Excessive Inflammation Research Articles

Inhibition of LPS-induced inflammatory response in RAW264.7 cells by natural Chlorogenic acid isomers involved with AKR1B1 inhibition

Inflammation is the physiological response of the immune system to injury or infection, typically manifested by local tissue congestion, swelling, heat, and pain. Prolonged or excessive inflammation can lead to tissue damage and the development of many diseases. The anti-inflammatory effects of natural ingredients have been extensively researched and confirmed. This study investigated the effects of Chlorogenic acid (CGA) isomers —— 3-Caffeolyquninic acid (3-CQA), 4-Caffeolyquninic acid (4-CQA), and 5-Caffeolyquninic acid (5-CQA) —— on the inflammatory response and oxidative stress reaction induced by LPS in RAW264.7 cells. Overall, 3-CQA exhibited the most significant reduction in levels of TNF-α, IL-6, NO, and ROS. 4-CQA showed superior inhibition of TNF-α compared to 5-CQA (p < 0.05), while no significant difference in other parameters. We further used DARTS and CETSA to demonstrate that CGA isomers have stable affinity with AKR1B1. As a positive control, the AKR1B1 antagonist epalrestat exhibited similar effects to the CGA isomers. 3-CQA having the smallest half-inhibitory concentration (IC50) for AKR1B1, while 4-CQA and 5-CQA have similar values. AutoDock simulations of the docking conformations revealed minimal differences in the average binding energies of the CGA isomers. The main differences were that VAL47 formed a hydrogen bond with 3-CQA, whereas GLN49 formed hydrogen bonds with 4-CQA and 5-CQA. Additionally, the number of hydrophobic bonds involving PHE122 and LEU300 varies. Our conclusion is that differences in non-covalent interactions result in the varying inhibitory abilities of CGA isomers on AKR1B1, which further affect the anti-inflammatory and antioxidant effects of CGA isomers.

Ethnic variations in post ST elevation myocardial infarction inflammatory kinetics

Abstract Introduction Sterile inflammation post myocardial infarction (MI) is essential to activation reparative mechanisms. However, excessive inflammation contributes to detrimental recovery and adverse outcomes(1). Several studies have reported an association between elevated leucocyte subpopulations and neutrophil-lymphocyte ratio (NLR) with poor prognosis after MI(2). In healthy volunteers, it is known that black individuals have a lower diurnal neutrophil, basophil, and monocyte count and the term ‘benign ethnic neutropenia’ has been used(3). However, the effect of ethnicity on leucocyte counts after MI is not known. Purpose We aimed to assess the interaction between ethnicity and leucocyte subpopulations and NLR. Understanding post-MI inflammation and its interaction with ethnicity is essential in providing personalised patient management and prognostication. Methods We conducted a single centre retrospective observational study of consecutive patients presenting with ST-segment elevation MI (STEMI) between 2016 and 2022. Patients were divided into white and other ethnic groups combined (‘ethnic minorities’) based on self-reported ethnicity. Leucocyte subpopulations, neutrophil and monocyte lymphocyte ratios (NLR and MLR, respectively) at baseline and for 4 days post admission were compared. Baseline variables were analysed with Shapiro-Wilk testing and presented as median (IQR). Area under the curve (AUC) was used to analyse magnitude of change in longitudinal analysis with smoothed conditional means (LOESS) to display trends in the data. Univariate and multivariate linear regression analyses were used to investigate for an association between ethnicity and baseline clinical variables. Results We included 1933 STEMI patients, of whom 1477 (76%) were white and 456 (24%) were from ethnic minority groups. Baseline neutrophils (7.73 [5.9-10] vs 9.04 [6.7-11.9] x109/L), monocytes (0.52 [0.38-0.69] vs 0.6 [0.44-0.82] x109/L), basophils (0.03 [0.02-0.04] vs 0.04 [0.02-0.06] x109/L), NLR (4.47 [2.93-7.19] vs 5.61 [3.64-8.89]) and MLR (0.3 [0.21-0.43] vs 0.36 [0.26-0.53]) were significantly lower (all p&amp;lt;0.001) in ethnic minority vs white patients. There were no differences in peak troponin T or CRP. Longitudinal assessment of leucocyte subgroups and NLR showed that white patients had a significantly higher AUC and difference between minimum and maximum values (delta) for neutrophils, monocytes, basophils and NLR (Panel 1). After correction, we observed a negative association between being in the ethnic minority group and baseline NLR (p=0.005) and basophil count (p&amp;lt;0.001). Conclusions Despite baseline differences in leucocyte subgroups and NLR according to ethnicity, there is a distinct interaction among patients with STEMI suggesting an ethnicity-specific inflammatory profile. Blunting of the magnitude and duration of leucocyte response is novel, and future work will focus on the implications for prognosis and tailored therapy.

Platelet Glycoprotein Ibα Cytoplasmic Tail Exacerbates Thrombosis During Bacterial Sepsis

Septic patients, coupling severe disseminated intravascular coagulation (DIC) and thrombocytopenia, have poor prognoses and higher mortality. The platelet glycoprotein Ibα (GPIbα) is involved in thrombosis, hemostasis, and inflammation response. However, it remains unclear whether the GPIbα cytoplasmic tail regulates sepsis-mediated platelet activation and inflammation, especially in Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infections. Using a mouse model of S. aureus-induced bacteremia, we found that both 10 amino acids of GPIbα C-terminal sequence deficiency and pharmacologic inhibition of protein kinase C (PKC) alleviated pathogenesis by diminishing platelet activation and aggregate formation. Furthermore, the GPIbα cytoplasmic tail promoted the phagocytosis of platelets by Kupffer cells in vivo. The genetically deficient GPIbα cytoplasmic tail also downregulated inflammatory cytokines and reduced liver damage, ultimately improving the survival rate of the septic mice. Our results illustrate that the platelet GPIbα cytoplasmic domain exacerbates excessive platelet activation and inflammation associated with sepsis through a PKC-dependent pathway. Thus, our findings provide insights for the development of effective therapeutic strategies using PKC inhibitor treatment against bacterial infection.

Evaluation of Rosmarinic Acid Attenuation Effect on Endoplasmic Reticulum Stress in Swiss-type Mice Affected With Nonalcoholic Steatohepatiti

Background and Objectives: Nonalcoholic steatohepatitis is a severe liver disease characterized by excess lipid accumulation (steatosis) and inflammation in the liver. Endoplasmic reticulum stress is considered one of the crucial factors in nonalcoholic steatohepatitis pathophysiology. Rosmarinic acid is a herbal medicine with antioxidant and anti-inflammatory properties. This study aimed to evaluate the effect of rosmarinic acid on reducing the endoplasmic reticulum stress induced by nonalcoholic steatohepatitis in male Swiss-type mice. Methods: The study animals were grouped into four: Saline, rosmarinic acid, nonalcoholic steatohepatitis, and nonalcoholic steatohepatitis-rosmarinic acid. Nonalcoholic steatohepatitis was induced by a diet without methionine-choline for 8 weeks, and rosmarinic acid was injected intraperitoneally daily for 8 weeks in mice. After 8 weeks, the animals were killed, and their liver samples were obtained. Real-time PCR was used for molecular studies. Data analyses were performed by one-way analysis of variance and Tukey's post hoc test. Results: Findings of this study showed that rosmarinic acid alleviated mRNA levels of GRP78, IRE-1, and PERK while increasing the Apo B expression. Conclusion: The results suggest that rosmarinic acid ameliorates endoplasmic reticulum stress parameters, upregulates Apo B expression as a key factor in triglyceride exit from the liver, and thereby improves nonalcoholic steatohepatitis in male Swiss-type mice.

Role of physicochemical properties in silica nanoparticle-mediated immunostimulation

Immunostimulation caused by nanoparticles may be beneficial or adverse depending on their intended application. Activation of immune cells is beneficial for indications targeting the immune system for therapeutic purposes, such as tumor microenvironment reprogramming, immunotherapy, and vaccines. When it is unwanted, however, immunostimulation may lead to excessive inflammation, cytokine storm, and hypersensitivity reactions. The increasing use of silica nanoparticles (SiNPs) for the delivery of drugs, imaging agents, and antigens warrants preclinical studies aimed at understanding carrier-mediated effects on the number, activation status, and function of immune cell subsets. Herein, we present an in vitro study utilizing primary human peripheral blood mononuclear cells (PBMC) to investigate the proinflammatory properties of four types of SiNPs varying in size and porosity. Cytokine analysis was performed in resting and LPS-primed PBMC cultures to understand the ability of silica nanoparticles to induce de novo and exaggerate preexisting inflammation, respectively. Changes in the number and activation status of lymphoid and myeloid cells were studied by flow cytometry to gain further insight into SiNP-mediated immunostimulation. Nonporous SiNPs were found to be more proinflammatory than mesoporous SiNPs, and larger-sized particles induced greater cytokine response. LPS-primed PBMC resulted in increased susceptibility to SiNPs. Immunophenotyping analysis of SiNP-treated PBMC resulted in T and B lymphocyte, natural killer cell, and dendritic cell activation. Additionally, a loss of regulatory T cells and an increase in γδ TCR T cell population were observed with all particles. These findings have implications for the utility of SiNPs for the delivery of drugs and imaging agents.

Determination of proinflammatory cytokine levels to assess the reparative potential of tissues in ischemic damage and local correction with hyaluronic acid

The hypothesis of the study was the assumption that local correction of secondary alteration stops excessive inflammation activity and promotes early activation of reparative processes. Objective: in an animal experiment, to evaluate the dynamics in blood plasma of the concentration of circulating inflammatory cytokines in acute ischemic damage to soft tissues and after local action of a hyaluronic acid-based drug. In anesthetized Wistar rats, acute ischemic damage to the soft tissues of the thigh was simulated by mechanical compression with a vise for 7 hours. After removing the vise, the rats were divided into 2 groups of 32 individuals: control (without treatment) and experimental (3 hours after removing the vise, the drug was injected into the area bordering the compression zone with a sterile syringe based on hyaluronic acid “Hyalift-3.5”, diluted with 0.9% solution to the final concentration of the drug – 1.75%). The concentration of cytokines in blood plasma was determined, histological sections of soft tissues in the compression area were examined. An increase in the plasma concentration of proinflammatory cytokines (IL-1β, TNFα, IL-6) was revealed during the entire follow-up period (21 days), especially 7 days after the injury. To the greatest extent, these changes were observed in animals in the control group, which was manifested by a statistically significant increase in the concentration of IL-1β, TNFα and IL-6, relative to the values in intact rats: on average by 7.2; 3.7 and 5.3 times, respectively. In rats in the experimental group, local administration of a hyaluronic acid-based drug already in the early period after injury limited the severity of inflammation (an increased concentration of IL-10 was recorded in blood plasma). The sanogenetic role of local administration of hyaluronic acid in the wound process is mediated by the relief of inflammation in the early period of damage and is realized in increasing the reparative potential of tissues according to the variant of earlier and significant formation of musculoskeletal tissue regenerates.

Advances in the study of artemisinin and its derivatives for the treatment of rheumatic skeletal disorders, autoimmune inflammatory diseases, and autoimmune disorders: a comprehensive review

Artemisinin and its derivatives are widely recognized as first-line treatments for malaria worldwide. Recent studies have demonstrated that artemisinin-based antimalarial drugs, such as artesunate, dihydroartemisinin, and artemether, not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. Researchers globally have synthesized artemisinin derivatives like SM735, SM905, and SM934, which offer advantages such as low toxicity, high bioavailability, and potential immunosuppressive properties. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells. This review summarized the mechanisms by which artemisinin and its analogs modulate excessive inflammation and immune responses in rheumatic and skeletal diseases, autoimmune inflammatory diseases, and autoimmune disorders, through pathways including TNF, Toll-like receptors, IL-6, RANKL, MAPK, PI3K/AKT/mTOR, JAK/STAT, and NRF2/GPX4. Notably, in the context of the NF-κB pathway, artemisinin not only inhibits NF-κB expression by disrupting upstream cascades and/or directly binding to NF-κB but also downregulates multiple downstream genes controlled by NF-κB, including inflammatory chemokines and their receptors. These downstream targets regulate various immune cell functions, apoptosis, proliferation, signal transduction, and antioxidant responses, ultimately intervening in systemic autoimmune diseases and autoimmune responses in organs such as the kidneys, nervous system, skin, liver, and biliary system by modulating immune dysregulation and inflammatory responses. Ongoing multicenter randomized clinical trials are investigating the effects of these compounds on rheumatic, inflammatory, and autoimmune diseases, with the aim of translating promising preclinical data into clinical applications.

Inflammation and resolution in obesity.

Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular diseaseand type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β,NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)inflammasome,tumour necrosis factor (TNF)and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease.

Safety Landscape of Therapeutic Nanozymes and Future Research Directions.

Oxidative stress and inflammation are at the root of a multitude of diseases. Treatment of these conditions is often necessary but current standard therapies to fight excessive reactive oxygen species (ROS) and inflammation are often ineffective or complicated by substantial safety concerns. Nanozymes are emerging nanomaterials with intrinsic enzyme-like properties that hold great promise for effective cancer treatment, bacterial elimination, and anti-inflammatory/anti-oxidant therapy. While there is rapid progress in tailoring their catalytic activities as evidenced by the recent integration of single-atom catalysts (SACs) to create next-generation nanozymes with superior activity, selectivity, and stability, a better understanding and tuning of their safety profile is imperative for successful clinical translation. This review outlines the current applied safety assessment approaches and provides a comprehensive summary of the safety knowledge of therapeutic nanozymes. Overall, nanozymes so far show good in vitro and in vivo biocompatibility despite considerable differences in their composition and enzymatic activities. However, current safety investigations mostly cover a limited set of basic toxicological endpoints, which do not allow for a thorough and deep assessment. Ultimately, remaining research gaps that should be carefully addressed in future studies are highlighted, to optimize the safety profile of therapeutic nanozymes early in their pre-clinical development.

Comparative Analysis of Plasma Protein Dynamics in Women with ST-Elevation Myocardial Infarction and Takotsubo Syndrome

Background: ST-elevation myocardial infarction (STEMI) and Takotsubo syndrome (TS) are two distinct cardiac conditions that both result in sudden loss of cardiac dysfunction and that are difficult to distinguish clinically. This study compared plasma protein changes in 24 women with STEMI and 12 women with TS in the acute phase (days 0–3 post symptom onset) and the stabilization phase (days 7, 14, and 30) to examine the molecular differences between these conditions. Methods: Plasma proteins from STEMI and TS patients were extracted during the acute and stabilization phases and analyzed via quantitative proteomics. Differential expression and functional significance were assessed. Data are accessible on ProteomeXchange, ID PXD051367. Results: During the acute phase, STEMI patients showed higher levels of myocardial inflammation and tissue damage proteins compared to TS patients, along with reduced tissue repair and anti-inflammatory proteins. In the stabilization phase, STEMI patients exhibited ongoing inflammation and disrupted lipid metabolism. Notably, ADIPOQ was consistently downregulated in STEMI patients in both phases. When comparing the acute to the stabilization phase, STEMI patients showed increased inflammatory proteins and decreased structural proteins. Conversely, TS patients showed increased proteins involved in inflammation and the regulatory response to counter excessive inflammation. Consistent protein changes between the acute and stabilization phases in both conditions, such as SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE, suggest shared underlying pathophysiological mechanisms. Conclusions: This study presents protein changes in women with STEMI or TS and identifies ADIPOQ, SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE as candidates for further exploration in both therapeutic and diagnostic contexts.

Dual Inhibition of Phosphodiesterase 3 and 4 Enzymes by Ensifentrine Protects against MRSA-Induced Lung Endothelial and Epithelial Dysfunction

Acute Respiratory Distress Syndrome (ARDS) is a severe lung condition with a high mortality rate for which there are no effective therapeutics. The failure of the alveolar–capillary barrier, composed of lung endothelial (EC) and alveolar epithelial (AEC) cells, is a critical factor leading to excessive inflammation and edema characteristic of acute lung injury (ALI) pathophysiology. Phosphodiesterases (PDE) are enzymes well-recognized for their roles in regulating endothelial permeability and inflammation. Although PDE inhibitors are used as therapeutics for inflammatory diseases like COPD (chronic obstructive pulmonary disease), their efficacy in treating ARDS has not yet been established. In this study, we investigated the effects of ensifentrine, an FDA-approved novel dual PDE 3/4 inhibitor, on lung endothelial and epithelial dysfunction caused by methicillin-resistant S. aureus (MRSA), a pathogen involved in bacterial ARDS. Human primary lung endothelial cells and alveolar epithelial cell lines (A549 and immortalized AEC) were treated with heat-killed MRSA, and their responses were assessed in the presence or absence of ensifentrine. Ensifentrine given either pre- or post-exposure attenuated MRSA-induced increased lung endothelial permeability. VE-cadherin junctions, which serve to stabilize the EC barrier, were disrupted by MRSA; however, ensifentrine effectively prevented this disruption. Pre-treatment with ensifentrine protected against MRSA-induced EC pro-inflammatory signaling by inhibiting the expression of VCAM-1, ICAM-1, and by reducing the IL-6 and IL-8 release. In AEC, MRSA caused the upregulation of ICAM-1, the activation of NF-kB, and the production of IL-8, all of which were inhibited by ensifentrine. These results indicate that the dual inhibition of phosphodiesterases 3 and 4 by ensifentrine is barrier protective and attenuates MRSA-induced inflammation in both lung endothelial and epithelial cells. The PDE3/4 inhibitor ensifentrine may represent a promising novel strategy for the treatment of MRSA-induced ARDS.

A versatile natural gelatin-based hydrogel for emergency wound treatment through hemostasis, antibacterial, and anti-inflammation.

Emergency wounds are often accompanied by bacterial infection, oxidative stress, and excessive inflammation due to the inability to quickly close and stop bleeding, resulting in chronic wounds that are difficult to heal. Clinically, surgical suturing is the fastest method for wound closure, but it is only suitable for wounds with small bleeding volumes and causes unsightly scar formation. Consequently, there is a critical need for hemostatic dressings versatile enough to address a spectrum of diverse and intricate wounds, especially in emergency scenarios. In this study, we constructed a unique versatile natural gelatin-based hydrogel with hemostasis, antibacterial, and anti-inflammation properties. The hydrogel was composed of 4-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy) butyrylethylenediamine-modified methacrylated gelatin (GelMA-NB) and epigallocatechin gallate-grafted polylysine (EPL-EGCG), which imparts adhesion, antibacterial and antioxidant properties to the hydrogel. Simultaneously, the hydrogel was loaded with GelMA microspheres encapsulating natural resveratrol (RES@GM). This combination not only exhibited outstanding hemostatic capabilities but also preserved the anti-inflammatory potential of RES. In different animal models, the hydrogel exhibited outstanding hemostatic and wound healing effects, down-regulated the expression of IL-1β to promote inflammatory regulation and potential for angiogenesis and anti-scar. In conclusion, unique versatile natural gelatin-based hydrogel suitable for various complex wounds provides a promising strategy for emergency wound dressing applications.

Neuroinflammation in Severe COVID-19: The Dynamics of Inflammatory and Brain Injury Markers During Hospitalization.

Patients with COVID-19 can develop excessive inflammation in the brain and consequent neurological complications. The aim of this study was to evaluate the inflammatory, endothelial and brain injury markers in hospitalized COVID-19 patients and compare those with or without neurological symptoms. A total of 30 intensive care unit (ICU) COVID-19 patients were allocated into COVID-19 (without neurological symptoms) or neuro-COVID-19 (with neurological symptoms) groups. Patients with respiratory infection symptoms but negative for COVID-19 were included as a control group. Peripheral blood samples were collected at hospital admission (T1) (controls and ICU patients) and during hospitalization (T2: last 72h before hospital discharge or in-hospital death) (ICU COVID-19 patients) to analyze inflammatory markers. Higher ICAM-1, CCL26 and VEGF at T1 were identified in both COVID-19 groups compared with control. Neuro-COVID-19 patients presented lower systemic BDNF levels compared with the control group and increased S100B compared with the control and COVID-19 groups. BDNF levels in survivors were lower in the neuro-COVID-19 group compared to the COVID-19 group, while S100B were higher, regardless of the outcome. In addition, all COVID-19 patients presented increased ICAM-1 and CCL26 levels over the hospitalization period (T2 > T1). Furthermore, S100B, ICAM-1, CCL26 and VEGF levels increased in relation to T1 in neuro-COVID-19 patients, with S100B and CCL26 being significantly higher in relation to the COVID-19 group. In conclusion, high levels of brain injury biomarkers were found in patients with neuro-COVID-19, indicating neuroinflammatory and consequent brain injury in the last 72h of hospitalization.

Iron Single-Atom Nanozyme with Inflammation-Suppressing for Inhibiting Multidrug-Resistant Bacterial Infection and Facilitating Wound Healing.

Infection with drug-resistant bacteria and the formation of biofilms are the main factors contributing to wound healing insufficiency. Antibacterial agents with enzyme-like properties have exhibited considerable potential for efficient eradication of drug-resistant microorganisms due to their superior sensitivities and minimal side effects. In this work, we prepared a kind of Fe-centered single-atom nanozyme (Fe-SAzyme) with high biocompatibility and stability via a facile one-pot hydrothermal method, which was suitable for the treatment of wounds infected with drug-resistant bacteria. The Fe-SAzyme exhibited remarkable peroxidase-like catalytic activities, catalyzing the conversion of hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH), which could not only damage bacterial cells but also inhibit, disrupt, and eradicate the formation of bacterial biofilms. Thus, Fe-SAzyme demonstrated a broad-spectrum antibacterial performance capable of effectively eliminating multidrug-resistant bacteria. The coexistence of ferrous (Fe2+) and ferric (Fe3+) ions in Fe-SAzyme conferred the nanozyme with anti-inflammatory activity, effectively suppressing excessive inflammation. Meanwhile, Fe-SAzyme could significantly downregulate inflammatory cytokines tumor necrosis factor-α and interleukin-1β and upregulate growth factors VEGF and epidermal growth factor, which can prevent bacterial infection, mitigate inflammation, promote fibroblast proliferation, and improve wound closure. Thus, Fe-SAzyme had shown favorable therapeutic efficiency in promoting bacteria-infected wound healing. This study provides Fe-SAzyme as a promising candidate for the development of new strategies to treat multidrug-resistant bacterial infections.

Microglia-mediated neuroinflammation in traumatic brain injury: a review.

Traumatic brain injury (TBI) is a leading cause of disability worldwide, characterized by a complex interplay of primary and secondary injury mechanisms. Microglia, the resident immune cells of the central nervous system, play a crucial role in the inflammatory response following TBI. To review the current understanding of microglia-mediated neuroinflammation in TBI, exploring its dual nature as a protective and detrimental process. A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Google Scholar. Relevant studies investigating the role of microglia in TBI were included. In the early stages of TBI, microglia exhibit a protective response, releasing cytokines and chemokines to promote neuronal survival and tissue repair. However, prolonged or excessive microglial activation can lead to neurotoxicity and exacerbate secondary injury. Microglia-mediated neuroinflammation involves complex signaling pathways, including Toll-like receptors, purinergic receptors, and the complement system. Microglia-mediated neuroinflammation in TBI is a double-edged sword. While acute microglial activation can promote repair, chronic or excessive inflammation contributes to neuronal damage and functional deficits. Understanding the temporal and molecular dynamics of microglial responses is crucial for developing therapeutic strategies to modulate neuroinflammation and improve outcomes after TBI.

Immunity and Coagulation in COVID-19.

Discovered in late 2019, the SARS-CoV-2 coronavirus has caused the largest pandemic of the 21st century, claiming more than seven million lives. In most cases, the COVID-19 disease caused by the SARS-CoV-2 virus is relatively mild and affects only the upper respiratory tract; it most often manifests itself with fever, chills, cough, and sore throat, but also has less-common mild symptoms. In most cases, patients do not require hospitalization, and fully recover. However, in some cases, infection with the SARS-CoV-2 virus leads to the development of a severe form of COVID-19, which is characterized by the development of life-threatening complications affecting not only the lungs, but also other organs and systems. In particular, various forms of thrombotic complications are common among patients with a severe form of COVID-19. The mechanisms for the development of thrombotic complications in COVID-19 remain unclear. Accumulated data indicate that the pathogenesis of severe COVID-19 is based on disruptions in the functioning of various innate immune systems. The key role in the primary response to a viral infection is assigned to two systems. These are the pattern recognition receptors, primarily members of the toll-like receptor (TLR) family, and the complement system. Both systems are the first to engage in the fight against the virus and launch a whole range of mechanisms aimed at its rapid elimination. Normally, their joint activity leads to the destruction of the pathogen and recovery. However, disruptions in the functioning of these innate immune systems in COVID-19 can cause the development of an excessive inflammatory response that is dangerous for the body. In turn, excessive inflammation entails activation of and damage to the vascular endothelium, as well as the development of the hypercoagulable state observed in patients seriously ill with COVID-19. Activation of the endothelium and hypercoagulation lead to the development of thrombosis and, as a result, damage to organs and tissues. Immune-mediated thrombotic complications are termed "immunothrombosis". In this review, we discuss in detail the features of immunothrombosis associated with SARS-CoV-2 infection and its potential underlying mechanisms.

MAVS signaling shapes microglia responses to neurotropic virus infection

Viral encephalitis is characterized by a series of immunological reactions that can control virus infection in the brain, but dysregulated responses may cause excessive inflammation and brain damage. Microglia are brain-resident myeloid cells that are specialized in surveilling the local CNS environment and in case of viral brain infection they contribute to the control of the infection and to restriction of viral dissemination. Here, we report that after exposure to neurotropic vesicular stomatitis virus (VSV), murine in vitro microglia cultures showed rapid upregulation of a broad range of pro-inflammatory and antiviral genes, which were stably expressed over the entire 8 h infection period. Additionally, a set of immunomodulatory genes was upregulated between 6 and 8 h post infection. In microglia cultures, the induction of several immune response pathways including cytokine responses was dependent on mitochondrial antiviral-signaling protein (MAVS). Consequently, in Mavs-deficient microglia the control of virus propagation failed as indicated by augmented virus titers and the accumulation of viral transcripts. Thus, in the analyzed in vitro system, MAVS signaling is critically required to achieve full microglia activation and to mediate profound antiviral effects. In Mavs-deficient mice, intranasal VSV instillation caused higher disease severity than in WT mice and virus dissemination was noticed beyond the olfactory bulb. Virus spread to inner regions of the olfactory bulb, i.e., the granular cell layer, correlated with the recruitment of highly inflammatory non-microglia myeloid cells into the olfactory bulb in Mavs−/− mice. Furthermore, increased cytokine levels were detected in the nasal cavity, the olfactory bulb and in other brain regions. Thus, microglial MAVS signaling is critically needed for virus sensing, full microglia activation, and for orchestration of protective immunity in the virus-infected CNS.

Inborn Errors of Immunity-related Immunological Mechanisms and Pharmacological Therapy Alternatives in Periodontitis.

Periodontitis is a frequent local inflammatory disease. The microbiota and repeated exposure to bacterial endotoxins triggers excessive inflammation through oral mucosal immunity, sometimes leading to a destructive effect on the supportive mucosal tissues around the teeth. Elimination of the pathogens and increasing the tolerance of the cellular immune response is crucial in addition to standard dental therapies like mechanical debridement. Based on our experience on immune-mediated diseases, especially primary immunodeficiency diseases (PIDs), we wrote this review to discuss the treatment alternatives for severe periodontal disease. Risk factors are malnutrition, vitamin deficiencies, smoking, systemic inherited and acquired immune-mediated diseases, infections, endocrinological diseases, and pharmacological agents may accompany periodontitis. The diagnosis and treatment of dietary deficiencies, as well as the addition of nutritional supplements, may aid in epithelial regeneration and immune system function. Recently, modifications to the therapeutic option for severe periodontitis have been made depending on the fact that the immune response against bacteria may modify the severity of periodontal inflammation. The anti-inflammatory therapies support or inhibit the host's immune response. The clinical approach to severe periodontitis should extend beyond classical therapies. There is a need for a diverse therapeutic strategy that supports the epithelial barrier, which is the crucial component of innate immunity against microbiota. Leukocytes are the main cellular component in periodontal inflammation. Anti-inflammatory therapeutic options directed at leukocytes, such as IL-17 and IL-23-targeted therapies, could be the candidates for the treatment of severe periodontitis. Therapy against other inflammatory cytokines, IL-1, IL-6, IL12, IL23, TNF-alpha, PGE2, and cytokine receptors, could also be used in periodontal inflammation control.

Post-Meningitic Syndrome: Pathophysiology and Consequences of Streptococcal Infections on the Central Nervous System.

Streptococcus species represent a significant global cause of meningitis, leading to brain damage through bacterial virulence factors and the host inflammatory response. Upon entering the central nervous system (CNS), excessive inflammation leads to various neurological and psychological complications. This review explores the pathophysiological mechanisms and associated outcomes of streptococcal meningitis, particularly its short- and long-term neurological sequelae. Neurological symptoms, such as cognitive impairment, motor deficits, and sensory loss, are shown to vary in severity, with children being particularly susceptible to lasting complications. Among survivors, hearing loss, cognitive decline, and cranial nerve palsies emerge as the most frequently reported complications. The findings highlight the need for timely intervention, including neurorehabilitation strategies that focus on optimizing recovery and mitigating long-term disabilities. Future recommendations emphasize improving early diagnosis, expanding vaccine access, and personalizing rehabilitation protocols to enhance patient outcomes. As a novel contribution, this review proposes the term "post-meningitic syndrome" to showcase the broad spectrum of CNS complications that persist following streptococcal meningitis, providing a framework for a future clinical and research focus.

Exploring the anti-inflammatory potential of phytochemicals against STING::TBK1 pathway

ABSTRACT Viral illnesses frequently cause excessive inflammation in the body, which adds to the severity of symptoms and problems. Understanding and regulating this inflammatory response is critical for successful viral infection management and therapy. It is traditional Ayurvedic understanding to reduce inflammation with formulations of Tulsi, Dalchini, Sunthi, and Krishan mirch. Using computer-aided drug discovery methodologies, this study aims to find phytochemicals that interact with TBK1 and are likely to have this anti-inflammatory effect. Molecular docking results revealed that Oleanolic acid, Astiaticoside A, Cepharadione A, Proanthrocyanidin, and Alpha carotene had binding scores of −8.1 kcal/mol, −7.8 kcal/mol, −6.8 kcal/mol, −6.75 kcal/mol, and −6.8 kcal/mol against TBK1, respectively. 20 ns MD simulations of TBK1 in complex with phytochemicals were performed to evaluate complex stability and protein conformational changes. The simulations showed stable complexes with favourable energy profiles, as evidenced by characteristics such as RMSD, RMSF, Rg, and hydrogen bonding. The MM-PBSA analysis produced precise binding affinity estimates. This work emphasises the potential of these phytochemicals and the need for additional in vitro and in vivo validation.