Search Results (722)

This study systematically analyzed the multidimensional effects of Lactobacillus fermentation on Pueraria lobata (PL) and investigated the potential mechanisms underlying its hypolipidemic activity. Results indicated that fermentation significantly increased the total acid content from 1.02 to 3.48 g·L⁻¹, representing a 2.41-fold increase. Although slight reductions were observed in total flavonoids (8.67%) and total phenolics (6.72%), the majority of bioactive components were well preserved. Other antioxidant capacities were retained at >74.71% of baseline, except hydroxyl radical scavenging. Flavor profiling showed increased sourness and astringency, accompanied by reduced bitterness, with volatile compounds such as β-pinene and trans-2-hexenyl butyrate contributing to a distinct aromatic profile. Untargeted metabolomics analysis revealed that fermentation specifically enhanced the abundance of low-concentration isoflavone aglycones, including daidzein and genistein, suggesting a compositional shift that may improve hypolipidemic efficacy. Integrated network pharmacology and computational modeling predicted that eight key components, including genistein, could stably bind to ten core targets (e.g., AKT1 and MMP9) primarily through hydrogen bonding and hydrophobic interactions, potentially regulating lipid metabolism via the PI3K-AKT, PPAR, and estrogen signaling pathways. This study reveals the role of Lactobacillus fermentation in promoting the conversion of isoflavone glycosides to aglycones in PL and constructs a multi-dimensional “components-targets-pathways-disease” network, providing both experimental evidence and a theoretical foundation for further research on the lipid-lowering mechanisms of fermented PL and the development of related functional products. Full article

Background/Objectives: Stroke is the second leading cause of death worldwide. There is an unmet need to manage stroke pathophysiology, including L-glutamate (L-Glu)-mediated neurotoxicity. The acai berry (Euterpe sp.) contains phytochemicals with potentially nutraceutical content. The aim of this study was to assess the ability of acai berry extracts to counter L-Glu neurotoxicity using human differentiated TE671 cells. Methods: The cytotoxicity of L-Glu and acai berry extracts was quantified using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial function was examined by a quantitation of cellular ATP levels, the maintenance of the mitochondrial membrane potential (MMP), and the production of reactive oxygen species (ROS). Whole-cell patch-clamp recordings monitored the activation of N-methyl-D-aspartate receptors (NMDARs). Candidate phytochemicals from acai berry extracts were modeled in silico for NMDAR binding. Results: L-Glu significantly reduced cell viability, ATP levels, the MMP, and increased cellular ROS. Generally, acai berry extracts alone were not cytotoxic, although high concentrations were detrimental to ATP production, maintenance of the MMP, and elevated ROS levels. Whole-cell patch-clamp recordings revealed that the combined addition of 300 µM L-Glu and 10 µM glycine activated currents in differentiated TE671 cells, consistent with triggering NMDAR activity. Acai berry extracts ameliorated the L-Glu-induced cytotoxicity, mitochondrial dysfunction, elevated ROS levels, and limited the NMDAR-mediated excitotoxicity (p < 0.001–0.0001). Several virtual ligands from acai berry extracts exhibited high-affinity NMDAR binding (arginine, 2,5-dihydroxybenzoic acid, threonine, protocatechuic acid, and histidine) as possible candidate receptor antagonists. Conclusions: Acai berry phytochemicals could be exploited to reduce the L-Glu-induced neurotoxicity often observed in stroke and other neurodegenerative diseases. Full article

Background: Cardiovascular diseases, driven significantly by dyslipidemia, remain a leading global mortality risk. Emerging evidence indicates that Lactobacillus plantarum (L. plantarum), which is a probiotic commonly used in a variety of food products, may contribute to the regulation of blood lipids, although prior studies report inconsistent efficacy and lack mechanistic clarity. This study aimed to evaluate the effects of L. plantarum supplementation on blood lipid profiles and explore its potential mechanisms through a systematic review, meta-analysis, and network pharmacology. Methods: We performed a comprehensive literature search across PubMed, Cochrane Library, EMBASE, and other databases. Meta-analysis was performed using random-effects models to assess changes in total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Network pharmacology was employed to predict molecular targets and pathways. Results: Twenty-six randomized controlled trials (RCTS) involving 2104 participants were included. L. plantarum supplementation significantly reduced TC (SMD: −0.233; 95% CI: −0.458, −0.008; p = 0.042), TG (SMD: −0.227; 95% CI: −0.432, −0.021; p = 0.030), and LDL-C (SMD: −0.251; 95% CI: −0.477, −0.025; p = 0.029), but not HDL-C. Subgroup analyses revealed greater efficacy with interventions lasting >8 weeks and single-strain formulations. Network pharmacology analysis highlighted IL-17/TNF signaling pathway, bile secretion, and other pathways as key mechanisms and targets such as PPARG and MMP9 as key targets. Conclusions: L. plantarum demonstrates significant lipid-lowering effects, particularly for TC, TG, and LDL-C, with sustained use and single-strain formulations yielding optimal outcomes. Mechanistically, it may modulate inflammation, oxidative stress, and lipid metabolism. These findings can support the development of a functional food and dietary supplement using L. plantarum to assist in the treatment of hyperlipidemia, though heterogeneity and strain-specific effects warrant further investigation. Full article

Hepatocellular carcinoma (HCC) is the main leading cause of cancer-related deaths. Treatments for advanced HCC include multikinase inhibitors (Sorafenib or Lenvatinib), with limited response rates and serious side effects, or immunotherapy applicable to a small fraction of patients. Thus, new strategies are needed to improve the management of HCC. We evaluate here the efficacy and safety of XON9, a first-in-class glyco-humanized polyclonal antibody (GH-pAb). Cytotoxic activity of XON9 against Hep3B, Huh7, HepG2 or primary hepatocytes was investigated. Apoptosis, caspase activity, production of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were evaluated. Efficacy of XON9 was then assessed in vivo in NMRI nude mice, while pharmacokinetics and safety were evaluated in a non-human primate. XON9 showed a potent complement-dependent cytotoxicity (CDC) against Hep3B and Huh7 (EC50 < 10 µg/mL), and to a less extent against HepG2. XON9 induced apoptosis of HCC cells with activation of caspases 8 and 9, increase in ROS and drop in MMP. Overall, in vitro lytic activity of XON9 was superior to that of Sorafenib. In vivo, XON9 significantly reduced tumor progression and outperformed Sorafenib. No toxicity was observed after repeated injections of XON9 in a non-human primate. XON9 represents a promising and selective immunotherapy against refractory HCC. Full article

Allergic rhinitis (hay fever) prevalence has increased in Australia. People with hay fever often experience many eye symptoms, especially itching. This study explores clinical correlations between tear IgE levels and ocular allergy signs in hay fever sufferers, focusing also on eyelid wiper friction damage from eye rubbing. In a cross-sectional study from November 2024 to January 2025, 16 individuals with self-reported hay fever and 17 healthy controls were recruited. Participants completed demographic and allergy-related questionnaires, including symptoms and quality of life assessments. Tear samples were analyzed for IgE and MMP-9 biomarkers. Ocular surface parameters-bulbar redness, palpebral roughness, and lid wiper epitheliopathy (LWE)-were graded. Corneal and conjunctival dendritic cells were also evaluated. Elevated tear IgE significantly correlated with self-reported hay fever, QUICK score, MiniRQLQ, eye rubbing frequency, and lower LWE grade. The hay fever group showed significantly higher LWE compared to healthy controls (p < 0.001), indicating frictional eyelid damage. ROC analysis of tear IgE yielded an AUC of 0.893 (cut-off 0.03 IU/mL; sensitivity 90%, specificity 85%). Tear IgE is a useful biomarker for ocular inflammation and may indicate friction-related eyelid damage in allergy sufferers. Incorporating LWE grading into clinical assessments of ocular allergy is recommended. Full article

Background/Objectives: Urothelial bladder carcinoma (UBC) is one of the most prevalent malignancies worldwide, and efforts have intensified to identify molecular markers that improve the prognosis and reduce treatment costs. Among the regulators of tumor behavior, microRNAs (miRNAs) have emerged as promising biomarkers for cancer diagnoses and treatment. The modulation of miR-25-3p has been associated with pancreatic, colorectal, and lung cancers; its role in UBC remains poorly explored. In this study, we investigated the effects of miR-25-3p modulation in a high-grade and muscle-invasive bladder cancer (MIBC) cell line (T24), using in vitro functional assays and bioinformatics approaches. Results: Bioinformatics analyses using TCGA-BLCA datasets revealed that miR-25-3p is upregulated in tumor tissues compared to non-tumor tissues, prompting an investigation into its molecular targets and related pathways. The transfection of T24 cells with an miR-25-3p mimic and inhibitor led to respective overexpression (11.16-fold) and downregulation (-2.82-fold) compared to the negative control. Functionally, miR-25-3p overexpression increased cell proliferation, viability, and migration, while its inhibition decreased the cell migration capacity. A gene expression analysis revealed that miR-25-3p overexpression resulted in the downregulation of TP53, AIFM1, NFE2L2, TFRC, ACSL4, SLC7A11, and SLC3A2, whereas MMP9, MMP11, and GPX4 were upregulated, suggesting a role in both migration and ferroptosis regulation. In the inhibitor group, increased SLC3A2 and decreased MMP11 expression further supported this connection. Our results using an in vitro model for MIBC with the transfection of T24 cells suggest that miR-25-3p influences key pathways involved in oxidative stress and cell death, promoting a more aggressive tumor phenotype. Conclusions: The modulation of miR-25-3p impacts the behavior of T24 bladder cancer cells and may indicate its role in disease progression. Our results underscore the potential of miR-25-3p as a prognostic biomarker and support further studies considering its therapeutic relevance in managing high-grade and muscle-invasive bladder cancer. Full article

Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, their protein levels and correlation with other biomarkers are not well understood. We measured total and active MMP-2/-9 and additional biomarkers (creatinine, neurofilament light, cystatin C, and alkaline phosphatase) in the serum of people with ALS (ALS, n = 30) and compared their levels with age-matched healthy controls (HC, n = 20) and other neurological diseases (diabetic nephropathy, Alzheimer’s disease, Parkinson’s disease; n = 8 each). We also measured MMP-2/-9 in a set of CSF samples from ALS (n = 30) and age-matched other neurological diseases (OND, n = 14). Lastly, we measured the competitive binding behavior of a dual MMP-2/MMP-9 inhibitor, AQU-118, against active MMP-9 in situ within the serum of ALS. We found significantly elevated levels of both total MMP-9 protein (two studies, 7.5 and 9.5-fold; both p < 0.0001) and active MMP-9 (2.5-fold; p < 0.0001) in ALS serum compared to HC. Serum NfL was significantly elevated (6-fold, p < 0.0001) and serum creatinine was significantly decreased (40%, p < 0.0001) in ALS compared to HC. There were significantly decreased levels of MMP-2 (two studies, 26 and 33%; p < 0.001 and p = 0.0001, respectively) in the serum of ALS as compared to HC. ALS also had significantly higher active MMP-9 in serum than patients with Alzheimer’s disease and higher than Parkinson’s disease or diabetic nephropathy. We confirmed that active MMP-9 in ALS is fully available for proteolytic activity in both serum and CSF and can be inhibited using an MMP-2/-9 inhibitor. Active MMP-9 is systemically elevated in ALS and therefore a therapeutic target for ALS drug development. Full article

Tissue inhibitor of metalloproteinase 3 (TIMP3) serves as a prominent endogenous inhibitor of matrix metalloproteinases (MMPs), playing a crucial role in inhibiting metastasis, and angiogenesis. However, its exact contributions to colorectal cancer (CRC) remain largely unidentified. We aimed to ascertain the prognostic significance of TIMP3 in CRC patients through a bioinformatic approach. GEPIA, UALCAN, Kaplan–Meier plotter, LinkedOmics, cBioPortal, GeneMANIA, TIMER, TISIDB, the ScTIME database, TISMO, TIDE, CAMOIP, and TISCH2 were employed to comprehensively analyze the differential expression, prognostic value, genetic alterations, signaling pathways, immune cell infiltration, tumor microenvironment (TME) and associated genes of TIMP3 in CRC patients. Compared to adjacent normal tissues, we observed a significant downregulation of TIMP3 expression in CRC samples. Gene interaction networks elucidated that TIMP3 and its associated genes play a pivotal role in cancer progression, particularly in processes critical to colorectal cancer, such as extracellular matrix organization and angiogenesis. Analysis of the TME further indicates that TIMP3 expression was intricately associated with diverse immune cell types infiltration levels, chemokines, and immunomodulators. Most importantly, those with elevated TIMP3 expression had improved immunological scores. Moreover, TIMP3 exhibited strong correlations with major infiltration-related immune cells, including B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils, dendritic cells, and fibroblasts. Furthermore, improved immunotherapeutic responses against PD-1/PD-L1 were linked to elevated TIMP3 levels. In TIMP3-high groups, there was a considerable increase in IL10, PDCD1, CD80, CXCL9, and CXCR3. This highlights the extensive influence of TIMP3 downregulation on the immune milieu within CRC. Our findings emphasize the multifaceted involvement of TIMP3 in CRC, not only influencing the molecular pathways associated with cancer progression, but also intricately shaping the immune microenvironment. As a result, TIMP3 appears promising as a potential CRC therapeutic target. Full article

Osteoarthritis (OA), the most common form of arthritis, affects the whole synovial joint. Post-traumatic osteoarthritis (PTOA) is an important subtype of OA which develops after joint injury. The anti-PTOA effects of iontophoretic liposome-encapsulated strontium ranelate (L-SR) combined with low-intensity pulsed ultrasound (LIPUS) were examined by a culture of human OA chondrocytes (HOACs) in alginate beads and verified on an anterior cruciate ligament transection PTOA rat model. The aim of this study is to evaluate and establish an anti-PTOA therapy combined with L-SR, transdermal iontophoresis, and LIPUS. Treatment with 10⁻⁴ M L-SR with LIPUS-enhanced type II collagen and glycosaminoglycans (GAGs) as L-SR with LIPUS reduced the MMP-13, IL-1β, and TNF-α in HOACs. Iontophoretic L-SR at 15 mg with LIPUS increased the weight bearing, exercise endurance, GAG density, and type II collagen intensity, while L-SR with or without LIPUS further decreased MMP13 and proinflammatory cytokines in vivo. The RBC, WBC, and serum biochemistry values were not significantly affected by the treatments. Liposome encapsulation and iontophoresis reinforce the anti-PTOA effects of SR and the addictive LIPUS further improves weight-bearing and endurance performance in the rats with PTOA. Thus, iontophoretic L-SR with LIPUS could be a potential therapy for PTOA. Full article

Osteoarthritis (OA), the most common joint disease, is marked by cartilage degradation and chronic inflammation. While 45S5-bioactive glass (45S5-BG) is well-established in bone regeneration and has been suggested to exert immunomodulatory effects, its impact on OA chondrocytes remains largely unexplored. Therefore, this in vitro study investigated the effects of 45S5-BG microparticles (0.125 mg/mL) on chondrocytes derived from OA patients, evaluating its therapeutic potential in OA. Chondrocytes were cultured with or without 45S5-BG for 1 and 7 days. Gene expression of cartilage markers, cytokines, matrix metalloproteinases (MMPs), and toll-like receptors (TLRs) was analyzed by qPCR. Protein levels were assessed by ELISA. 45S5-BG stimulation significantly altered chondrocyte activity, inducing upregulation of IL-6, IL-1β, TNF-α, MMP-1/-3/-13, and TLR4. Expression of ACAN and COL2A1 was reduced, while COL10A1—a marker of chondrocyte hypertrophy—was significantly increased at day 1. These findings show a catabolic and pro-inflammatory shift in chondrocyte phenotype upon 45S5-BG exposure, showing no therapeutic benefit of 45S5-BG on OA chondrocytes. However, considering the pronounced effects on chondrocyte activity and the well-established bioactivity and biocompatibility of 45S5-BG, our findings suggest that modified BG formulations could be developed to enhance chondroprotective and anti-inflammatory properties, warranting further investigation in co-culture and in vivo models. Full article

The dried root extract of Astragalus membranaceus, also known as Astragali radix, is widely used in traditional Chinese medicine for its multiple health benefits and well-established safety profile. Astragalus root extract exhibits several bioactive properties, including anti-inflammatory, antioxidant, antiviral and hepatoprotective effects. Due to its unique features, it is being investigated in a novel application as a complementary remedy in the management of joint disorders. In this study, we evaluated the effect of Astragalus membranaceus hydroalcoholic root extract (0.01 and 0.1 mg/mL) in vitro on the HTB-94 cell line, a well-known model for studying inflammatory pathways in human chondrocytes. The mRNA modulation levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR), while the protein secretion levels were assessed using an Enzyme-Linked Immunosorbent Assay (ELISA). Results obtained demonstrated that this extract is able to decrease the tumor necrosis factor-α (TNF-α)-induced inflammatory response by downregulating both the mRNA expression and release of the pro-inflammatory mediators Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and Interelukin-8 (IL-8), as well as matrix metalloproteases, including Matrix Metalloprotease-3 (MMP-3), Matrix Metalloprotease-13 (MMP-13) and A disintegrin, and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5). Moreover, the interleukin and matrix metalloprotease production was also assessed in non-TNF-α-stimulated cells, revealing that the extract did not alter the basal levels of these mediators. Finally, our findings highlight the potential benefits of Astragalus membranaceus extract, both in terms of its favorable safety profile and its efficacy mitigating joint inflammatory responses. These results support the potential of this extract as a nutraceutical agent for joint health support. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by chronic inflammation and progressive cartilage breakdown. This study investigated the synergistic protective effects of oleaster fruit extract (OE) and Sophora japonica L. fruit extract (SJE) against interleukin-1β (IL-1β) -induced inflammation in human chondrocytes. OE and SJE were tested individually and in combination at various ratios (3:1, 2:1, 1:1, 1:2, and 1:3). Among the tested mixtures, the 3:1 OE:SJE ratio exhibited the most pronounced synergistic effect. When used individually, the concentrations required to achieve 90% cell viability were 313.6 µg/mL for OE and 4135.8 µg/mL for SJE. In contrast, the same viability level was achieved with a combined treatment of 26.4 µg/mL OE and 8.8 µg/mL SJE, yielding a combination index of 0.25, indicative of strong synergy. The 3:1 OE:SJE combination also significantly suppressed inflammatory mediators, including nitric oxide, interleukin-6, and tumor necrosis factor-α. This treatment also led to the downregulation of matrix-degrading enzymes, such as matrix metalloproteinase (MMP)-9 and MMP-13, and it promoted the preservation of hyaluronan, a key extracellular matrix component. These findings suggest that the 3:1 OE:SJE combination exerts a synergistic protective effect by modulating both inflammatory and catabolic pathways and may represent a promising therapeutic strategy for OA prevention or treatment. Full article

Walnuts (Juglans regia L.) are recognized for their rich nutritional profile and health-promoting properties. This study investigates the impact of biostimulation, via wood distillate application, on the chemical composition and therapeutic potential of walnut kernels, focusing on their wound healing activity. Biostimulated walnuts showed enhanced levels of phenolic compounds including antioxidants, sugars, and amino acids compared to untreated or agrochemically treated controls. Phytocomplexes extracted from walnut kernels using green methodologies were tested on human keratinocytes (HaCaT), revealing pro-migratory effect, boosted by biostimulation. Molecular analyses demonstrated the activation of epithelial–mesenchymal transition (EMT) pathways, marked by downregulation of epithelial markers and upregulation of mesenchymal genes such as MMP3, MMP9, vimentin, and SMAD3. Furthermore, a synergistic effect was observed between extracts derived from biostimulated kernels and manuka honey in promoting wound closure. These findings suggest that kernels from biostimulated walnuts may serve as functional foods, paving the way for their use in regenerative medicine. Full article

Plant-derived compounds offer immense therapeutic potential, yet many suffer from limited solubility, instability, and poor bioavailability, restricting their clinical application. Curcumin, a polyphenol extracted from Curcuma longa, is one such molecule, with proven antioxidant and anti-inflammatory properties. To overcome its pharmacokinetic limitations, we developed Jamamina, a sustainable nanostructured lipid carrier (NLC) system incorporating curcumin and a Natural Deep Eutectic Solvent (NaDES) phase composed of malic acid and betaine. The bioinspired formulation, based on Amazonian tucumã butter and jambu oil, achieved high encapsulation efficiency (>80%) and curcumin amorphization, enhancing solubility and colloidal stability. In vitro assays with L132 demonstrated potent antioxidant activity (DPPH), a significant reduction in pro-inflammatory cytokines (TNF-α and IL-6), and upregulation of IL-10. The system also suppressed MMP-2/9 activity and preserved cytoskeletal integrity under oxidative stress. These findings highlight Jamamina as a multifunctional, eco-friendly nanoplatform that enables the pharmacological application of plant-derived curcumin, representing a promising platform for modulating redox balance and investigating inflammation in epithelial-like contexts. Full article

Background/Objectives: Glucagon-like peptide-1 (GLP-1) is an endogenous hormone with receptors widely expressed across multiple organs. GLP-1 receptor agonists (GLP-1RAs), primarily used for diabetes management, have demonstrated anti-inflammatory and antioxidant properties beyond glucose regulation. This study explores the protective effect of semaglutide, a GLP-1RA, in reducing oxidative stress and promoting wound healing in human dermal fibroblasts. Additionally, it assesses whether semaglutide offers the direct protection of retinal endothelial cells under oxidative stress. Methods: Human dermal fibroblasts and retinal endothelial cells were treated with semaglutide at concentrations ranging from 0 to 45 pg/mL for 24 h under oxidative stress induced by hydrogen peroxide (H₂O₂). Cell viability and ATP levels were measured via MTT and ATP assays. Apoptosis was evaluated using propidium iodide staining. Intracellular reactive oxygen species (ROS) and mitochondrial superoxide were assessed through confocal microscopy with specific fluorescent probes. Wound healing was tested using scratch assays, with closure monitored over time and quantified with ImageJ (version 1.51). Gene expression levels of antioxidants, extracellular matrix components, inflammatory cytokines, and MMPs (MMP3, MMP9) were determined via real-time PCR. Results: Semaglutide significantly improved cell viability and ATP production under oxidative stress (p < 0.001), while reducing apoptosis and intracellular ROS levels. It notably accelerated fibroblast wound closure, achieving near-complete restoration. Gene analysis revealed increased expression of antioxidant and ECM-related genes, along with decreased pro-inflammatory cytokines and MMPs, indicating reduced inflammation and enhanced tissue remodeling. Conclusions: Semaglutide offers robust antioxidative and cytoprotective effects in dermal fibroblasts and retinal endothelial cells, promoting wound healing. These findings highlight its therapeutic potential for diabetic foot ulcers and diabetic retinopathy, supporting further in vivo investigation. Full article