viral loads and a cytokine storm. However, the details of how these pathological features unfold in severe influenza infections remain unclear. Accumulation of Gr1 + CD11b + myeloid cells has been observed in highly pathogenic influenza infections but it is not clear how and why they accumulate in the severely inflamed lung. In this study, we selected this cell population as a target to investigate the extreme inflammatory response during severe influenza infection.ResultsWe established H1N1 IAV-infected mouse models using three viruses of varying pathogenicity and noted the accumulation of a defined Gr1 + CD11b + myeloid population correlating with the pathogenicity. Herein, we reported that CCR2+ inflammatory monocytes are the major cell compartments in this population. Of note, impaired clearance of the high pathogenicity virus prolonged IFN expression, leading to CCR2+ inflammatory monocytes amplifying their own recruitment via an interferon-α/β receptor 1 (IFNAR1)-triggered chemokine loop. Blockage of IFNAR1-triggered signaling or inhibition of viral replication by Oseltamivir significantly suppresses the expression of CCR2 ligands and reduced the influx of CCR2+ inflammatory monocytes. Furthermore, trafficking of CCR2+ inflammatory monocytes from the bone marrow to the lung was evidenced by a CCR2-dependent chemotaxis. Importantly, leukocyte infiltration, cytokine storm and expression of iNOS were significantly reduced in CCR2−/− mice lacking infiltrating CCR2+ inflammatory monocytes, enhancing the survival of the infected mice.ConclusionsOur results indicated that uncontrolled viral replication leads to excessive production of inflammatory innate immune responses by accumulating CCR2+ inflammatory monocytes, which contribute to the fatal outcomes of high pathogenicity virus infections.

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Adrenomedullin (AM) is a highly conserved peptide that can act as a potent vasodilator, anti-microbial factor and anti-inflammatory factor. Several studies have implicated diverse roles for AM in regulating the inflammatory and hemodynamic responses to septic shock. Moreover, during sepsis the receptors that mediate AM signaling [calcitonin receptor-like receptor ( calcrl) and receptor activity modifying proteins ( RAMP) 2 and 3] undergo dynamic and robust changes in their expression. Although numerous studies have used animal models to study the role of administered or increased AM in septic animals, genetic studies to determine the consequences of reduced AM during septic shock have not yet been performed. Here, we used a murine model of lipopolysaccharide (LPS)-induced septic shock to assess the inflammatory response in mice heterozygous for the AM gene. Following LPS challenge, AM +/− mice had higher expression of TNF-α and IL-1β than LPS-treated wild-type (WT) controls. Consequently, serum TNF-α was also significantly elevated in LPS-treated AM +/− mice compared to WT LPS-treated mice. We also observed higher serum levels of liver enzymes, suggesting more advanced end-organ damage in mice with genetically reduced AM. Finally, we found that RAMP2 and calcrl expression levels were markedly reduced in LPS-treated mice, whereas RAMP3 expression was significantly elevated. Importantly, these changes in receptor gene expression were conserved in AM +/− mice, demonstrating that AM peptide itself does not impact directly on the expression of the genes encoding its receptors. We, therefore, conclude that during septic shock the dynamic modulation of AM and its receptors primarily functions to dampen the inflammatory response.

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Disturbance of leucocyte circulation and adhesion to the endothelium as factors in circulatory pathology

Advances in molecular biology have given us the tools to dissect the mechanisms which control the circulation of leucocytes. In particular, a sequence of intermolecular adhesive interactions has been described which underlies leucocyte attachment to the vessel wall, and the factors which promote and limit these interactions have begun to be appreciated. These discoveries have led to a rekindling of interest in the inflammatory response arising from extravasation of neutrophils and to a growing understanding of the basis of lymphocyte recirculation and targeting to specific organs [9, 72, 97]. Much work has been based, of necessity, on in vitro model systems, but animal studies and intravital techniques have enabled the molecular concepts to be tested, so that there is growing confidence that they are indeed the basis of physiological and pathological processes. Multiple organ failure (MOF) is attended by disturbance of tissue perfusion and degradative damage associated with an extreme inflammatory response, which may arise, in part at least, from a loss of the normal mechanisms controlling leucocyte circulation and migration into tissue [109]. It is thus our aim to review the circulatory and adhesive behaviour of leucocytes (especially neutrophilic granulocytes or neutrophils), along with its molecular basis and control mechanisms, and to evaluate the evidence that disruption of the normal physiological processes contributes to pathologies such as MOF.

Alkaline phosphatase isoenzymes in liver cirrhosis.

The study of a group of 114 hepatic patients allowed us to demonstrate the presence of an isophosphatase band, called ALP4, which can be of value as an index of evolutive cirrhosis. A certain correlation between the presence of this alkaline phosphatase isoenzyme in serum and histological evidence of moderate or extreme inflammatory response in liver biopsies was shown.