Search Results (84)

Background: Allergic rhinitis (AR) is a prevalent allergic disorder characterized by a complex pathogenesis. Drawing on traditional Chinese medicine theory and contemporary pharmacological principles, this study developed an inhalation-based herbal formulation, ZHW, to explore a novel non-invasive therapeutic approach. Objective: To investigate the therapeutic effects of ZHW on AR and elucidate its underlying mechanisms and potential targets through an integrated analysis of network pharmacology and proteomics. Materials and Methods: The volatile components of ZHW were analyzed by gas chromatography–mass spectrometry (GC-MS). The mouse model of AR was induced by OVA sensitization. The therapeutic efficacy of ZHW was assessed based on nasal symptom scores, histopathological examination, and inflammatory cytokine levels. Furthermore, the underlying mechanisms and potential targets of ZHW were investigated through integrated network pharmacology and proteomics analyses. Results: GC-MS analysis identified 39 bioactive compounds in ZHW. Inhalation treatment with ZHW demonstrated significant anti-allergic effects in OVA-sensitized mice, as evidenced by (1) reduced sneezing frequency and nasal rubbing behaviors; (2) decreased serum levels of IL-4, histamine, and OVA-specific IgE; (3) attenuated IL-4 concentrations in both nasal lavage fluid and lung tissue; (4) diminished nasal mucosal thickening; and (5) suppression of inflammatory cell infiltration. Integrated network pharmacology and proteomics analyses indicated that ZHW’s therapeutic effects were mediated through the modulation of multiple pathways, including the PI3K-Akt signaling pathway, the B cell receptor signaling pathway, oxidative phosphorylation, and the FcεRI signaling pathway. Key molecular targets involved Rac1, MAPK1, and SYK. Molecular docking simulations revealed strong binding affinities between ZHW’s primary bioactive constituents (linalool, levomenthol, linoleic acid, Linoelaidic acid, and n-Valeric acid cis-3-hexenyl ester) and these target proteins. Conclusions: The herbal formulation ZHW demonstrates significant efficacy in alleviating allergic rhinitis symptoms through multi-target modulation of key signaling pathways, including PI3K-Akt- and FcεRI-mediated inflammatory responses. These findings substantiate ZHW’s therapeutic potential as a novel, non-invasive treatment for AR and provide a strong basis for the development of new AR therapies. Future clinical development will require systematic safety evaluation to ensure optimal therapeutic outcomes. Full article

The systematics and phylogeny of the most speciose genus (Leopardus) of the felidae have historically been contentious and problematic. These issues have been compounded with the recent advancement of genetic techniques that make it possible to detect events such as incomplete lineage sorting (ILS), punctual historical ancestral introgression (PHAI), and repetitive introgression or recent hybridization (RI-RH). Each of these events have noteworthily affected the Leopardus genus. One Leopardus taxon (Leopardus tigrinus, herein called tigrina) has been especially complex from a phylogenetic point of view. In the last decade, one new species has been reported (L. guttulus) and two other new species likely exist within the tigrinas (L. emiliae and L. pardinoides). However, the most surprising find was the discovery of a new and not previously reported tigrina, the Nariño cat, from the southern Andean region of Colombia (2023). Later that same year, a new paper criticized the discovery. In response to that criticism, herein, we provide new molecular genetics results of the Nariño cat as well as new insights into the molecular phylogeny of the tigrinas inside the Leopardus genus: (1) In this new work, we analyzed the mtND5 gene of Nariño cat samples collected over four years (2001, 2007, 2017, 2023) as well as analyzed mitogenomes of Nariño cat samples collected in three different years (2001, 2017, 2023). The temporal Nariño cat samples (2001, 2007, 2017, 2023) refer to samples taken from a single specimen across different years. Based on these analyses, data from 2001 and 2007 represent the most reliable information. In contrast, samples from 2017 and 2023 may be contaminated with DNA from the Pampas cat and tigrina, respectively. (2) On the other hand, based on sequencing the mtND5 gene of 164 specimens of Leopardus, northern Andean and Central American tigrinas (37 specimens) are divided into at least six different groups (without counting the Nariño cat). Based on our analysis of sequenced mitogenomes of 102 specimens (including 34 northern Andean and Central American tigrinas) of the Leopardus genus, there are at least eight different groups of tigrinas (without counting the Nariño cat). Henceforth, there are strong datasets which support the existence of multiple lineages within the presumed “a priori” northern Andean tigrina and thus much of the genetic diversity of this wild cat has gone unnoticed. There are a series of potential taxa that have gone unnoticed due to a lack of sampling of this polyphyletic Andean feline. Full article

Background/Objectives: Chronic obstructive pulmonary disease (COPD) remains a leading cause of death worldwide, with emphysema progression providing valuable insights into disease development. Clinical assessment approaches, including pulmonary function tests and high-resolution computed tomography, are limited by accessibility constraints and radiation exposure. This study, therefore, proposed an alternative approach by integrating the novel biomarker long non-coding interleukin-7 receptor α-subunit gene (lnc-Il7R), along with other easily accessible clinical and biochemical metrics, into machine learning (ML) models. Methods: This cohort study collected baseline characteristics, COPD Assessment Test (CAT) scores, and biochemical details from the enrolled participants. Associations with emphysema severity, defined by a low attenuation area percentage (LAA%) threshold of 15%, were evaluated using simple and multivariate-adjusted models. The dataset was then split into training and validation (80%) and test (20%) subsets. Five ML models were employed, with the best-performing model being further analyzed for feature importance. Results: The majority of participants were elderly males. Compared to the LAA% <15% group, the LAA% ≥15% group demonstrated a significantly higher body mass index (BMI), poor pulmonary function, and lower expression levels of lnc-Il7R (all p < 0.01). Fold changes in lnc-IL7R were strongly and negatively associated with LAA% (p < 0.01). The random forest (RF) model achieved the highest accuracy and area under the receiver operating characteristic curve (AUROC) across datasets. A feature importance analysis identified lnc-IL7R fold changes as the strongest predictor for emphysema classification (LAA% ≥15%), followed by CAT scores and BMI. Conclusions: Machine learning models incorporated accessible clinical and biochemical markers, particularly the novel biomarker lnc-IL7R, achieving classification accuracy and AUROC exceeding 75% in emphysema assessments. These findings offer promising opportunities for improving emphysema classification and COPD management. Full article

Allergen immunotherapy (AIT) is a well-established treatment aimed at reducing allergen sensitivity by gradually exposing the immune system to increasing doses of allergens. This promotes desensitization and immune tolerance through multiple mechanisms. AIT offers long-term immune modulation and is considered a potentially curative certain forms of allergic diseases. Altered antibody responses is a key mechanism of AIT in the production of allergen-specific IgG4 antibodies, which act as blocking antibodies to prevent allergen binding to IgE on mast cells (MCs) and basophils. However, IgG4 responses are sometimes ineffective due to variations in antibody affinity and epitope targeting. Reverse class switching from IgE to IgG4 and selective depletion of IgE-producing B cells represent potential strategies to improve AIT efficacy. Tregs play a central role in AIT by suppressing Th2-driven allergic responses and promoting immune tolerance through anti-inflammatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. However, genetic and environmental factors may impair Treg function, leading to AIT failure. AIT reduces MC and basophil activation, leading to long-term suppression of allergic inflammation. It modulates IgE-FcεRI interactions and cytokine signaling pathways, but in some cases, anaphylactic reactions or resistance to MC desensitization may occur. Discussion and conclusions: While AIT is a highly effective allergy treatment, variability in immune responses can impact its success. Advances in biologic therapies offer potential synergies with AIT. Understanding these interactions will help refine AIT strategies and improve patient outcomes. Full article

Background/Objectives: Arthritis encompasses a range of joint-related conditions, including osteoarthritis and rheumatoid arthritis, along with inflammatory diseases such as gout and lupus. This research study explores the underlying causes, challenges, and treatment options for arthritis, aiming to enhance the effectiveness of therapies. Methods: This research study evaluated current treatment strategies and examined the effectiveness of selected biological disease-modifying antirheumatic drugs (bDMARDs), i.e., abatacept, golimumab, and sarilumab, with a focus on emerging drug classes and their distinct mechanisms of action. Results: Biologic DMARDs like abatacept, golimumab, and sarilumab offer hopeful treatment alternatives for patients who fail to respond to conventional therapies. However, individual outcomes differ because of the disease’s complexity and the influence of accompanying health conditions. Conclusions: Treating arthritis continues to be challenging due to its numerous underlying causes and the varied ways in which patients respond to treatment. Although biologics and targeted therapies have brought progress, additional research is needed to identify new treatment targets and enhance patient results. Full article

Data are limited for assessing the effect of COVID infection on endothelial function, pre- and post-pandemic. The objective of this study was to assess changes in pre-pandemic cardiovascular parameters after COVID-19 infection. This prospective cohort study used EndoPAT2000 Itamar Medical Ltd., Caesarea, Israel, to measure the augmentation index (AI; arterial elasticity) and reactive hyperemic index (RHI; endothelial function). Markers of endothelial function, inflammation, and gut integrity were collected at pre- and post-pandemic visits. COVID-negative and COVID-positive participants were matched on pre-pandemic covariates, and AI ≥ 5.0 was defined as having worse AI. Among the 156 participants, 50% had documented COVID-19 infection. Groups were balanced (p > 0.05) on pre-pandemic characteristics. Increases in oxLDL (p = 0.03) were observed in the COVID-positive group, and COVID infection had a negative effect on inflammatory markers (sVCAM-1, sTNF-RI, sTNF-RII, sCD14) and gut integrity (I-FABP, BDG) compared to COVID-negative participants (p < 0.05). There was a 16.7% (p = 0.02) increase in the proportion of COVID-positive participants with AI ≥ 5.0, without a significant change (p = 0.09) among the COVID-negative group. COVID-positive status, female sex, and higher IL-6 and sCD163 were associated (p < 0.05) with an increase in having worse AI. COVID infection is independently associated with arterial stiffness. For COVID survivors, female sex and higher markers of inflammation were associated with arterial stiffness. Full article

Nigella sativa (NS) is a promising medicinal plant with diverse therapeutic properties. This study aimed to investigate the impact of NS oil (NSO) on memory functions in rats with LPS (lipopolysaccharide)-induced neuroinflammation, as well as its effect on serum levels of inflammatory cytokines, neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). Male rats were divided into four groups: control, LPS-control, LPS+NSO 3 and 5 mL/kg. Neuroinflammation was induced by a single intraperitoneal LPS injection (2 mg/kg). The novel object recognition test (NORT) and Y-maze were used for the evaluation of memory processes. Recognition index (RI) and % spontaneous alteration (%SA) were registered, respectively. Blood samples for TNF-α, IL-1β, IL-10, BDNF, and NPY serum levels were taken. Thymoquinone, the active compound of the oil, was detected by high-performance liquid chromatography. NSO administration resulted in an improvement in spatial and episodic memory, as evidenced by increased % SA and RI compared to LPS-control. Treatment with NSO led to a significant reduction in pro-inflammatory cytokines and NPY, along with an increase in IL-10 and BDNF levels, when compared to LPS-control. In conclusion, NSO enhances BDNF production and regulates pro- and anti-inflammatory cytokines release, which probably contributes to the observed cognitive improvement in animals with experimental neuroinflammation. Full article

High-affinity IgE receptors (FcεRI) are expressed on human blood eosinophils and may be upregulated on eosinophils at sites of allergic inflammation including atopic dermatitis and allergic asthma. FcεRI engagement, however, fails to elicit “effector” responses from eosinophils. Thus, a functional role for FcεRI on eosinophils has been uncertain. We evaluated the role of FcεRI in enhancing eosinophil antigen presentation in vivo by using humanized FcεRI α chain (hFcεRIα) transgenic mice. Eosinophils from hFcεRIα transgenic mice expressed humanized FcεRIα, with higher levels of eosinophils from the bronchoalveolar lavage of experimental asthma than those from polymyxin-elicited peritoneal lavage. The hFcεRIα-bearing eosinophils instilled intratracheally (i.t.) into recipient wild-type mice migrated from airways into paratracheal lymph nodes (pLNs) and spleens. Eosinophils, pretreated in vitro with nitrophenyl-ovalbumin ((NP)-OVA) and anti-NP human IgE complexes and instilled i.t., presented NP antigen via hFcεRIα to T cells more effectively than those pretreated with NP-OVA only, as assessed by pLN cell proliferation. IgE/FcεRIα-facilitated eosinophil antigen presentation resulted in increased IL-4 but not INF-γ production by pLN cells, with a bias towards Th2 cytokine production. Furthermore, cross-linking hFcεRIα on eosinophils increased eosinophil expressions of T cell costimulatory proteins CD40, CD80, and CD86. Humanized FcεRIα on murine eosinophils functions to enhance eosinophil antigen presentation capacities by mediating IgE-facilitated antigen presentation and upregulating expression of requisite T cell costimulatory proteins. Thus, a functional, non-“effector” role for FcεRI on eosinophils is revealed through identifying a means by which IgE may act on eosinophils to mediate their immunomodulatory, enhanced antigen presentation capabilities. Full article

Immune enhancement is an important factor that not only helps prevent infections but also affects overall health. This study aims to evaluate the immunostimulatory effects of a novel Lactobacillus strain, Lactobacillus paracasei L-30, and to elucidate its underlying mechanisms. The extract obtained from Lactobacillus paracasei L-30 significantly increased phagocytosis and the production of NO and ROS in RAW264.7 macrophages. The protein and mRNA expression levels of COX-2 and iNOS which are immune regulators were upregulated by the L-30 extract. The levels of cytokines and chemokines, such as G-CSF, IL-6, MIP-1α, MIP-1γ, RANTES, sTNF RI, and sTNF RII, were increased by the treatment with the L-30 extract. In addition, the L-30 extract degraded IκB-α and induced the phosphorylation of NF-κB. Furthermore, the MAPK signaling pathways ERK, JNK, and p38 were activated by the L-30 extract. The production of iNOS, COX-2, and NO was inhibited by MAPK pathway inhibitors. Therefore, our data suggest that the Lactobacillus paracasei L-30 extract has the potential to be developed as a healthy functional food that can enhance immune responses by activating macrophages. Full article

A water-soluble polysaccharide from foxtail millet (FM-D1) was isolated and purified through gradient ethanol precipitation and column chromatography. Size-Exclusion Chromatography–Multi-Angle Light Scattering–Refractive Index (SEC-MALLS-RI) and high-performance anion-exchange chromatography (HPAEC) analyses revealed that FM-D1 constitutes a highly purified neutral polysaccharide exclusively composed of glucose as the sugar unit, with a molecular weight of 14.823 kDa. The structural characterization results obtained from gas chromatography–mass spectrometer (GC–MS) and nuclear magnetic resonance spectroscopy (NMR) spectra suggest that FM-D1 primarily consists of a main chain linked by →4)-α-D-Glcp-(1→ and minor quantities of →4,6)-α-D-Glcp-(1→ to form the main chain, with branching mainly composed of α-D-Glcp-(1→ attached to the O-6 position of →4,6)-α-D-Glcp-(1→ sugar residues. Based on these findings, the antioxidant and immunomodulatory activities of FM-D1 were evaluated in vitro. The results indicated that FM-D1 exhibited moderate 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) radical scavenging capacity and total antioxidant capacity (TAOC). Furthermore, FM-D1 stimulated macrophage proliferation and inhibited the production of nitric oxide (NO) and inflammatory factors (TNF-α, IL-1β, and IL-6) in lipopolysaccharide (LPS)-stimulated RAW 246.7 cells. Overall, the findings of this study suggest that foxtail millet holds promise as a potential antioxidant agent and immunologic substance in functional foods. Full article

Background: Marek’s disease (MD) is a pathology affecting chickens caused by Marek’s disease virus (MDV), an acute transforming alphaherpesvirus of the genus Mardivirus. MD is characterized by paralysis, immune suppression, and the rapid formation of T-cell (primarily CD4+) lymphomas. Over the last 50 years, losses due to MDV infection have been controlled worldwide through vaccination; however, these live-attenuated vaccines are non-sterilizing and potentially contributed to the virulence evolution of MDV field strains. Mutations common to field strains that can overcome vaccine protection were identified in the C-terminal proline-rich repeats of the oncoprotein Meq (Marek’s EcoRI-Q-encoded protein). These mutations in meq have been found to be distinct to their region of origin, with high virulence strains obtained in Europe differing from those having evolved in the US. The present work reports on meq mutations identified in MDV field strains in Nigeria, arising at farms employing different vaccination practices. Materials and Methods: DNA was isolated from FTA cards obtained at 12 farms affected by increased MD in the Plateau State, Nigeria. These sequences included partial whole genomes as well as targeted sequences of the meq oncogenes from these strains. Several of the meq genes were cloned for expression and their localization ability to interact with the chicken NF-IL3 protein, a putative Meq dimerization partner, were assessed. Results: Sequence analysis of the meq genes from these Nigerian field strains revealed an RB1B-like lineage co-circulating with a European Polen5-like lineage, as well as recombinants harboring a combination of these mutations. In a number of these isolates, Meq mutations accumulated in both N-terminal and C-terminal domains. Discussion: Our data, suggest a direct effect of the vaccine strategy on the selection of Meq mutations. Moreover, we posit the evolution of the next higher level of virulence MDVs, a very virulent plus plus pathotype (vv++). Full article

Eosinophils are central inflammatory cells in asthma; however, a portion of patients with chronic obstructive pulmonary disease (COPD) have blood or sputum eosinophilia, a condition termed eosinophilic COPD (eCOPD), which may contribute to the progression of the disease. We hypothesize that eosinophilic inflammation in eCOPD patients is related to Type 2 (T2)-high inflammation seen in asthma and that serum mediators might help us to identify T2-high inflammation in patients and choose an appropriate personalized treatment strategy. Thus, we aimed to investigate ten serum levels of T2-high inflammation mediators in eCOPD patients and compare them to severe non-allergic eosinophilic asthma (SNEA) patients. We included 8 subjects with eCOPD, 10 with SNEA, and 11 healthy subjects (HS) as a control group. The concentrations of biomarkers in serum samples were analyzed using an enzyme-linked immunosorbent assay (ELISA). In this study, we found that eCOPD patients were distinguished from SNEA patients by elevated serum levels of sIL-5Rα, MET, TRX1, ICTP, and IL-4, as well as decreased serum levels of eotaxin-1 and sFcεRI. Moreover, MET, ICTP, eotaxin-1, and sFcεRI demonstrated high sensitivity and specificity as potential biomarkers for eCOPD patients. Furthermore, serum levels of IL-5 and IL-25 in combination with sIL-5Rα, MET, and IL-4 demonstrated a high value in identifying T2-high inflammation in eCOPD patients. In conclusion, this study highlights that while T2-high inflammation drives eosinophilic inflammation in both eCOPD and SNEA through similar mechanisms, the distinct expression of its mediators reflects an imbalance between T1 and T2 inflammation pathways in eCOPD patients. A combined analysis of serum mediators may aid in identifying T2-high inflammation in eCOPD patients and in selecting an appropriate personalized treatment strategy. Full article

Although antimicrobial peptides (AMPs) exhibit a range of biological functions, reports on AMPs with therapeutic effects in allergic disorders are limited. In this study, we investigated the anti-allergic effects of Pro10-1D, a 10-meric AMP derived from insect defensin protaetiamycine. Our findings demonstrate that Pro10-1D effectively inhibits antigen-induced degranulation of mast cells (MCs) with IC₅₀ values of approximately 11.6 μM for RBL-2H3 cells and 2.7 μM for bone marrow-derived MCs. Furthermore, Pro10-1D suppressed the secretion of cytokines with IC₅₀ values of approximately 2.8 μM for IL-4 and approximately 8.6 μM for TNF-α. Mechanistically, Pro10-1D inhibited the Syk-LAT-PLCγ1 signaling pathway in MCs and decreased the activation of mitogen-activated protein kinases (MAPKs). Pro10-1D demonstrated a dose-dependent reduction in IgE-mediated passive cutaneous anaphylaxis in mice with an ED₅₀ value of approximately 7.6 mg/kg. Further investigation revealed that Pro10-1D significantly reduced the activity of key kinases Fyn and Lyn, which are critical in the initial phase of the FcεRI-mediated signaling pathway, with IC₅₀ values of approximately 22.6 μM for Fyn and approximately 1.5 μM for Lyn. Collectively, these findings suggest that Pro10-1D represents a novel therapeutic candidate for the treatment of IgE-mediated allergic disorders by targeting the Lyn/Fyn Src family kinases in MCs. Full article

Background: Increased inflammation and heightened physiological stress reactivity have been associated with pathophysiology of depressive symptoms. The underlying biological mechanisms by which inflammation and stress may influence neurogenesis are changes in the kynurenine (KYN) pathway, which is activated under stress. Supplementation with n-3 polyunsaturated fatty acids (n-3 PUFAs) has anti-inflammatory properties and can increase stress resilience. Whether n-3 PUFAs alter KYN stress response is unknown. Objectives: This placebo-controlled study investigated the effect of n-3 PUFAs on KYN metabolism, inflammation, depressive symptoms, and mood. Moreover, stress-induced changes following a laboratory stressor have been assessed. Methods: In this placebo-controlled study, 47 healthy male adults received either 4 g n-3 PUFAs per day (Omega-3 group) or a placebo (Placebo group) for 12 weeks. Results: A significant group-by-time interaction was found for the inflammatory markers gp130 (F = 7.07, p = 0.011), IL-6R alpha (F = 10.33, p = 0.003), and TNF_RI (F= 10.92, p = 0.002). No significant group-by-time interactions were found for KYN metabolites, depressive symptoms, and mood (except for Hedonic tone (F = 6.50, p = 0.014)), nor for stress-induced changes in KYN metabolites and mood following a laboratory stressor. Conclusions: Overall, increased n-3 PUFA levels in healthy men ameliorate inflammatory markers but do not ameliorate KYN metabolism, depressive symptoms, mood, or KYN metabolism and mood following a stress induction. This study was registered at ClinicalTrials.gov with the identifier NCT05520437 (30/08/2022 first trial registration). Full article

Endothelial dysfunction (ED) is closely associated with most cardiovascular diseases. Experimental models are needed to analyze the potential impact of ED on cardioprotection in constant pressure Langendorff systems (CPLS). One cardioprotective strategy against ischemia/reperfusion injury (I/RI) is conditioning with the lipid emulsion Intralipid (IL). Whether ED modulates the cardioprotective effect of IL remains unknown. The aim of the study was to transfer a protocol using a constant flow Langendorff system for the induction of ED into a CPLS, without the loss of smooth muscle cell functionality, and to analyze the cardioprotective effect of IL against I/RI under ED. In isolated hearts of male Wistar rats, ED was induced by 10 min perfusion of a Krebs–Henseleit buffer containing 60 mM KCl (K+), and the vasodilatory response to the vasodilators histamine (endothelial-dependent) and sodium–nitroprusside (SNP, endothelial-independent) was measured. A CPLS was employed to determine cardioprotection of pre- or postconditioning with 1% IL against I/RI. The constant flow perfusion of K+ reduced endothelial response to histamine but not to SNP, indicating reduced vasodilatory functionality of endothelial cells but not smooth muscle cells. Preconditioning with IL reduced infarct size and improved cardiac function while postconditioning with IL had no effect. The induction of ED neither influenced infarct size nor affected the cardioprotective effect by preconditioning with IL. This protocol allows for studies of cardioprotective strategies under ED in CLPS. The protection by preconditioning with IL seems to be mediated independently of a functional endothelium. Full article