Activation Pathways of Murine Macrophages by Lipophosphoglycan from Strains of Leishmania major (FV1 and LV39).

Lipophosphoglycan (LPG) is an important Leishmania virulence factor. It is the most abundant surface glycoconjugate in promastigotes, playing an important role in the interaction with phagocytic cells. While LPG is known to modulate the macrophage immune response during infection, the activation mechanisms triggered by this glycoconjugate have not been fully elucidated. This work investigated the role that LPGs purified from two strains of Leishmania major (FV1 and LV39) play in macrophage activation, considering the differences in their biochemical structures. Bone marrow-derived macrophages from BALB/c mice were stimulated with 10 µg/mL purified LPG from the LV39 and FV1 strains. We then measured the production of nitric oxide (NO) and cytokines, the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and the activation of MAPK pathways. LPG from the LV39 strain, which has longer poly-galactosylated side chains, induced a more pro-inflammatory profile than that from the FV1 strain. This included higher production of NO, TNF-α, and PGE2, and increased expression of COX-2 and iNOS. Additionally, the phosphorylation of ERK-1/2 and JNK was elevated in macrophages exposed to LPG from the LV39 strain. No difference in IL-10 production was observed in cells stimulated by both LPG. Thus, intraspecific structural differences in LPG contribute to distinct innate immune responses in macrophages.

COVID-19 Inflammatory Syndrome: Lessons from TNFRI and CRP about the Risk of Death in Severe Disease.

Background/Objectives: Cytokine storm in severe COVID-19 is responsible for irreversible tissue damage and death. Soluble mediators from the TNF superfamily, their correlation with clinical outcome, and the use of TNF receptors as a potent predictor for clinical outcome were evaluated. Methods: Severe COVID-19 patients had the levels of soluble mediators from the TNF superfamily quantified and categorized according to the clinical outcome (death versus survival). Statistical modeling was performed to predict clinical outcomes. Results: COVID-19 patients have elevated serum levels from the TNF superfamily. Regardless of sex and age, the sTNFRI levels were observed to be significantly higher in deceased patients from the first weeks following the onset of symptoms. We analyzed hematological parameters and inflammatory markers, and there was a difference between the groups for the following factors: erythrocytes, hemoglobin, hematocrit, leukocytes, neutrophils, band cells, lymphocytes, monocytes, CRP, IL-8, IFN-γ, IL-10, IL-6, IL-4, IL-2, leptin MIF sCD40L, and sTNFRI (p < 0.05). A post hoc analysis showed an inferential capacity over 70% for some hematological markers, CRP, and inflammatory mediators in deceased patients. sTNFRI was strongly associated with death, and the sTNFRI/sTNFRII ratio differed between outcomes (p < 0.001; power above 90%), highlighting the impact of these proteins on clinical results. The final logistic model, including sTNFRI/sTNFRII and CRP, indicated high sensitivity, specificity, accuracy, and an eight-fold higher odds ratio for an unfavorable outcome. Conclusions: The joint use of the sTNFRI/sTNFRII ratio with CRP proves to be a promising tool to assist in the clinical management of patients hospitalized for COVID-19.

A research agenda to advance the study of implementation mechanisms.

BACKGROUND: Implementation science scholars have made significant progress identifying factors that enable or obstruct the implementation of evidence-based interventions, and testing strategies that may modify those factors. However, little research sheds light on how or why strategies work, in what contexts, and for whom. Studying implementation mechanisms-the processes responsible for change-is crucial for advancing the field of implementation science and enhancing its value in facilitating equitable policy and practice change. The Agency for Healthcare Research and Quality funded a conference series to achieve two aims: (1) develop a research agenda on implementation mechanisms, and (2) actively disseminate the research agenda to research, policy, and practice audiences. This article presents the resulting research agenda, including priorities and actions to encourage its execution. METHOD: Building on prior concept mapping work, in a semi-structured, 3-day, in-person working meeting, 23 US-based researchers used a modified nominal group process to generate priorities and actions for addressing challenges to studying implementation mechanisms. During each of the three 120-min sessions, small groups responded to the prompt: "What actions need to be taken to move this research forward?" The groups brainstormed actions, which were then shared with the full group and discussed with the support of facilitators trained in structured group processes. Facilitators grouped critical and novel ideas into themes. Attendees voted on six themes they prioritized to discuss in a fourth, 120-min session, during which small groups operationalized prioritized actions. Subsequently, all ideas were collated, combined, and revised for clarity by a subset of the authorship team. RESULTS: From this multistep process, 150 actions emerged across 10 priority areas, which together constitute the research agenda. Actions included discrete activities, projects, or products, and ways to shift how research is conducted to strengthen the study of implementation mechanisms. CONCLUSIONS: This research agenda elevates actions to guide the selection, design, and evaluation of implementation mechanisms. By delineating recommended actions to address the challenges of studying implementation mechanisms, this research agenda facilitates expanding the field of implementation science, beyond studying what works to how and why strategies work, in what contexts, for whom, and with which interventions.

The Effect of Ionizing Irradiation on the Autotaxin-Lysophasphatidic Acid Axis and Interleukin-6/8 Secretion in Different Breast Cancer Cell Lines.

BACKGROUND: The Autotaxin (ATX)-lysophosphatidic acid (LPA) axis is involved in decreasing radiation sensitivity of breast tumor cells. This study aims to further elucidate the effect of irradiation on the ATX-LPA axis and cytokine secretion in different breast cancer cell lines to identify suitable breast cancer subtypes for targeted therapies. METHODS: Different breast cancer cell lines (MCF-7 (luminal A), BT-474 (luminal B), SKBR-3 (HER2-positive), MDA-MB-231 and MDA-MB-468 (triple-negative)) and the breast epithelial cell line MCF-10A were irradiated. The influence of irradiation on LPA receptor (LPAR) expression, ATX expression, and Interleukin (IL)-6 and IL-8 secretion was analyzed. Further, the effect of IL-6 and IL-8 on ATX expression of adipose-derived stem cells (ADSC) was investigated. RESULTS: Irradiation increased ATX and LPAR2 expression in MDA-MB-231 cells. Additionally, IL-6 secretion was enhanced in MDA-MB-231, and IL-8 secretion in MDA-MB-231 and MDA-MB-468. Stimulation of ADSC with IL-6 and IL-8 increased ATX expression in ADSC. CONCLUSIONS: Targeting ATX or its downstream signaling pathways might enhance the sensitivity of triple-negative breast cancer cells to radiation. Further exploration of the interplay between irradiation, the ATX-LPA axis, and inflammatory cytokines may elucidate novel pathways for overcoming radioresistance and improving individual treatment outcomes.

A Patent-Pending Ointment Containing Extracts of Five Different Plants Showed Antinociceptive and Anti-Inflammatory Mechanisms in Preclinical Studies.

Background/Objectives: The antinociceptive and anti-inflammatory effects of a patent-pending ointment containing plant extracts from Eucalyptus globulus, Curcuma longa, Hamamelis virginiana, Echinacea purpurea, and Zingiber officinale were evaluated. Methods: Plant extracts were chemically characterized by gas chromatography-mass spectroscopy. The antinociceptive activity of the ointment was assessed using the hot plate, tail flick, and formalin tests, whereas the anti-inflammatory activity was measured using the acute and chronic TPA-induced ear edema tests. Mechanisms of action were evaluated using inhibitors from signaling pathways related to pain response and by using histological analysis and assessing the expression and activity of pro-inflammatory mediators. Results: The ointment showed antinociceptive and anti-inflammatory effects like those observed with diclofenac gel (1.16% v/v) and ketoprofen gel (2.5% v/v). The antinociceptive actions of the ointment are mediated by the possible participation of the opiodergic system and the nitric oxide pathway. The anti-inflammatory response was characterized by a decrease in myeloperoxidase (MPO) activity and by a reduction in ear swelling and monocyte infiltration in the acute inflammation model. In the chronic model, the mechanism of action relied on a decrease in pro-inflammatory mediators such as COX-2, IL-1ß, TNF-α, and MPO. An in-silico study with myristic acid, one of the compounds identified in the ointment's plant mixture, corroborated the in vivo results. Conclusions: The ointment showed antinociceptive activities mediated by the decrease in COX-2 and NO levels, and anti-inflammatory activity due to the reduction in IL-1ß and TNFα levels, a reduction in MPO activity, and a decrease in NF-κB and COX-2 expression.

MASH: MEDIATION ANALYSIS OF SURVIVAL OUTCOME AND HIGH-DIMENSIONAL OMICS MEDIATORS WITH APPLICATION TO COMPLEX DISEASES.

Environmental exposures such as cigarette smoking influence health outcomes through intermediate molecular phenotypes, such as the methylome, transcriptome, and metabolome. Mediation analysis is a useful tool for investigating the role of potentially high-dimensional intermediate phenotypes in the relationship between environmental exposures and health outcomes. However, little work has been done on mediation analysis when the mediators are high-dimensional and the outcome is a survival endpoint, and none of it has provided a robust measure of total mediation effect. To this end, we propose an estimation procedure for Mediation Analysis of Survival outcome and High-dimensional omics mediators (MASH) based on sure independence screening for putative mediator variable selection and a second-moment-based measure of total mediation effect for survival data analogous to the R 2 measure in a linear model. Extensive simulations showed good performance of MASH in estimating the total mediation effect and identifying true mediators. By applying MASH to the metabolomics data of 1919 subjects in the Framingham Heart Study, we identified five metabolites as mediators of the effect of cigarette smoking on coronary heart disease risk (total mediation effect, 51.1%) and two metabolites as mediators between smoking and risk of cancer (total mediation effect, 50.7%). Application of MASH to a diffuse large B-cell lymphoma genomics data set identified copy-number variations for eight genes as mediators between the baseline International Prognostic Index score and overall survival.

Features of the regulation of reparative processes of chronic wounds in response to the effect of photobiomodulation therapy on a wound defect. Photobiomodulation therapy for chronic wounds.

BACKGROUND: One of the promising methods of influencing the wound process is photobiomodulation (PBM) therapy. The optimal parameters of PBM therapy have not yet been found because the molecular mechanisms of light interaction with tissue are not fully understood. OBJECTIVE: Studying the influence of PBM of various parameters on the regulation of reparative process- es of chronic wounds using the example of indicators of aggregation activity of platelets, platelet-derived growth factor (PDGF), interleukin-8 (IL-8), and amino-terminal propeptide of type III procollagen (PIIINP) at the remodeling stage. And also the study of the structural and functional features of chronic wound heal- ing in an experiment under various parameters of PBM therapy. METHODS: Experiments were carried out on Wistar rats. Chronic wounds were simulated. Experimental animals were exposed to PBM at a wavelength of 660 nm and an energy density of 1 J/cm2. In serum, PDGF, IL-8, and PIIINP levels were measured by enzyme-linked immunosorbent assay. The functional activity of platelets was measured using the turbidimetric method. Histological analysis was performed. RESULTS: The work noted the dose-dependent effect of PBM using the example of platelet aggregation at the remodeling stage during the healing of chronic wounds. The use of PBM therapy resulted in increased serum PDGF levels. Histological examination data indicate a positive effect of PBM therapy on the wound healing process. CONCLUSIONS: The effectiveness of the use of PBM therapy for the healing of chronic wounds to regulate reparative processes has been proven.

Biosynthesis of resolvin D1, resolvin D2, and RCTR1 from 7,8(S,S)-epoxytetraene in human neutrophils and macrophages.

While the acute inflammatory response to harmful stimuli is protective, unrestrained neutrophil swarming drives collateral tissue damage and inflammation. Biosynthesized from omega-3 essential polyunsaturated fatty acids, resolvins are a family of signaling molecules produced by immune cells within the resolution phase to orchestrate return to homeostasis. Understanding the mechanisms that govern biosynthesis of these potent molecules gives insight into stimulating endogenous resolution and offers fresh opportunities for preventing and treating excessive inflammation. In this report, using materials prepared by total synthesis and liquid chromatography and tandem mass spectrometry-based matching studies, we established the role of 7,8(S,S)-epoxytetraene intermediate in the biosynthesis of resolvin D1, resolvin D2, and the resolvin conjugate in tissue regeneration (RCTR1) by human phagocytes. We demonstrated that this 7,8(S,S)-epoxy-containing intermediate is directly converted to resolvin D2 by human M2-like macrophages and to resolvin D1 and RCTR1 by human macrophages, neutrophils, and peripheral blood mononuclear cells. In addition, both human recombinant soluble epoxide hydrolase (sEH) and the glutathione S-transferase leukotriene C4 synthase (LTC4S) each catalyze conversion of this epoxide to resolvin D1 and RCTR1, respectively. MS3 ion-trap scans and isotope incorporation of 18O from H218O with sEH indicated that the oxygen atom at C-8 in resolvin D1 is derived from water. Results from molecular docking simulations with biosynthetic precursor 17S-hydroperoxy-4,7,10,13,19-cis-15-trans-docosahexaenoic acid and the epoxy intermediate were consistent with 5-lipoxygenase production of resolvin D1. Together, these results give direct evidence for the role of resolvin 7,8(S,S)-epoxytetraene intermediate in the endogenous formation of resolution-phase mediators resolvin D1, resolvin D2, and RCTR1 by human phagocytes.

Research progress in the mechanisms and functions of specialized pro-resolving mediators in neurological diseases.

The nervous system interacts with the immune system through a variety of cellular regulators, signaling pathways, and molecular mechanisms. Disruptions in these interactions lead to the development of multiple neurological diseases. Recent studies have identified that specialized pro-resolving mediators (SPMs) play a regulatory role in the neuroimmune system. This study reviews recent research on the function of SPMs in the inflammatory process and their association with the nervous system. The review aims to provide new perspectives for studying the pathogenesis of neurological diseases and identify novel targets for clinical therapy.

Deciphering the Potential Role of Specialized Pro-Resolving Mediators in Obesity-Associated Metabolic Disorders.

Obesity-related metabolic disorders, including diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease, increasingly threaten global health. Uncontrolled inflammation is a key pathophysiological factor in many of these conditions. In the human body, inflammatory responses generate specialized pro-resolving mediators (SPMs), which are crucial for resolving inflammation and restoring tissue balance. SPMs derived from omega-3 polyunsaturated fatty acids (n-3 PUFAs) such as resolvins, protectins, and maresins hold promise in attenuating the chronic inflammatory diseases associated with lipid metabolism disorders. Recent research has highlighted the therapeutic potential of n-3 PUFA-derived metabolites in addressing these metabolic disorders. However, the understanding of the pharmacological aspects of SPMs, particularly in obesity-related metabolic disorders, remains limited. This review comprehensively summarizes recent advances in understanding the role of SPMs in resolving metabolic disorders, based on studies in animal models and humans. These studies indicate that SPMs have potential as therapeutic targets for combating obesity, as well as offering insights into their mechanisms of action.

Decreased NETosis-related regulators in neuromyelitis optica spectrum disorders after plasma exchange.

OBJECTIVES: To investigate the impact of plasma exchange (PLEX) on NETosis-related regulators and their correlation with neurological improvement in NMOSD patients. METHODS: Twelve aquaporin-4 antibodies seropositive NMOSD patients were enrolled. NETosis-related regulators (myeloperoxidase [MPO], citrullinated histone H3 [CIT-H3], peptidyl arginine deiminase 4 [PAD4], neutrophil elastase [NE], CD64), pro-inflammatory cytokines (IL-1, IL-6, IL-12, TNF-α) and anti-inflammatory cytokines (IL-10, TGF-ß1) were quantitatively assessed before and after PLEX treatment. Clinical assessments included expanded disability status scale (EDSS) and visual outcome scale (VOS) scores. RESULTS: Following PLEX, all patients showed symptom improvement, with 66.7 % achieving marked-to-moderate improvement (MMI) at 3 months. Key regulators, such as MPO, CIT-H3, PAD4, NE, and pro-inflammatory cytokines such as IL-1, IL-6, IL-12, and TNF-α, exhibited a statistically significant decrease immediately after the initial PLEX session (P < 0.05). Furthermore, CD64 levels demonstrated a substantial decline after the second PLEX session (P < 0.05). Conversely, the levels of anti-inflammatory cytokines, including IL-10 and TGF-ß1, displayed an ascending trend post-PLEX. In clinical relevance analysis, among patients who reached MMI, the reductions in MPO, IL-1, and IL-6 exhibited statistically significant differences when compared to patients in the mild-to-no improvement group (P < 0.05). Pearson correlation analysis revealed that the percentage reduction in IL-6 levels after PLEX was positively correlated with the percentage reduction in patient EDSS/VOS scores (r = 0.638, P < 0.05). CONCLUSIONS: This study highlights that reduced levels of NETosis-related regulators after PLEX contribute to clinical improvement, suggesting the potential involvement of NETosis in the acute neurological impairment observed in NMOSD.

The assessment of usefulness of cytokines and other soluble mediators as the predictors of sequalae development in various forms of tick-borne encephalitis (TBE).

AIM: The aim of the study was to assess the usefulness of cytokines and other soluble mediators in differentiation between severe and mild course of tick-borne encephalitis (TBE) as well as the predictor of sequalae development. MATERIAL AND METHODS: 122 patients (mean age 47.66 ± 14.77 years, 43 females, 79 males) with TBE were included in the study. Concentrations of 82 cytokines, growth factors, selectins, matrix metalloproteinases and other soluble mediators were measured in serum and CSF samples according to the manufacturer's instruction on a Bio-Plex 200 System using the custom made Luminex assays. Enzyme-linked immunosorbent assays for the quantitative detection of human IL-26, IL-29 IL-22, CXCL12 were performed. RESULTS: No significant differences between serum concentrations of examined factors between group with sequelae and group with complete recovery were observed. In the CSF the concentrations of GM-CSF, Il-1α, Il-2, Il-4, Il-6, Il-12p70, Il-17A, CXCL1, CXCL6, Il-8, CCL4, CCL20, TRAIL, CD40L, MMP8 were significantly higher in patients who developed sequelae than in patients with complete recovery. For TRAIL concentration over 26.65 pg/ml in CSF the probability of sequalae development was 10.5 higher. In case of CCL20 - the concentration over 21.38 pg/ml in CSF the odds ratio was 6.429 times. For MMP-8 over 4210.54 pg/ml, the odds ratio was 11.222 times. CONCLUSIONS: TRAIL, CCL-20 and MMP-8 are promising biomarkers of prediction of the sequalae development of TBE. Pro-inflammatory cytokines IL-8, IL-1, IL-2, IL-12, IL-17A also associate well with the risk of sequelae and could be further evaluated as prognostic markers in TBE, individually or as elements of a larger model.

Levels of matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, osteopontin, pentraxin-3, and thymic stromal lymphopoietin in crevicular fluid samples from peri-implantitis, periodontitis, and healthy sites.

AIM: Periodontitis and peri-implantitis are chronic inflammatory diseases characterized by the destruction of supporting tissues. Despite some similarities, it is essential to understand the differences in how these diseases elicit unique host responses within the oral tissues, including the production of selected matrix metalloproteinases (MMPs) and inflammatory mediators involved in tissue remodelling. The aim of this study was to evaluate the levels of proteolytic enzymes MMP-1, MMP-2, MMP-3, as well as the inflammatory mediators osteopontin (OPN), pentraxin-3 (PTX3), and thymic stromal lymphopoietin (TSLP) in crevicular fluid samples collected from healthy, periodontitis-affected, and peri-implantitis sites. METHODS: Gingival crevicular fluid (GCF) and peri-implant crevicular fluid (PICF) samples were collected from healthy and diseased teeth and implant sites of 163 patients. The MMP-1, MMP-2, MMP-3, OPN, PTX3, and TSLP levels were determined using commercially available immunoassays. A linear mixed model procedure was adopted for multilevel analyses, using biomarker levels as the outcome variable to compare two types of sites. The diagnostic accuracy of the biomarkers was evaluated by Youden's index to estimate the sensitivity, specificity and the area under curve (AUC). RESULTS: The levels of MMP-1, MMP-2, MMP-3, OPN, and TSLP were higher at sites with periodontitis and peri-implantitis compared to the levels at sites with healthy teeth and healthy implants. No significant differences were observed in the levels of the measured markers between the sites diagnosed with periodontitis and those diagnosed with peri-implantitis. The highest diagnostic potential at implant sites was found for MMP-2 (AUC = 0.74) and TSLP (AUC = 0.72). The highest AUC (0.82) at tooth sites was found for OPN. CONCLUSIONS: The findings indicate that the proteolytic enzyme MMP-2 and the cytokine TSLP might be potential biomarkers for both periodontitis and peri-implantitis, whereas the proinflammatory cytokine OPN may serve as a biomarker for periodontitis. Further studies are required to confirm the utility of these biomarkers and explore their potential clinical applications.

Impact of adding eicosapentaenoic and docosahexaenoic acid-rich fish oil in sow and piglet diets on blood oxylipins and immune indicators of weaned piglets.

Weaning is a decisive event in piglets' life. This study aimed to evaluate whether the inclusion of fish oil, rich in eicosapentaenoic and docosahexaenoic acids (EPA and DHA), in sow and piglet diets, increased the concentration of anti-inflammatory molecules in the blood of weaned piglets and whether the effect was dependent on the pigs being born with either low or a high birth BW (bBW). Thirty-six sows in four consecutive batches were randomly distributed between a control diet with animal fat (15 g/kg in gestation and 30 g/kg in lactation) or a n-3 long-chain fatty acid diet (LCFA; totally or half replacing animal fat by fish oil during gestation and lactation, respectively) from service until weaning (ca. 28 days). At birth, the two lightest (LBW) and the two heaviest (HBW) piglets in each litter were identified and, at weaning, grouped in pens by pairs prioritising their bBW. Pens were further distributed into a control (30 g/kg animal fat) or n-3 LCFA diet (totally replacing animal fat by fish oil) for 28 days. At the end of the trial, blood was collected from piglets in the first batch (n = 48). Serum fatty acids (FAs) were quantified by GC, plasma oxylipins by ultra-HPLC-MS, and plasma immune indicators by ELISA. An interaction between piglet diet and bBW for average daily gain (P = 0.020) and average daily feed intake (P = 0.014) during the whole postweaning indicated that dietary n-3 LCFA-promoted LBW piglets to have a similar growth and intake than HBW piglets reaching 1.5 kg average BW more at the end of the postweaning period than LBW control piglets. Fish oil in piglet diets also increased the concentrations of total n-3 FA, EPA and DHA (all P < 0.001), their resultant oxylipins, particularly their hydroxy derivatives from lipoxygenase enzymatic pathway (all P < 0.001) and tended to increase immunoglobulin M (P = 0.067) in blood. Regarding the bBW category, LBW piglets tend to increase tumour necrosis factor α in plasma (P = 0.083) compared to HBW. It is concluded that fish oil in postweaning diets could enhance the daily gain and feed intake of LBW piglets, increasing the concentration of serum n-3 FAs and their derived oxylipins in plasma.

Development and Validation of Methodologies for the Identification of Specialized Pro-Resolving Lipid Mediators and Classic Eicosanoids in Biological Matrices.

Lipid mediators, which include specialized pro-resolving mediators and classic eicosanoids, are pivotal in both initiating and resolving inflammation. The regulation of these molecules determines whether inflammation resolves naturally or persists. However, our understanding of how these mediators are regulated over time in various inflammatory contexts is limited. This gap hinders our grasp of the mechanisms underlying the disease onset and progression. Due to their localized action and low endogenous levels in many tissues, developing robust and highly sensitive methodologies is imperative for assessing their endogenous regulation in diverse inflammatory settings. These methodologies will help us gain insight into their physiological roles. Here, we establish methodologies for extracting, identifying, and quantifying these mediators. Using our methods, we identified a total of 37 lipid mediators. Additionally, by employing a reverse-phase HPLC method, we successfully separated both double-bond and chiral isomers of select lipid mediators, including Lipoxin (LX) A4, 15-epi-LXA4, Protectin (PD) D1, PDX, and 17R-PD1. Validation of the method was performed in both solvent and surrogate matrix for linearity of the standard curves, lower limits of quantitation (LLOQ), accuracy, and precision. Results from these studies demonstrated that linearity was good with r2 values > 0.98, and LLOQ for the mediators ranged from 0.01 to 0.9 pg in phase and from 0.1 to 8.5 pg in surrogate matrix. The relative standard deviation (RSD) for inter- and intraday precision in solvent ranged from 5% to 12% at low, intermediate, and high concentrations, whereas the RSD for the inter- and intraday variability in the accuracy ranged from 95% to 87% at low to high concentrations. The recovery in biological matrices (plasma and serum) for the internal standards used ranged from 60% to 118%. We observed a marked ion suppression for molecules evaluated in negative ionization mode, while there was an ion enhancement effect by the matrix for molecules evaluated in positive ionization mode. Comparison of the integration algorithms, namely, AutoPeak and MQ4, and approaches for calculating signal-to-noise ratios (i.e., US Pharmacopeia, relative noise, peak to peak, and standard deviation) demonstrated that different integration algorithms tested had little influence on signal-to-noise ratio calculations. In contrast, the method used to calculate the signal-to-noise ratio had a more significant effect on the results, with the relative noise approach proving to be the most robust. The methods described herein provide a platform to study the SPM and classic eicosanoids in biological tissues that will help further our understanding of disease mechanisms.

The principles and promising future of sonogenetics for precision medicine.

Sonogenetics is an emerging medical technology that uses acoustic waves to control cells through sonosensitive mediators (SSMs) that are genetically encoded, thus remotely and non-invasively modulating specific molecular events and/or biomolecular functions. Sonogenetics has opened new opportunities for targeted spatiotemporal manipulation in the field of gene and cell-based therapies due to its inherent advantages, such as its noninvasive nature, high level of safety, and deep tissue penetration. Sonogenetics holds impressive potential in a wide range of applications, from tumor immunotherapy and mitigation of Parkinsonian symptoms to the modulation of neural reward pathway, and restoration of vision. This review provides a detailed overview of the mechanisms and classifications of established sonogenetics systems and summarizes their applications in disease treatment and management. The review concludes by highlighting the challenges that hinder the further progress of sonogenetics, paving the way for future advances.

The Omega-6 Lipid pathway shift is associated with neutrophil influx and structural lung damage in early cystic fibrosis lung disease.

Objectives: In cystic fibrosis (CF), an imbalanced lipid metabolism is associated with lung inflammation. Little is known about the role that specific lipid mediators (LMs) exert in CF lung inflammation, and whether their levels change during early disease progression. Therefore, we measured airway LM profiles of young CF patients, correlating these with disease-associated parameters. Methods: Levels of omega (ω)-3/6 PUFAs and their LM derivatives were determined in bronchoalveolar lavage fluid (BALF) of children with CF ages 1-5 using a targeted high-performance liquid chromatography-tandem mass spectrometry approach. Hierarchical clustering analysis was performed on relative LM levels. Individual relative LM levels were correlated with neutrophilic inflammation (BALF %Neu) and structural lung damage (PRAGMA-CF %Disease). Significant correlations were included in a backward multivariate linear regression model to identify the LMs that are best related to disease progression. Results: A total of 65 BALF samples were analysed for ω-3/6 lipid content. LM profiles clustered into an arachidonic acid (AA)-enriched and a linoleic acid (LA)-enriched sample cluster. AA derivatives like 17-OH-DH-HETE, 5-HETE, 5,15-diHETE, 15-HETE, 15-KETE, LTB4 and 6-trans-LTB4 positively correlated with BALF %Neu and/or PRAGMA %Dis. Contrastingly, 9-HoTrE and the LA derivatives 9-HoDE, 9(10)-EpOME, 9(10)-DiHOME, 13-HoDE, 13-oxoODE and 12(13)-EpOME negatively correlated with BALF %Neu and/or PRAGMA %Dis. 6-trans-LTB4 was the strongest predictor for BALF %Neu. 5-HETE and 15-KETE contributed most to PRAGMA %Dis prediction. Conclusions: Our data provide more insight into the lung lipidome of infants with CF, and show that a shift from LA derivatives to AA derivatives in BALF associates with early CF lung disease progression.

Camel Whey Protein and Baicalein Suppressed Mast Cell Degranulation in Mice Models of IgE- and Non-IgE-Mediated Anaphylaxes: Potential Mechanisms on Downstream Cell Signaling of Mast Cells.

INTRODUCTION: Novel treatments are being researched to develop more safe and effective protective medications for anaphylaxis. Camel whey protein (CWP) and baicalein (BAC, one of the major flavones) have multiple beneficial properties including anti-inflammatory and antioxidant activities. METHODS: The current study investigated/compared the therapeutic protection of repeated intragastric administration of CWP (100 mg/kg body weight, as an animal extract) and BAC (10 mg/kg body weight, as a plant extract), before the challenge with ovalbumin (OVA) or receiving the compound 48/80 (C48/80), against mice models for IgE-independent and dependent anaphylaxes. Besides, their effects on mast cells (MCs) downstream cell signaling were explored. RESULTS: The results revealed that CWP and BAC reduced the mortality rate, as compared with a MCs stabilizer "sulfasalazine (SSZ, 100 mg/kg body weight, intraperitoneally)," in both mice models. Furthermore, they prevented the MCs degranulation and significantly reduced (p < .05) lung tissue levels of cell signaling (p-AKT, p-ERK, and p-IκBα). Additionally, they decreased histamine, tryptase, leukotriene C4, prostaglandin D2, interleukin (IL)-4, and IL-10 levels in broncho-alveolar and peritoneal lavages in systemic anaphylaxis mice models. They also restored the stabilization of peritoneal MCs membrane in inverted light microscopy results accompanied by amelioration of the lung histology. DISCUSSION: The present study provided evidence for the protective therapeutic effect of CWP and BAC against anaphylaxis. As a result, CWP and BAC may be used as preventative supplemented regimens for both non-vegetarian and vegetarian consumers to treat allergy through downregulation of MCs signal transduction pathways, and hence controlling the production of inflammatory mediators.

Potential Antiallergic Activity of Two Chemically/Enzymatically-Modified Natural Products Against Active Atopic and Systemic Anaphylaxes in CD1 Mice Models.

INTRODUCTION: Anaphylaxis is a globally increasing allergic reaction that is often fatal. Recently, our previous study reported the possibility of using the modified natural products "sodium R-lipoate (NaRLA) and enzymatically modified isoquercitrin (EMIQ)" as potential novel safe agents against the non-immunological-degranulation of mast cells. METHODS: Here, we extended our previous findings by determining the antianaphylactic activity of 50 and 100 mg/kg body weight of NaRLA and EMIQ (given orally and prior to local or systemic challenge) in mice models of ovalbumin (OVA)-induced IgE-dependent active cutaneous anaphylaxis (ACA) and active systemic anaphylaxis (ASA) in comparison with sulfasalazine (SSZ, amast cell stabilizer). RESULTS: The pre-treatment of mice with NaRLA or EMIQ completely succeeded, as SSZ, in suppression of the increased vascular permeability associated with IgE-dependent ACA and protected the OVA-sensitized mice from fatal ASA by reducing (p < .001) the skin mast cell degranulation, the elevated peritoneal histamine and interleukin-4 levels, along with decreasing the associated sever gastrointestinal and lung histopathological alterations and inflammation. The high dose of EMIQ prevented death in 70% of mice with anaphylactic shock, better than SSZ. DISCUSSION: Our data indicated that NaRLA and EMIQ may be potential prophylactic and therapeutic candidates for the alleviation of atopic and systemic anaphylaxis.

Advances in the application and mechanism of bioactive peptides in the treatment of inflammation.

Inflammation is a normal immune response in organisms, but it often triggers chronic diseases such as colitis and arthritis. Currently, the most widely used anti-inflammatory drugs are non-steroidal anti-inflammatory drugs, albeit they are accompanied by various adverse effects such as hypertension and renal dysfunction. Bioactive peptides (BAPs) provide therapeutic benefits for inflammation and mitigate side effects. Herein, this review focuses on the therapeutic effects of various BAPs on inflammation in different body parts. Emphasis is placed on the immunomodulatory mechanisms of BAPs in treating inflammation, such as regulating the release of inflammatory mediators, modulating MAPK and NF-κB signaling pathways, and reducing oxidative stress reactions for immunomodulation. This review aims to provide a reference for the function, application, and anti-inflammation mechanisms of BAPs.