Search Results (123)

Background: Reducing cardiovascular risk markers is an essential target in chronic kidney disease (CKD). Thus, this study aimed to evaluate the effect of royal jelly plus green propolis supplementation on cardiovascular disease (CVD) risk factors in patients with CKD undergoing hemodialysis (HD). Methods: This randomized, double-blind, placebo-controlled trial involved HD patients allocated to receive either royal jelly plus green propolis EPP-AF^® (100 mg RJ + 500 mg GP) or placebo capsules daily for 2 months. Before and after the intervention period, the biochemical parameters, inflammatory cytokines, and uremic toxins were measured. Results: A total of 38 HD patients completed the 2-month supplementation study, with 19 patients in each group. After 2 months, the treated group showed a significant reduction in plasma levels of IL-6 (0.78 to 0.63 pg/mL, p = 0.008) and total cholesterol (138.60 to 111.85 mg/dL, p = 0.03), whereas no changes were observed in the placebo group. Uremic toxins did not change after intervention. Conclusion: Apitherapy with RJ + GP EPP-AF^® extract significantly reduced plasma IL-6 and total cholesterol in HD patients. This supplementation shows promise as a non-pharmacological strategy to reduce cardiovascular risk markers in this population. Full article

The venom of Bothrops jararaca (BjV) induces intense and prolonged pain, which is not alleviated by antivenom, along with hemorrhage and inflammation. In this study, we investigated the effects of the specialized pro-resolving lipid mediator (SPM) maresin 2 (MaR2) in a murine model of BjV-evoked pain and inflammation. Mice received a single intraperitoneal (i.p.) injection of MaR2 30 min before the intraplantar BjV injection. MaR2 treatment significantly attenuated mechanical (electronic aesthesiometer) and thermal (hot plate) hyperalgesia in a dose-dependent manner. Additionally, MaR2 restored the balance for the hind-paw static weight distribution. When BjV (0.01, 0.1, and 1 μg) stimulus was administered intraperitoneally, pre-treatment with MaR2 (0.3, 1, or 3 ng) ameliorated mechanical and thermal hyperalgesia in a dose-dependent manner. Moreover, MaR2 (3 ng) effectively reduced the levels of myeloperoxidase activity and cytokines (TNF-α, IL-1β, and IL-6) and superoxide anion (O₂^•−) production induced by intraplantar injection of BjV while enhancing total antioxidant levels (ABTS scavenging). For the peritonitis model induced by BjV, MaR2 pretreatment decreased leukocyte recruitment, hemorrhage, nitric oxide (NO), and O₂^•− generation and gp91phox and inducible nitric oxide synthase (iNOS) mRNA expression. In conclusion, this study presents the first evidence that MaR2 effectively mitigated BjV-induced pain, hemorrhage, and inflammation. Full article

Ultraviolet B (UVB) irradiation drives skin photodamage, prompting exploration of natural therapeutics. This study investigated the reparative effects and mechanisms of crude Gastrodia elata polysaccharides (GP) on UVB-induced acute skin damage. GP was extracted from fresh G. elata via water extraction and alcohol precipitation. It is a homogeneous polysaccharide with a weight-average molecular weight of 808.863 kDa, comprising Ara, Glc, Fru, and GalA. Histopathological analysis revealed that topical application of GP on the dorsal skin of mice effectively restored normal physiological structure, suppressing epidermal hyperplasia and collagen degradation. Biochemical assays showed that GP significantly reduced the activities of MPO and MDA following UVB exposure while restoring the enzymatic activities of SOD and GSH, thereby mitigating oxidative stress. Moreover, GP treatment markedly upregulated the anti-inflammatory cytokines TGF-β and IL-10 and downregulated the pro-inflammatory mediators IL-6, IL-1β, and TNF-α, suggesting robust anti-inflammatory effects. Transcriptomics revealed dual-phase mechanisms: Early repair (day 5) involved GP-mediated suppression of hyper inflammation and accelerated necrotic tissue clearance via pathway network modulation. Late phase (day 18) featured enhanced anti-inflammatory, antioxidant, and tissue regeneration processes through energy-sufficient, low-inflammatory pathway networks. Through a synergistic response involving antioxidation, anti-inflammation, promotion of collagen synthesis, and acceleration of skin barrier repair, GP achieves comprehensive repair of UVB-induced acute skin damage. Our findings not only establish GP as a potent natural alternative to synthetic photoprotective agents but also reveal novel pathway network interactions governing polysaccharide-mediated skin regeneration. Full article

Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. As a critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high-throughput structure-based computational screening using ensemble docking for small-molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scoring ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with the second-highest calculated binding affinity experimentally showed an ~84% inhibitory effect on IL6-induced STAT3 reporter activity at 10 μM concentration. This finding may pave the way for designing small-molecule inhibitors of hIL-6 of therapeutic significance. Full article

UVB skin pathology is initiated by reactive oxygen species (ROS), differentiating this condition from other inflammatory diseases involving first the immune cell activation by danger or pathogen molecular patterns followed by oxidative stress. Resolvin D2 (RvD2) has been found to reduce inflammation in preclinical models. However, whether or not RvD2 reduces skin pathology caused by UVB irradiation is not yet known. Therefore, the efficacy of RvD2 on skin pathology triggered by UVB irradiation in female hairless mice was assessed. RvD2 (0.3, 1 or 3 ng/mouse, i.p.) was found to protect the skin against UVB inflammation, as observed in the reduction in edema (46%), myeloperoxidase activity (77%), metalloproteinase-9 activity (39%), recruitment of neutrophils/macrophages (lysozyme⁺ cells, 76%) and mast cells (106%), epidermal thickening (93%), sunburn cell formation (68%), collagen fiber breakdown (55%), and production of cytokines such as TNF-α (100%). Considering the relevance of oxidative stress to UVB irradiation skin pathologies, an important observation was that the skin antioxidant capacity was recovered by RvD2 according to the results that show the ferric reducing antioxidant power (68%), cationic radical scavenges (93%), catalase activity (74%), and the levels of reduced glutathione (48%). Oxidative damage was also attenuated, as observed in the reduction in superoxide anion production (69%) and lipid hydroperoxides (71%). The RvD2 mechanism involved the inhibition of NF-κB activation, as observed in the diminished degradation of IκBα (48%) coupled with a reduction in its downstream targets that are involved in inflammation and oxidative stress, such as COX-2 (66%) and gp91^phox (77%) mRNA expression. In conclusion, RvD2 mitigates the inflammatory and oxidative pathologic skin aggression that is triggered by UVB. Full article

Background/Objectives: Gypenosides (Gps) are the main active compounds of Gynostemma and show promise in managing diabetes; nevertheless, the mechanism by which Gps exert anti-diabetic effects is still not fully understood. The aim of this study is to clarify the molecular mechanisms of Gps in ameliorating glucose dysregulation. Methods: Qualitative and quantitative analyses on the chemical components of Gps were performed, respectively. Type 2 diabetes mellitus mouse models were established, and the mice were subsequently treated with Gps at doses of 200, 100, or 50 mg/kg for 4 weeks. Biochemical markers were measured. Histopathological assessments of hepatic and colonic tissues were conducted. The compositions of the intestinal microbiota, short-chain fatty acids (SCFAs), and bile acids (BAs) in fecal samples were analyzed. Western blotting was applied to examine the activation of relevant signaling pathways. Results: Gps have potent regulatory effects on metabolic homeostasis by improving glucose and lipid profiles and alleviating hepatic tissue damage. Treatment with Gps significantly reduced serum levels of lipopolysaccharides and key pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α). Moreover, Gps enhanced the integrity of the gut barrier by upregulating the level of tight junction proteins (ZO-1 and occludin). Microbiota profiling revealed that Gps markedly increased microbial diversity and richness, decreased the ratio of Firmicutes/Bacteroidetes, and elevated Bacteroidia abundance from the phylum to the genus level. Targeted metabolomics further demonstrated that Gps modulated gut microbial metabolites by promoting SCFA production and reshaping BA profiles. Specifically, Gps elevated the primary-to-secondary BA ratio while reducing the 12α-hydroxylated to non-12α-hydroxylated BA ratio. Mechanistically, Western blotting demonstrated that Gps triggered the hepatic PI3K/AKT pathway and the intestinal BA/FXR/FGF15 axis, suggesting the coordinated regulation of metabolic and gut–liver axis signaling pathways. Conclusions: Gps significantly ameliorate hyperglycemia and hyperlipidemia through a multifaceted mechanism involving gut microbiota modulation, the restoration of intestinal barrier function, and the regulation of microbial metabolites such as SCFAs and BAs. These findings offer novel insights into their mechanism of action via the gut–liver axis. Full article

Background: Grape pomace (GP), a by-product of winemaking, is a rich source of bioactive polyphenols known for their antioxidant and anti-inflammatory properties. While the cardiovascular benefits of red grape pomace have received significant scientific attention, the therapeutic potential of white grape pomace remains largely unexplored, particularly in glucocorticoid-induced hypertension. Given the rising prevalence of hypertension and the oxidative-inflammatory mechanisms underlying its progression, this study investigates the effects of white GP on blood pressure regulation, oxidative stress, and pro-inflammatory cytokine expression in an experimental model of dexamethasone (DEXA)-induced hypertension (HTN). By focusing on white GP, this research addresses a significant gap in current knowledge and proposes a novel, sustainable approach to managing hypertension through valorising winemaking by-products. Methods: The first concentration used, GP1, was 795 mg polyphenols/kg bw, while the second concentration, GP2, was 397.5 mg polyphenols/kg bw. Results: White GP polyphenols extract in the DEXA_GP1 group had reduced systolic and diastolic blood pressure. The extract with a higher content of polyphenols (GP1) prevented the elevation of serum levels of total oxidative stress (TOS), malondialdehyde (MDA), and oxidative stress index (OSI), while the extract with a lower content of polyphenols (GP2) slightly reduced serum levels of MDA. Both concentrations of GP increased serum levels of NO and Total Thiols, significantly higher (p < 0.05) than in the group treated with lisinopril. The serum levels of tumour necrosis factor-alpha (TNF-α) increased in all groups where HTN was induced. Both doses of GP extract prevented the elevation of TNF-α. Heart tissue levels of the studied cytokines (TNF-α, interleukin (IL)-1β, and IL-6 were not influenced (p > 0.05) by either the HTN induction or the treatment administered. Conclusions: These findings suggest that grape pomace may serve as a promising nutraceutical intervention for hypertension management, particularly in conditions associated with oxidative stress. Full article

This study explores the potential of ginseng-derived peptides (GPs) as multifunctional bioactive agents for skincare. Unlike previous research into ginseng saponins and polysaccharides, we identified that ginseng extracts containing water-soluble small molecules and polypeptides exhibit potent antioxidant, anti-inflammatory, and anti-aging properties. In vitro assays revealed that ginseng peptide extract (GPE) reduced reactive oxygen species (ROS) and inflammatory cytokines (IL-6, TNF-α, IL-1β) in RAW264.7 macrophages while enhancing collagen synthesis in human skin fibroblasts (HSFs). Validation using 3D epidermal and dermal models further confirmed GPE’s ability to mitigate UV-induced damage, restore skin barrier proteins (filaggrin, loricrin), and increase collagen content. In addition, we screened 19 candidate peptides from ginseng extract using machine learning and prioritized their interaction with skin aging and inflammation-related targets. Three peptides (QEGIYPNNDLYRPK, VDCPTDDATDDYRLK, and ADEVVHHPLDKSSEVE) demonstrated significant collagen-promoting, antioxidant, and anti-inflammatory effects in cellular models. These findings highlight the efficacy of computational approaches in identifying natural bioactive ingredients, positioning ginseng peptides as promising candidates for innovative cosmeceutical formulations targeting inflammaging and skin rejuvenation. Full article

Cardiac glycosides (CGs), historically used to treat heart failure and arrhythmias, bind to the α subunit of the Na⁺/K⁺-ATPase pump and inhibit its activity. Their anticancer and antiviral activities are of interest. The α subunit of the Na⁺/K⁺-ATPase pump has four isoforms (α1–4), each with unique tissue distribution and expression pattern; their contributions to antiviral activities have not been studied. We previously reported that CGs inhibit human CMV (HCMV) in vitro but not mouse CMV (MCMV). In addition to the low affinity of mouse α1 for CGs, we hypothesized that other isoforms contribute to the anti-CMV activities of CGs. We show here that infection with HCMV significantly induced α3 in human foreskin fibroblasts, while MCMV did not induce mouse α3. Infection with guinea pig CMV (GPCMV) in GP fibroblasts also induced α3, and CGs inhibited GPCMV replication. HCMV inhibition with digitoxin reduced α3 expression. The concentration-dependent inhibition of HCMV with digitoxin analogs also correlated with α3 expression. Intriguingly, α3 was localized to the nucleus, and changes in its expression during infection and digitoxin treatment were mostly limited to the nucleus. At 4 h post-infection, α3 colocalized with immediate early 1 (IE1) and the promyelocytic leukemia protein (PML). An interaction of α3-PML-IE1 at 24 h post-infection was disrupted by digitoxin. The mRNA levels of IE1, major immediate early promoter (MIEP)-derived IE, and antiviral cytokines were reduced in infected digitoxin-treated cells. Summarized, these findings suggest a new role for α3 in the anti-HCMV activities of CGs via nuclear antiviral signaling pathways. Full article

Grape pomace (GP), the residue left after grape pressing in winemaking, is rich in polyphenols, including flavonoids, tannins, and phenolic acids, which have antioxidant and anti-inflammatory properties. The present study aimed to evaluate the cardioprotective effects of white grape pomace (WGP) extract in two concentrations rich in polyphenols (795 mg polyphenols from WGP/kg body weight (bw) and 397.5 mg polyphenols from WGP/kg bw)), on isoproterenol (ISO)-induced myocardial infarction (MI), focusing on its anti-inflammatory and antioxidant effects. White grape pomace administration for 14 days offered a cardio-protective effect and prevented prolongation of the QT and QTc intervals on the electrocardiogram. Both concentrations of WGP prevented the elevation of nitric oxide (NO) and malondialdehyde (MDA) in the serum, with the best results being observed for the highest concentration (p < 0.05). White grape pomace administration offered a reduction in pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β) in both serum and tissue in a dose-dependent manner, with the highest WGP concentration having the best effect (p < 0.05). Moreover, WGP reduced histological changes associated with MI. The findings of the present study demonstrate that WGP extract exerts cardio protective effects by reducing MI-associated inflammation and oxidative stress. Full article

Objectives: Polysaccharides from Glycyrrhiza are known to have several bioactive effects. Previous studies have found that low-molecular-weight Glycyrrhiza polysaccharide (GP1) is degraded by Muribaculum_sp_H5 and promotes the production of beneficial bacteria and metabolites, which improves immune disorder and intestinal injury, and then enhances the body’s immune regulation ability. However, the immune regulation effect of GP1 on a healthy body has not been studied. In this study, we aimed to reveal the immune enhancement effect and mechanism of GP1 on healthy mice. Methods: The cytotoxicity and immunomodulatory activity of GP1 were analyzed by cell experiment; the effects of GP1 on antioxidation, immune regulation and gut microbiota structure of healthy body were studied in vivo. In addition, the mechanism of GP1 enhancing immune response of healthy body was analyzed by multi-omics. Results: The results show that GP1 enhanced the immune function of healthy mice by increasing the index of immune organs, improving the organizational structure of immune organs, and increasing the secretion of immune cytokines and immunoglobulin. GP1 also increased the contents of antioxidant factors such as total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in various organs and reduced the content of oxide malondialdehyde (MDA), thus enhancing the body’s antioxidant capacity, promoting cell proliferation and prolonging life. Moreover, GP1 promoted the proliferation of beneficial bacteria, including Muribaculaceae_unclassified, Muribaculum, Prevotellaceae_UCG-001, and Paramuribaculum, and the production of characteristic metabolites (collectively referred to as postbiotics), including α-tocopherol, arachidonic acid, melibiose, taurine, and nicotinic acid. These beneficial bacteria and postbiotics have been proven to have health maintaining functions. Conclusions: GP1 promoted the proliferation of beneficial bacteria and increased the production of postbiotics, which should be the mechanism of its beneficial effect. It is expected to be a promising immune dietary supplement. Full article

Background/Objective: The blood–brain barrier (BBB) is selectively permeable, but it also poses significant challenges for treating CNS diseases. Low-intensity focused ultrasound (LiFUS), paired with microbubbles is a promising, non-invasive technique for transiently opening the BBB, allowing enhanced drug delivery to the central nervous system (CNS). However, the downstream physiological effects following BBB opening, particularly secondary responses, are not well understood. This study aimed to characterize the time-dependent changes in BBB permeability, transporter function, and inflammatory responses in both sonicated and non-sonicated brain tissues following LiFUS treatment. Methods: We employed in situ brain perfusion to assess alterations in BBB integrity and transporter function, as well as multiplex cytokine analysis to quantify the inflammatory response. Results: Our findings show that LiFUS significantly increased vascular volume and glucose uptake, with reduced P-gp function in brain tissues six hours post treatment, indicating biphasic BBB disruption. Additionally, elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6, were observed in both sonicated and non-sonicated regions. A comparative analysis between wild-type and immunodeficient mice revealed distinct patterns of cytokine release, with immunodeficient mice showing lower serum concentrations of IFN-γ and TNF-α, highlighting the potential impact of immune status on the inflammatory response to LiFUS. Conclusions: This study provides new insights into the biphasic nature of LiFUS-induced BBB disruption, emphasizing the importance of understanding the timing and extent of secondary physiological changes. Full article

Background: In ovo stimulation introduces bioactive compounds, such as prebiotics, probiotics, or synbiotics into incubating eggs to enhance gut health and immune system development in chickens. This study aimed to determine the genetic and environmental effects modulating responses to in ovo stimulation in commercial broilers and Green-legged Partridge-like (GP) native chickens. Methods: Eggs were stimulated on day 12 of incubation with prebiotics (GOS—galactooligosaccharides), probiotics (Lactococcus lactis subsp. cremoris), or synbiotics (GOS + L. lactis), with controls being mock-injected. Hatched chicks were reared in group pens and challenged with lipopolysaccharide (LPS) on day 42 post-hatching. Cecal tonsils (CT) and spleens were harvested 2 h post-challenge. RT-qPCR was used to analyze the relative gene expression of cytokine genes: IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p40, and IL-17. Results: The results show that genotype influenced the expression of all immune-related genes, with broiler chickens exhibiting stronger innate inflammatory responses than native chickens. LPS induced both mucosal (CT) and systemic (spleen) immune responses in broilers but only systemic (spleen) responses in native chickens. Conclusions: In ovo stimulation had less of an impact on cytokine gene expression than LPS challenge. Broilers expressed higher inflammatory immune responses than GP native chickens. Full article

Marburg hemorrhagic fever (MHF) is a fatal infectious disease caused by Marburg virus (MARV) infection, and MARV has been identified as a priority pathogen for vaccine development by the WHO. The glycoprotein (GP) of MARV mediates viral adhesion and invasion of host cells and therefore can be used as an effective target for vaccine development. Moreover, DNA vaccines have unique advantages, such as simple construction processes, low production costs, and few adverse reactions, but their immunogenicity may decrease due to the poor absorption rate of plasmids. Lysosome-associated membrane protein 1 (LAMP1) can direct antigens to lysosomes and endosomes and has great potential for improving the immunogenicity of nucleic acid vaccines. Therefore, we constructed a DNA vaccine based on a codon-optimized MARV GP (ID MF939097.1) fused with LAMP1 and explored the effect of a LAMP targeting strategy on improving the immunogenicity of the MARV DNA vaccine. ELISA, ELISpot, and flow cytometry revealed that the introduction of LAMP1 into the MARV DNA candidate vaccine improved the humoral and cellular immune response, enhanced the secretion of cytokines, and established long-term immune protection. Transcriptome analysis revealed that the LAMP targeting strategy significantly enriched antigen processing and presentation-related pathways, especially the MHC class II-related pathway, in the candidate vaccine. Our study broadens the strategic vision for enhanced DNA vaccine design and provides a promising candidate vaccine for MHF prevention. Full article

Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK/STAT3, NF-κB and ERK1/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-κB pathways, but it failed to rescue PACAP, PACAP/VIP receptors and Erk1/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences. Full article