DAMPening COVID-19 Severity by Attenuating Danger Signals

COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a “cytokine storm.” Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs’ effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.

Cytokine-, Neurotrophin-, and Motor Rehabilitation-Induced Plasticity in Parkinson’s Disease

Neuroinflammation and cytokine-dependent neurotoxicity appear to be major contributors to the neuropathology in Parkinson’s disease (PD). While pharmacological advancements have been a mainstay in the treatment of PD for decades, it is becoming increasingly clear that nonpharmacological approaches including traditional and nontraditional forms of exercise and physical rehabilitation can be critical adjunctive or even primary treatment avenues. Here, we provide an overview of preclinical and clinical research detailing the biological role of proinflammatory molecules in PD and how motor rehabilitation can be used to therapeutically modulate neuroinflammation, restore neural plasticity, and improve motor function in PD.

Role of inflammation in the development of colorectal cancer

: Chronic inflammation can lead to the development of many diseases including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation together with genetic and epigenetic changes has been shown to lead to the development and progression of CRC. Various cell types present in the colon such as enterocytes, Paneth cells, goblet cells and macrophages express receptors for inflammatory cytokines and respond to tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6 and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key proinflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of proinflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy), to alleviate the symptoms or treat inflammationassociated CRC by using monoclonal antibodies or aptamers to block proinflammatory molecules, inhibitors of tyrosine kinases in inflammatory signaling cascade, competitive inhibitors of proinflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/proinflammatory cytokine gene expression.

Cuantificarea moleculelor proinflamatorii (IL1-alfa, IL1-beta, IL2, IL 12, IFN-gama, TNF-alfa) in lichid crevicular si ser la pacientii cu leziuni endo-parodontale

The present research proposes an assessment of the localized inflammatory burden but also at the systemic level by quantitating the pro-inflammatory molecules (IL1-a, IL1-b, IL2, IL12, IFN-g, TNF-a) with endo-periodontal lesions. The study was performed on a group of 146 subjects who, following clinical and radiological examinations, were divided into five groups: healthy endo-periodontal patients, patients with periodontitis, patients with moderate periodontitis, patients with severe periodontitis and patients presenting combined endo-periodontal lesions. IL1-a, IL1-b, IL2, IL12, IFN-g, TNF-a were analysed in crevicular fluid by ELISA and serum by fluorescence flowcytometry. IL1-a and IL1-b showed serum and crevicular fluid values significantly higher than the healthy subjects. Values for IL2, IL12, TNF-a and IFN-g measured in crevicular fluid were higher for groups II, III, IV, and V compared to the group of healthy endo-periodontal subjects. IL2 showed significantly higher serum values for groups III, IV and V than group I. Serum IL12 values were significantly higher than healthy periodontal subjects only for patients with severe periodontitis and endo-periodontal syndrome. Following serum determinations of proinflammatory molecules, patients with endo-periodontal lesions demonstrated significantly higher values even in subjects with severe periodontitis; these data indicate a much higher risk for these patients to develop and maintain systemic maladies, as is the role local inflammation can play over the general inflammatory status of the patient.

Macronutrient-Mediated Inflammation and Oxidative Stress: Relevance to Insulin Resistance, Obesity, and Atherogenesis

Context The intake of macronutrients as components of a Western dietary pattern leads to oxidative stress and inflammation. Evidence Acquisition Data were largely retrieved from our previous and most recent work. PubMed and Google Scholar were searched for recent articles on the effect of macronutrients/dietary intake on inflammation, insulin resistance, obesity, and atherogenesis. The most relevant, high-quality articles were included in our review. Evidence Synthesis Our previous work has demonstrated the molecular mechanisms of macronutrient-mediated oxidative stress and inflammation. With the induction of inflammation, proinflammatory molecules potentially interfere with insulin signal transduction, thus causing insulin resistance. In addition, other molecules promote atherogenic inflammation. More recently, our work has also shown that certain foods are noninflammatory or anti-inflammatory and thus, do not interfere with insulin signaling. Finally, as obesity is induced by chronic excessive caloric intake, it is characterized by an increase in the expression of proinflammatory molecules, which are induced acutely by a Western diet. Caloric restriction, including fasting, is associated with a reduction in oxidative and inflammatory stress. Conclusions This review summarizes and attempts to provide an up-to-date profile of the molecular mechanisms involved in macronutrient-mediated oxidative/inflammatory stress and its potential consequences. An understanding of these underlying mechanisms is crucial for making appropriate dietary choices.

Role of Apple Phytochemicals, Phloretin and Phloridzin, in Modulating Processes Related to Intestinal Inflammation

Plant-derived food consumption has gained attention as potential intervention for the improvement of intestinal inflammatory diseases. Apple consumption has been shown to be effective at ameliorating intestinal inflammation symptoms. These beneficial effects have been related to (poly)phenols, including phloretin (Phlor) and its glycoside named phloridzin (Phldz). To deepen the modulatory effects of these molecules we studied: i) their influence on the synthesis of proinflammatory molecules (PGE2, IL-8, IL-6, MCP-1, and ICAM-1) in IL-1β-treated myofibroblasts of the colon CCD-18Co cell line, and ii) the inhibitory potential of the formation of advanced glycation end products (AGEs). The results showed that Phlor (10–50 μM) decreased the synthesis of PGE2 and IL-8 and the formation of AGEs by different mechanisms. It is concluded that Phlor and Phldz, compounds found exclusively in apples, are positively associated with potential beneficial effects of apple consumption.

Platelets release proinflammatory microparticles in anti-neutrophil cytoplasmic antibody-associated vasculitis

Objective The biological functions of the platelets contributing to ANCA-associated vasculitis (AAV) are largely unclear. The current study aimed to investigate the potential role of platelet-derived microparticles (PMPs) in AAV. Methods In the current study, microparticles in AAV patients were analysed by flow cytometry, and PMPs were probed for relative levels of 640 bioactive proteins secreted from patients’ platelets using antibody microarrays. These data were then correlated with clinical and pathological parameters. Results PMPs were significantly increased in 69 AAV patients, predominantly MPO-ANCA positive patients in active stage compared with in remission [4406.8/μl (2135.4, 5485.0) vs 549.7/μl (350, 708.5), P < 0.0001], and 43% of microparticles in active AAV were PMPs. Compared with 15 patients in remission, highly expressed proinflammatory molecules in the microparticles from platelets in 15 AAV patients in active stage revealed that potential functions of PMPs were promotion of the effect of chemotaxis, adhesion, growth and apoptosis (all the patients for array analysis were MPO-ANCA positive). The level of PMPs had a significant association with disease activity, inflammation, and renal damage. Conclusion PMPs may serve as inflammatory propagators through their wide production of proinflammatory cytokines in AAV, potentially providing a novel therapeutic target.

Neisseria gonorrhoeaePBP3 and PBP4 Facilitate NOD1 Agonist Peptidoglycan Fragment Release and Survival in Stationary Phase

ABSTRACTNeisseria gonorrhoeaereleases peptidoglycan fragments during growth, and these molecules induce an inflammatory response in the human host. The proinflammatory molecules include peptidoglycan monomers, peptidoglycan dimers, and free peptides. These molecules can be released by the actions of lytic transglycosylases or an amidase. However, >40% of the gonococcal cell wall is cross-linked, where the peptide stem on one peptidoglycan strand is linked to the peptide stem on a neighboring strand, suggesting that endopeptidases may be required for the release of many peptidoglycan fragments. Therefore, we characterized mutants with individual or combined mutations in genes for the low-molecular-mass penicillin-binding proteins PBP3 and PBP4. Mutations in eitherdacB, encoding PBP3, orpbpG, encoding PBP4, did not significantly reduce the release of peptidoglycan monomers or free peptides. A mutation indacBcaused the appearance of a larger-sized peptidoglycan monomer, the pentapeptide monomer, and an increased release of peptidoglycan dimers, suggesting the involvement of this enzyme in both the removal of C-terminald-Ala residues from stem peptides and the cleavage of cross-linked peptidoglycan. Mutation of bothdacBandpbpGeliminated the release of tripeptide-containing peptidoglycan fragments concomitantly with the appearance of pentapeptide and dipeptide peptidoglycan fragments and higher-molecular-weight peptidoglycan dimers. In accord with the loss of tripeptide peptidoglycan fragments, the level of human NOD1 activation by thedacB pbpGmutants was significantly lower than that by the wild type. We conclude that PBP3 and PBP4 overlap in function for cross-link cleavage and that these endopeptidases act in the normal release of peptidoglycan fragments during growth.

Elevated IL-6 and IL-1β are associated with temporal lobe epilepsy: A study in Chinese patients

Activation of proinflammatory cytokines in seizures has been well characterized. However, role of cytokines in epilepsy and association with different clinical phenotype has not been well investigated. Reports on possible link between proinflammatory molecules and epilepsy are very limited. In this study, we performed a hospital-based case control study to investigate the association of plasma cytokines and their expression with different clinical categories of epilepsy. Patients admitted to Neurology Department of Renmin Hospital were enrolled in this study after clinical investigations. In all, 92 patients with temporal lobe epilepsy (TLE) and 45 with extra-temporal lobe epilepsy (XTLE) were included in this study. Furthermore, we included 86 healthy controls from the similar geographical population. Plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β were quantified by enzyme-linked immunosorbent assay (ELISA). All plasma cytokines were elevated in TLE and XTLE compared to healthy controls ( P < 0.0001). Furthermore, IL-6 and IL-1β were significantly higher in TLE when compared to extra-temporal epilepsy. Incidentally, no difference in mean plasma TNF-α levels was noticed among TLE and XTLE. Positive correlations were observed between all plasma proinflammatory molecules (TNF-α, IL-6, and IL-1β) investigated in this study. Epilepsy patients displayed higher proinflammatory molecules, namely, IL-6, IL-1β, and TNF-α. Plasma IL-6 and IL-1β can be use as biomarkers for differentiation of TLE from XTLE.