Release Of Proinflammatory Mediators Research Articles

Development, optimization, and characterization of rhein loaded nanoemulgel for treatment of osteoarthritis

This work aimed to design a transdermal delivery of rhein loaded nanoemulgel to improve the bioavailability and efficacy of rhein in the treatment of osteoarthritis and reduce its systemic side effects. Rhein loaded nanoemulsion (Rh-NE) prepared by application of ternary phase diagram and spontaneous emulsification method. Box-Behnken design (BBD) was employed to optimize formulation and preparation process of Rh-NE. The optimal formulation was 11.09% mixed oil (rhein and caproyl 90), 22.96% mixed emulsifier (kolliphor RH 40: transcutol HP, 1:1, w/w), and the preparation process was 23.08 min ultrasonic time and 179.5 W ultrasonic power. The particle size of the optimized Rh-NE was 24.5 ± 3.2 nm, PDI was 0.15 ± 0.02, and zeta potential was −18.6 ± 1.8 mV. The Rh-NE was incorporated into hydrogel consisted of 0.85% carbomer, 0.2% poloxamer 188 and 8.0% glycerol to form rhein loaded nanoemulgel (Rh-NE/Gel). In vitro transdermal flux of Rh-NE/Gel was 91.4 ± 0.9 μg/cm2·h. It was found that the inhibition rate of swelling degree of auricle caused by xylene was (54%), inhibition rate of writhing reaction was (60%), percentage increase in pain threshold was (P < 0.01), and the inhibition rate of capillary permeability was (69%). The therapeutic effect of Rh-NE/Gel on osteoarthritis in model rats was significantly improved compared with control group; the swelling degree of joint and toe were significantly reduced by 91% and 71%, respectively, and the contents of inflammatory factors IL-1β and NO were decreased 35.7% and 52.4%, respectively. The developed Rh-NE/Gel could provide anti-osteoarthritis effect and reduce the release of proinflammatory mediators in OA model rats.

Do respiratory virus infections modify associations of asthma exacerbation with aeroallergens or fine particulate matter? A time series study in Philadelphia PA

ABSTRACT Respiratory virus infections are related to over 80% of childhood asthma exacerbations. They enhance pro-inflammatory mediator release, especially for sensitized individuals exposed to pollens/molds. Using a time-series study design, we investigated possible effect modification by respiratory virus infections of the associations between aeroallergens/PM2.5 and asthma exacerbation rates. Outpatient, emergency department (ED), and inpatient visits for asthma exacerbation among children with asthma (28,540/24,444 [warm/cold season]), as well as viral infection counts were obtained from electronic health records of the Children’s Hospital of Philadelphia from 2011 to 2016. Rate ratios (RRs, 90th percentile vs. 0) for late-season grass pollen were 1.00 (0.85–1.17), 1.04 (0.95–1.15), and 1.12 (0.96–1.32), respectively, for respiratory syncytial virus (RSV) counts within each tertile. However, similar trends were not observed for weed pollens/molds or PM2.5. Overall, our study provides little evidence supporting effect modification by respiratory viral infections.

Complanatuside A improves functional recovery after spinal cord injury through inhibiting JNK signaling-mediated microglial activation

Background and aimsComplanatuside A (ComA) is a flavonoid-rich compound in Astragalus membranaceus that has anti-inflammatory and neuroprotective effects. In this study, we focused on the effect of ComA on spinal cord injury (SCI) in mice and explored its possible mechanisms. MethodsThe SCI model was constructed using C57BL/6J mice, and the effect of ComA on motor function recovery in SCI mice was evaluated through the BMS (Basso Mouse Scale) and footprint test. The histological effects of ComA on SCI mice were evaluated by hematoxylin-eosin (H&E) staining, Luxol-fast blue (LFB) staining, and Nissl staining. In both in vivo and in vitro experiments, we detected the activation of microglia and the release of inflammatory factors through molecular experiments. Immunofluorescence and Western blotting confirmed that ComA can prevent neuronal apoptosis caused by activated microglia through the c-Jun N-terminal kinase (JNK) pathway. ResultsOur research results confirm that ComA can improve motor function in mice after SCI. Our in vitro results indicate that ComA can inhibit the activation of BV2 cells and the release of proinflammatory mediators. In addition, ComA can prevent neuronal cell apoptosis caused by activated BV2 cells. Finally, we found that ComA works through the JNK signaling pathway. ConclusionsComA can accelerate the restoration of motor function in mice after SCI, possibly by reducing neuronal apoptosis via inhibition of JNK-related signaling pathways, a reduction in microglial activation, and inhibition of inflammatory factor release. Our data indicate that ComA is a promising drug candidate for improving functional recovery in patients with SCI.

The Role of Marine n-3 Polyunsaturated Fatty Acids in Inflammatory-Based Disease: The Case of Rheumatoid Arthritis.

Inflammation is a conserved process that involves the activation of immune and non-immune cells aimed at protecting the host from bacteria, viruses, toxins and injury. However, unresolved inflammation and the permanent release of pro-inflammatory mediators are responsible for the promotion of a condition called "low-grade systemic chronic inflammation", which is characterized by tissue and organ damage, metabolic changes and an increased susceptibility to non-communicable diseases. Several studies have demonstrated that different dietary components may influence modifiable risk factors for diverse chronic human pathologies. Marine n-3 polyunsaturated fatty acids (n-3 PUFAs), mainly eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are well-recognized anti-inflammatory and immunomodulatory agents that are able to influence many aspects of the inflammatory process. The aim of this article is to review the recent literature that relates to the modulation of human disease, such as rheumatoid arthritis, by n-3 PUFAs.

Rubusoside mitigates neuroinflammation and cellular apoptosis in Parkinson's disease, and alters gut microbiota and metabolite composition

BackgroundParkinson's disease (PD) is a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the substantia nigra. Neuroinflammation plays a pivotal role in the pathogenesis of PD, involving the activation of microglia cells, heightened production of proinflammatory cytokines, and perturbations in the composition of the gut microbiota. Rubusoside (Ru), the principal steviol bisglucoside present in Rubus chingii var. suavissimus (S.K.Lee) L.T.Lu (Rosaceae), has been documented for its anti-inflammatory properties in diverse disease models. Nonetheless, there is an imperative need to comprehensively assess and elucidate the protective and anti-inflammatory attributes of Ru concerning PD, as well as to uncover the underlying mechanism involved. ObjectiveThe aim of this study is to evaluate the neuroprotective and anti-inflammatory effects of Ru on PD and investigate its potential mechanisms associated with microbes. Research design and methodsWe pre-treated mice and cell lines with Ru in order to simulate the progression of PD and the neuroinflammatory state. The mouse model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), SN4741 cells were induced by 1-methyl-4-phenylpyridine (mpp+), and BV-2 cells were induced by lipopolysaccharide (LPS). We assessed the impact of Ru on motor function, neuroinflammation, neuron apoptosis, the composition of gut microbes, and their metabolites. ResultsRu treatment reduces the release of pro-inflammatory mediators by inhibiting microglia activation. It also prevents neuronal apoptosis, thereby safeguarding dopaminergic neurons and ameliorating motor dysfunction. Furthermore, it induces alterations in the fecal microbiota composition and metabolites profile in PD mice. In vitro experiments have demonstrated that Ru inhibits neuronal apoptosis in SN4741 cells induced by mpp+, suppresses the production of pro-inflammatory mediators, and activates the c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (p38 MAPK), and nuclear factor kappa-B (NF-κB) signaling pathways. ConclusionRu exhibits inhibitory effects on the MPTP-induced PD model by mitigating neuroinflammation and neuronal apoptosis while also inducing changes in the gut microbiota and metabolite composition.

Global proteomics insights for a novel small compound targeting the non-integrin Laminin Receptor in a macrophage cell model

Introduction: Monocytes and macrophages are the first barrier of the innate immune system, which interact with agents causing osteoarthritis or other conditions, leading to the release of proinflammatory mediators that exacerbate inflammation.Methods: The aim of this study was to investigate the proteomic changes in THP-1 monocytes differentiated to macrophages, pre- or -post small compound treatments and in the presence or absence of a proinflammatory stimulus, Lipopolysaccharide (LPS). This study aimed to discover and isolate small compounds that mimic the interaction between Pigment derived growth factor (PEDF) and its 37/67 kDa Laminin receptor (LR) with potential anti-inflammatory activity.Results: Our results suggested that novel compounds targeting the LR-PEDF interface can be useful for modulating anti-inflammatory effects. Several compounds were selected based on in silico docking at the PEDF/LR interface and examined for their ability to reduce IL-1β expression in a macrophage cell model. Compound C3 showed the highest efficacy in reducing IL-1β expression in the presence of LPS proinflammatory stimulus. Proteomics analysis revealed that C3 treatment altered the global proteomic profile of THP-1 activated macrophages, affecting pathways such as MYC targets, oxidative phosphorylation, and mTORC1 signaling.Discussion: The analysis also highlighted the involvement of key regulators, including RPSA and MYC, and their interactions with other proteins such as ribosome proteins and cell cycle regulators. Furthermore, the downregulated proteome analysis revealed shared and unique pathways affected by the treatments, including processes related to actin cytoskeleton, translation, and the inflammatory response. Protein-protein interaction networks suggested the potential involvement of transcription factors like MYC and the interconnectedness of signaling pathways in mediating such as the effects of the treatments. Overall, these findings provide valuable insights into the potential anti-inflammatory activity and underlying mechanisms of compound C3, emphasizing its relevance for further investigation in the context of inflammatory conditions.

LncRNA xist regulates sepsis associated neuroinflammation in the periventricular white matter of CLP rats by miR-122-5p/PKCη Axis.

Neuroinflammation is a common feature of many neurological diseases, and remains crucial for disease progression and prognosis. Activation of microglia and astrocytes can lead to neuroinflammation. However, little is known about the role of lncRNA xist and miR-122-5p in the pathogenesis of sepsis-associated neuroinflammation (SAN). This study aims to investigate the role of lncRNA xist and miR-122-5p in the pathogenesis of SAN. Levels of miR-122-5p and proinflammatory mediators were detected in the cerebrospinal fluid (CSF) of patients with intracranial infection (ICI) by ELISA and qRT-PCR. miRNA expression in the periventricular white matter (PWM) in rats was analyzed by high-throughput sequencing. Levels of lncRNA xist, miR-122-5p and proinflammatory mediators in the PWM were measured using qRT-PCR and western blot. Bioinformatics analysis was used to predict the upstream and downstream of miR-122-5p. The interaction between miR-122-5p and its target protein was validated using luciferase reporter assay. BV2 and astrocytes were used to detect the expression of lncRNA xist, miR-122-5p. The level of miR-122-5p was significantly decreased in the CSF of ICI patients, while the expression of IL-1β and TNF-α were significantly upregulated. Furthermore, it was found that the expression of IL-1β and TNF-α were negatively correlated with the level of miR-122-5p. A high-throughput sequencing analysis showed that miR-122-5p expression was downregulated with 1.5-fold changes in the PWM of CLP rats compared with sham group. Bioinformatics analysis found that lncRNA xist and PKCη were the upstream and downstream target genes of miR-122-5p, respectively. The identified lncRNA xist and PKCη were significantly increased in the PWM of CLP rats. Overexpression of miR-122-5p or knockdown of lncRNA xist could significantly downregulate the level of PKCη and proinflammatory mediators from activated microglia and astrocytes. Meanwhile, in vitro investigation showed that silencing lncRNA xist or PKCη or enhancing the expression of miR-122-5p could obviously inhibit the release of proinflammatory mediators in activated BV2 cells and astrocytes. LncRNA xist could regulate microglia and astrocytes activation in the PWM of CLP rats via miR-122-5p/PKCη axis, further mediating sepsis associated neuroinflammation.

Adiponectin inhibits LPS-induced nucleus pulposus cell pyroptosis through the miR-135a-5p/TXNIP signaling pathway.

Pyroptosis, a newly discovered programmed cell death process, is characterized by NLRP3 inflammasome activation and pro-inflammatory mediator release. Nucleus pulposus (NP) cell pyroptosis is an important cause of intervertebral disc degeneration (IDD). Adiponectin (APN) is an adipokine and has an anti-inflammatory effect. However, whether and how APN protects against NP cell pyroptosis remains unexplored. Our results showed that human degenerated NP tissue displayed a significant increase in the protein levels of NLRP3, caspase-1 and GSDMD-N. APN expression was down-regulated in human degenerated NP tissue and NP cells challenged with lipopolysaccharide (LPS). Lentivirus-mediated overexpression of APN increased miR-135a-5p levels, decreased thioredoxin-interacting protein (TXNIP) expression and its interaction with NLRP3, and inhibited pyroptosis in human NP cells stimulated with LPS. TXNIP was identified as a direct target of miR-135a-5p. The inhibitory effects of APN on pyroptosis were reversed by pretreatment with miR-135a-5p inhibitor or lentiviral vector expressing TXNIP in LPS-treated human NP cells. In summary, these data suggest that APN restrains LPS-induced pyroptosis through the miR-135a-5p/TXNIP signaling pathway in human NP cells. Increasing APN levels could be a new approach to retard IDD.

Potential Utilization of Phenolic Acid Compounds as Anti-Inflammatory Agents through TNF-α Convertase Inhibition Mechanisms: A Network Pharmacology, Docking, and Molecular Dynamics Approach.

Inflammation is a dysregulated immune response characterized by an excessive release of proinflammatory mediators, such as cytokines and prostanoids, leading to tissue damage and various pathological conditions. Natural compounds, notably phenolic acid phytocompounds from plants, have recently garnered substantial interest as potential therapeutic agents to bolster well-being and combat inflammation recently. Based on previous research, the precise molecular mechanism underlying the anti-inflammatory activity of phenolic acids remains elusive. Therefore, this study aimed to predict the molecular mechanisms underpinning the anti-inflammatory properties of selected phenolic acid phytocompounds through comprehensive network pharmacology, molecular docking, and dynamic simulations. Network pharmacology analysis successfully identified TNF-α convertase as a potential target for anti-inflammatory purposes. Among tested compounds, chlorogenic acid (-6.90 kcal/mol), rosmarinic acid (-6.82 kcal/mol), and ellagic acid (-5.46 kcal/mol) exhibited the strongest binding affinity toward TNF-α convertase. Furthermore, phenolic acid compounds demonstrated molecular binding poses similar to those of the native ligand, indicating their potential as inhibitors of TNF-α convertase. This study provides valuable insights into the molecular mechanisms that drive the anti-inflammatory effects of phenolic compounds, particularly through the suppression of TNF-α production via TNF-α convertase inhibition, thus reinforcing their anti-inflammatory attributes.

Clonal Derivation and Dynamics in Rhesus Macaques Following Hematopoietic Stem Cell Transplantation and the Impact of Clonal Hematopoiesis

Microglia (MG) are the resident macrophages of the central nervous system (CNS). Under steady-state conditions, MG play essential roles in immune surveillance; phagocytosis and processing of pathogens, dying cells and protein aggregates; and synaptic pruning to maintain neuronal health. MG dysfunction has been linked to various CNS disorders, including neurodegenerative disorders such as Alzheimer's disease, with multiple pathways implicated, including increased and prolonged activation with excessive release of pro-inflammatory mediators. Lineage tracing studies in mice have demonstrated that yolk sac macrophages form the CNS MG compartment during development, with little ongoing replacement from circulating monocyte/macrophages at steady state or even following hematopoietic stem/progenitor cell (HSPC) transplantation. However, improvements in disease outcomes in human patients with CNS disorders such as adrenoleukodystrophy and metachromatic leukodystrophy following HSPC gene therapies have suggested that adult HSPC-derived cells can contribute to MG function. Recently, Bouzid et al reported that individuals with somatic HPSC mutations in hematopoietic expansion driver genes (clonal hematopoiesis/CH) had a significantly lower risk of Alzheimer's disease (AD). The same study utilized nuclear chromatin profiling of a small set of postmortem brain samples to suggest substantial contribution of CH-derived HSPC to the MG compartment. The authors suggested that enhanced function of CH-derived MG enables them to better clear AD plaques. To more directly investigate the replacement and clonal source of adult CNS resident MG/myeloid cells by HSPC-derived cells and to and assess the impact of CH mutations on MG replacement, we utilized clinically-relevant rhesus macaque (RM) models. Fresh MG and other tissue-resident myeloid cells were purified from the brains of RM that had undergone autologous transplantation 2- 9 years previously with HSPCs transduced with a barcoded lentiviral vector expressing GFP following ablative total body irradiation (TBI, n=6) (Koelle et al, Blood, 2017) or busulfan (n=1, vector without GFP)(Abraham et al, MTMCD, 2023); or HSPCs engineered to carry TET2 mutations using CRISPR/Cas9 (n=2)(Shin et al, Blood, 2022). In addition, we studied an aged RM with natural CH ( RUNX1 mutation) in order to investigate MG replacement in the absence of conditioning and transplantation. We optimized RM MG (CD45+CD11b+CX3CR1+) and CNS myeloid cell (CD45+CD11B+CX3CR1-) purification. To ensure separation of bona fide tissue-resident CNS cells away from perivascular cells or contaminating blood, we incorporated CD45-specific antibody serial intravascular staining (SIVS) (Mortlock et al., 2022) and sorted SIVS- parenchymal MG, SIVS- perivascular MG, and SIVS+ myeloid cells. In all 6 TBI-conditioned lentiviral-barcoded animals, at most 2% of tissue-resident SIVS- MG cells were GFP+ (Fig 1A), with a mean ratio of &amp;lt;0.01 compared to the level of GFP+ circulating blood monocytes in each animal (Fig 1B). Barcode analyses demonstrated similar clonal derivation of GFP+ MG cells to peripheral blood (PB) monocytes, representing output from stable long-term multipotent HSPC clones. A higher MG repopulation level was found in the busulfan-conditioned animal by vector copy number. MG replacement with CH-derived cells was no higher absolutely or relative to blood monocytes in the two engineered TET2-CH animals nor in the aged animal with natural CH (Fig 1B). These results demonstrate only low-level replacement of MG from HSPCs even many years following ablative conditioning and autologous transplantation, and no evidence for enhanced repopulation in the setting of engineered or natural clonal hematopoiesis. The clonal ontogeny of the HSPC-derived MG cells matched that of blood myeloid cells. Further characterization of MG derived from transplanted HSPCs versus control MG is ongoing, as is functional characterization of CH versus unmutated macrophages, asking whether mutated cells are hyper-functional. Our clinically-relevant macaque model provides insights into MG ontogeny, and information relevant to improving CNS-directed HSPC gene therapies, as well as information relevant to interpreting a potential protective impact of CH on human AD.

Docosahexaenoic Acid (DHA) Reduces LPS-Induced Inflammatory Response Via ATF3 Transcription Factor and Stimulates Src/Syk Signaling-Dependent Phagocytosis in Microglia.

Microglial cells play a crucial role in the development of neuroinflammation in response to harmful stimuli, such as infection, ischemia or injury. Their chronic activation, however, is associated with a progression of neurodegenerative diseases. Therefore, looking for potential factors limiting microglial activation, the effect of docosahexaenoic acid (DHA) on the inflammatory response and TREM2-dependent phagocytic activity in microglia was investigated. In LPS-induced primary microglia preincubated with DHA, or without preincubation the expression of ATF3 and TREM2 genes and TREM2, Syk, Akt proteins were determined by RT-PCR and WB, respectively. Cell viability was assayed by MTT and cytokine and chemokine expression was determined by the Proteome Profiler assay. Moreover, the phagocytic activity of microglia was assayed using immunofluorescence. We found that DHA significantly increased the expression of ATF3 , and decreased the levels of CINC-1, CINC-2αβ, CINC-3 chemokines, IL-1α and IL-1β cytokines, and ICAM-1 adhesion protein. Additionally, preincubation of microglia with DHA resulted in increased Src/Syk kinases activation associated with increased phagocytic microglia activity. These findings indicate that DHA efficiently inhibits ATF3-dependent release of proinflammatory mediators and enhances phagocytic activity of microglia. The study provides a new mechanism of DHA action in reactive microglia, which may help limit neuronal damage caused by the pro-inflammatory milieu in the brain.

2-Pentadecyl-2-oxazoline inhibits lipopolysaccharide-induced microglia activation interfering with TLR4 signaling

Aim2-Pentadecyl-2-oxazoline (PEA-OXA), the oxazoline derivative of N-palmitoylethanolamine, exerts anti-inflammatory activity; however, very little is known about the molecular mechanisms underlying this effect. Here, we tested the anti-neuroinflammatory effect of PEA-OXA in primary microglia and we also investigated the possible interaction of the molecule with the Toll-like receptor 4 (TLR4)–myeloid differentiation protein-2 (MD-2) complex. Main methodsThe anti-inflammatory effect of PEA-OXA was analyzed by measuring the expression and release of pro-inflammatory mediators in primary microglia by real-time PCR and ELISA, respectively. The effect of PEA-OXA on the activation of TLR4 signaling was assessed using two stably TLR4-transfected cell lines (i.e., HEK-293 and Ba/F3 cells). Finally, the putative binding mode of PEA-OXA to TLR4–MD-2 was investigated by molecular docking simulations. Key findingsTreatment with PEA-OXA resulted in the following effects: (i) it down-regulated gene expression of several pro-inflammatory molecules and the secretion of pro-inflammatory cytokines in LPS stimulated microglia cells; (ii) it did not prevent microglia activation after stimulation with TLR2 ligands; (iii) it prevented TLR4/NF-κB activation triggered by LPS in HEK-Blue™ hTLR4 cells; and (iv) it interfered with the binding of LPS to TLR4–MD-2 complex. Furthermore, molecular docking studies suggested that PEA-OXA could bind MD-2 with a 1:3 (MD-2/PEA-OXA) stoichiometry. ConclusionWe show for the first time that the anti-neuroinflammatory effect of PEA-OXA involves its activity against TLR4 signaling, making this molecule a valuable tool for the development of new compounds directed to control neuroinflammation via inhibiting TLR4 signaling.

Salvianolic acid A alleviates heart failure with preserved ejection fraction via regulating TLR/Myd88/TRAF/NF-κB and p38MAPK/CREB signaling pathways

Heart failure with preserved ejection fraction (HFpEF) is a morbid, fatal, and common syndrome for which lack of evidence-based therapies. Salvianolic acid A (SAA), a major active ingredient of Salvia miltiorrhiza Burge, has shown potential to protect against cardiovascular diseases. This study aims to elucidate whether SAA possessed therapeutic activity against HFpEF and explore the potential mechanism. HFpEF mouse model was established infusing a combination of high-fat diet (HFD) and Nω-nitro-L-arginine methyl ester (L-NAME) for 14 weeks. After 10 weeks of feeding, HFpEF mice were given SAA (2.5, 5, 10 mg/kg) via oral gavage for four weeks. Body weight, blood pressure, blood lipids, glucose tolerance, exercise performance, cardiac systolic/diastolic function, cardiac pathophysiological changes, and inflammatory factors were assessed. Experimental results showed that SAA reduced HFpEF risk factors, such as body weight gain, glucose intolerance, lipid disorders, and increased exercise tolerance in HFpEF mice. Moreover, SAA not only relieved myocardial hypertrophy and fibrosis by reducing interventricular septal wall thickness, left ventricular posterior wall thickness, left ventricular mass, heart index, cardiomyocyte cross-sectional area and cardiac collagen content, but also improved cardiac diastolic function via reducing E/E′ ratio. Finally, SAA inhibited TLR2/TLR4-mediated Myd88 activation and its downstream molecules TRAF6 and IRAK4, which decreases the release of proinflammatory cytokines and mediators through NF-κB and p38 MAPK pathways. In conclusion, SAA could attenuate cardiac inflammation and cardiac disfunction by TLR/Myd88/TRAF/NF-κB and p38MAPK/CREB signaling pathways in HFpEF mice, which provides evidence for SAA as a potential drug for treatment of HFpEF in clinic.

Gasdermins in sepsis.

Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune responses are dynamically altered at different pathogenic stages. Gasdermins (GSDMs) proteins are pore-forming executors in the membrane, subsequently mediating the release of pro-inflammatory mediators and inflammatory cell death. With the increasing research on GSDMs proteins and sepsis, it is believed that GSDMs protein are one of the most promising therapeutic targets in sepsis in the future. A more comprehensive and in-depth understanding of the functions of GSDMs proteins in sepsis is important to alleviate the multi-organ dysfunction and reduce sepsis-induced mortality. In this review, we focus on the function of GSDMs proteins, the molecular mechanism of GSDMs involved in sepsis, and the regulatory mechanism of GSDMs-mediated signaling pathways, aiming to provide novel ideas and therapeutic strategies for the diagnosis and treatment of sepsis.

INDIVIDUAL ARTICLE: Prurigo Nodularis: Current Clinicopathologic Overview and Psychodermatological Perspectives.

Prurigo nodularis (PN) is a quintessential neurocutaneous condition characterized by neural sensitization and intractable itch leading to intense scratching. This causes the formation of nodules with epidermal thickening and further release of pro-inflammatory mediators that recruit immune cells and increase dermal nerve proliferation and hypertrophy perpetuating the itch-scratch cycle. Those with PN have a significant quality-of-life (QoL) burden due to itch, anxiety, and sleep disturbance. In addition, PN exhibits psychiatric comorbidities that affect mental wellbeing such as depression, mood disorders, and substance abuse. This paper serves as an overview of the clinicopathologic aspects of PN, the burden of PN on QoL, and the psychodermatological aspects of the disease state.&nbsp; J Drugs Dermatol. 2023;22:12(Suppl 2):s6-11.

Neutrophils' Contribution to Periodontitis and Periodontitis-Associated Cardiovascular Diseases.

Neutrophils represent the primary defense against microbial threats playing a pivotal role in maintaining tissue homeostasis. This review examines the multifaceted involvement of neutrophils in periodontitis, a chronic inflammatory condition affecting the supporting structures of teeth summarizing the contribution of neutrophil dysfunction in periodontitis and periodontal-related comorbidities. Periodontitis, a pathological condition promoted by dysbiosis of the oral microbiota, is characterized by the chronic inflammation of the gingiva and subsequent tissue destruction. Neutrophils are among the first immune cells recruited to the site of infection, releasing antimicrobial peptides, enzymes, and reactive oxygen species to eliminate pathogens. The persistent inflammatory state in periodontitis can lead to aberrant neutrophil activation and a sustained release of proinflammatory mediators, finally resulting in tissue damage, bone resorption, and disease progression. Growing evidence now points to the correlation between periodontitis and systemic comorbidities. Indeed, the release of inflammatory mediators, immune complexes, and oxidative stress by neutrophils, bridge the gap between local and systemic immunity, thus highlighting neutrophils as key players in linking periodontal inflammation to chronic conditions, including cardiovascular diseases, diabetes mellitus, and rheumatoid arthritis. This review underscores the crucial role of neutrophils in the pathogenesis of periodontitis and the complex link between neutrophil dysfunction, local inflammation, and systemic comorbidities. A comprehensive understanding of neutrophil contribution to periodontitis development and their impact on periodontal comorbidities holds significant implications for the management of oral health. Furthermore, it highlights the need for the development of novel approaches aimed at limiting the persistent recruitment and activation of neutrophils, also reducing the impact of periodontal inflammation on broader health contexts, offering promising avenues for improved disease management and patient care.

Benzydamine plays a role in limiting inflammatory pain induced by neuronal sensitization.

Benzydamine is an active pharmaceutical compound used in the oral care pharmaceutical preparation as NSAID. Beside from its anti-inflammatory action, benzydamine local application effectively reliefs pain showing analgesic and anaesthetic properties. Benzydamine mechanism of action has been characterized on inflammatory cell types and mediators highlighting its capacity to inhibit pro-inflammatory mediator's synthesis and release. On the other hand, the role of benzydamine as neuronal excitability modulator has not been yet fully explored. Thus, we studied benzydamine's effect over primary culture DRG nociceptors excitability and after acute and chronic inflammatory sensitization, as a model to evaluate nociceptor response. Benzydamine demonstrated to effectively inhibit neuronal basal excitability reducing its firing frequency and increasing rheobase and afterhyperpolarization amplitude. Its effect was time and dose-dependent. At higher doses, benzydamine induced changes in action potential wavelength, decreasing its height and slightly increasing its duration. Moreover, the compound reduced neuronal acute and chronic inflammatory sensitization. It inhibited neuronal excitability mediated either by an inflammatory cocktail, acidic pH or high external KCl. Notably, higher potency was evidenced under inflammatory sensitized conditions. This effect could be explained either by modulation of inflammatory and/or neuronal sensitizing signalling cascades or by direct modulation of proalgesic and action potential firing initiating ion channels. Apparently, the compound inhibited Nav1.8 channel but had no effect over Kv7.2, Kv7.3, TRPV1 and TRPA1. In conclusion, the obtained results strengthen the analgesic and anti-inflammatory effect of benzydamine, highlighting its mode of action on local pain and inflammatory signalling.

Effect of specialized pro-resolving lipid mediators in the regulation of vascular tone and inflammation in human saphenous vein

Specialized pro-resolving lipid mediators (SPMs), derived from polyunsaturated fatty acids are important mediators in the resolution of inflammation. Recent studies have focused on the effects of SPMs in cardiovascular health and diseases. However, little is known about the effect SPMs on human vascular tone. Therefore, in this study it is aimed to investigate the effect of various SPMs including resolvin D- and E-series, maresin-1 (MaR1) and lipoxin-A4 (LxA4) on the vascular tone of human isolated saphenous vein (SV) preparations under inflammatory conditions. In addition, we aimed to evaluate the effects of SPMs on the release of pro-inflammatory mediators, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF- α) from human SV. Pretreatment of isolated of human SV with resolvin E1 (RvE1), resolvin D1 (RvD1) and MaR1 (100 nM, 18 h) significantly reduced the contractile responses to thromboxane A2 mimetic, U46619 whereas pretreatment with LxA4 and RvD2 (100 nM, 18 h) had no significant effect on the vascular tone of SV. Moreover, RvE1, RvD1 and MaR1 but not LxA4 and RvD2 (100 nM, 18 h) pretreatment diminished the release of MCP-1 and TNF-α from SV. In conclusion, our findings suggest that pre-treatment with RvE1, RvD1, and MaR1 could have potential benefits in decreasing graft vasospasm and vascular inflammation in SV.

Effects of HMGB1/RAGE/cathespin B inhibitors on alleviating hippocampal injury by regulating microglial pyroptosis and caspase activation in neonatal hypoxic-ischemic brain damage.

Microglia play a crucial role in regulating neuroinflammation in the pathogenesis of neonatal hypoxic-ischemic brain damage (HIBD). Pyroptosis, an inflammatory form of programmed cell death, has been implicated in HIBD; however, its underlying mechanism remains unclear. We previously demonstrated that high-mobility group box 1 protein (HMGB1) mediates neuroinflammation and microglial damage in HIBD. In this study, we aimed to investigate the association between HMGB1 and microglial pyroptosis and elucidate the mechanism involved in rats with HIBD (both sexes were included) and in BV2 microglia subjected to oxygen-glucose deprivation. Our results showed that HMGB1 inhibition by glycyrrhizin (20 mg/kg) reduced the expression of microglial pyroptosis-related proteins, including caspase-1, the N-terminus fragment of gasdermin D (N-GSDMD), and pyroptosis-related inflammatory factors, such as interleukin (IL) -1β and IL-18. Moreover, HMGB1 inhibition resulted in reduced neuronal damage in the hippocampus 72 h after HIBD and ultimately improved neurobehavior during adulthood, as evidenced by reduced escape latency and path length, as well as increased time and distance spent in the target quadrant during the Morris water maze test. These results revealed that HIBD-induced pyroptosis is mediated by HMGB1/receptor for advanced glycation end products (RAGE) signaling (inhibition by FPS-ZM1, 1 mg/kg) and the activation of cathespin B (cat B). Notably, cat B inhibition by CA074-Me (5 mg/kg) also reduced hippocampal neuronal damage by suppressing microglial pyroptosis, thereby ameliorating learning and memory impairments caused by HIBD. Lastly, we demonstrated that microglial pyroptosis may contribute to neuronal damage through the HMGB1/RAGE/cat B signaling pathway in vitro. In conclusion, these results suggest that HMGB1/RAGE/cat B inhibitors can alleviate hippocampal injury by regulating microglial pyroptosis and caspase activation in HIBD, thereby reducing the release of proinflammatory mediators that destroy hippocampal neurons and induce spatial memory impairments.

The role of IL-6, ferritin, and coagulopathy in Covid-19 clinical progression.

Background In COVID-19, the release of pro-inflammatory mediators in the cytokine storm, primarily interleukin-6 (IL-6), has been hypothesized to induce pulmonary intravascular coagulation. However, the relationship between IL-6 and coagulopathy remains unclear in COVID-19 progression. We aimed to investigate the correlation of IL-6 with D-dimer, fibrinogen, prothrombin time (PT), and ferritin. Furthermore, we also analyzed the effect of those parameters on the worsening of COVID-19 patients. Methods A prospective cohort study was conducted in moderate and severe COVID-19 patients from June 2020 to January 2021. A serial evaluation of IL-6, D-dimer, fibrinogen, ferritin, and PT was performed and correlated with the patient's condition at admission and on the 14th day. The outcomes (improvement, worsening, or discharged patients) were recorded during the study. Results Of 374 patients, 73 study subjects (61 severe and 12 moderate COVID-19) were included in this study. A total of 35 out of 61 severe and one out of 12 moderate illness subjects had experienced worsening. Spearman-rank correlation of IL-6 with with ferritin, D-dimer, fibrinogen, and PT was 0.08 ( p=0.5), -0.13 ( p=0.27), 0.01 ( p=0.91), and 0.03 ( p=0.77), respectively. In ROC analysis, D-dimer (74,77%) and IL-6 (71,32%) were the highest among other variables (>60%). Conclusions In COVID-19 patients, there was a correlation between elevated IL-6 and D-dimer levels with disease deterioration. There was no correlation between elevated IL-6 levels with ferritin, D-dimer, fibrinogen, and PT levels. Therefore, changes in IL-6 and D-dimer can predict worsening in moderate and severe COVID-19 patients.