Alzheimer\'s disease (AD) is closely associated with the neurotoxic effects of amyloid-β (Aβ), leading to synaptic damage, neuronal loss and cognitive dysfunction. Previous in vitro studies have demonstrated the potential of corilagin to counteract Aβ-induced oxidative stress, inflammatory injury, and β-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity in Aβ production. However, the in vivo protective effects of corilagin on Alzheimer\'s disease remain unexplored. The purpose of this study was to investigate the protective effects of corilagin on APP/PS1 mice and the underlying mechanisms. The cognitive function of the mice was assessed by step-through passive avoidance and Morris water maze tests. Nissl staining was used to evaluate neuronal damage in the hippocampus. ELISA and Western blotting analyses were used to determine the associated protein expression. Transmission electron microscopy was utilized to observe the synaptic ultrastructure of hippocampal neurons. Golgi staining was applied to assess dendritic morphology and dendritic spine density in hippocampal pyramidal neurons. Immunohistochemistry and Western blotting were performed to examine the expression of synaptic-associated proteins. The results showed that corilagin improves learning and memory in APP/PS1 mice, reduces hippocampal neuron damage, inhibits BACE1 and reduces Aβ generation. It also improves synaptic plasticity and the expression of synaptic-associated proteins. Corilagin effectively reduces Aβ generation by inhibiting BACE1, ultimately reducing neuronal loss and enhancing synaptic plasticity to improve synaptic transmission. This study sheds light on the potential therapeutic role of corilagin in Alzheimer\'s disease.

Corilagin (CLG) has antitumor activities in certain human malignant cancers. Herein, the effects and mechanisms of CLG on osteosarcoma (OS) were investigated. OS cell viability and proliferation were detected by MTT and colony formation assay. Cell cycle and apoptosis were examined using flow cytometry. The interaction between TRAF6 and FLT3 was investigated using a co-immunoprecipitation assay. Results demonstrated that CLG treatment inhibited OS cell viability and proliferation but promoted OS cell autophagy and apoptosis in a concentration-dependent manner. Mechanically, CLG inhibited TRAF6-mediated FLT3 ubiquitination degradation. TRAF6 overexpression abolished the effects of CLG on OS cell proliferation, autophagy, and apoptosis. Finally, CLG administration inhibited OS tumor growth in mice by inducing autophagy-dependent apoptosis. Taken together, CLG inhibited OS progression by facilitating mTOR/ULK1 pathway-mediated autophagy through inhibiting TRAF6-mediated FLT3 ubiquitination, which indicated that CLG was a promising candidate for the treatment of OS.

This study aimed to investigate the anti-allergic activity of compounds isolated from Geranium wilfordii Maxim. and to suggest potential therapeutic agents for allergies. Nine compounds were isolated from an ethanolic G. wilfordii extract using chromatographic methods and identified chemically and by spectroscopic analysis. These compounds were identified using reported literature data as brevifolin carboxylic acid (1), chlorogenic acid (2), corilagin (3), ellagic acid (4), geraniol (5), kaempferol 3-O-dirhamnoside (6), kaempferol 3-O-neohesperidoside (7), protocatechuic acid (8), and gallic acid (9). All nine identified compounds were assessed for including IL-4 mRNA expression and β-hexosaminidase release in RBL-2H3 cells stimulated with PMA/ionomycin or IgE + DNP-BSA. IL-4 gene expression assay showed that corilagin (3) potently inhibited IL-4 production, and β-hexosaminidase release assay showed that protocatechuic acid (8) markedly reduced histamine release. The study shows that of the nine compounds isolated from G. wilfordii, corilagin (3), and protocatechuic acid (8) are potential treatments for allergy-related diseases.

BACKGROUND: Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of atherosclerosis remain unclear. In this study, we investigated the impact of corilagin on the toll-like receptor (TLR)4 signaling pathway in a mouse vascular smooth muscle cell line (MOVAS) stimulated by oxidized low-density lipoprotein (ox-LDL). Additionally, we examined the effects of corilagin in Sprague-Dawley rats experiencing atherosclerosis.
METHODS: The cytotoxicity of corilagin was assessed using the CCK8 assay. MOVAS cells, pre-incubated with ox-LDL, underwent treatment with varying concentrations of corilagin. TLR4 expression was modulated by either downregulation through small interfering (si)RNA or upregulation via lentivirus transfection. Molecular expression within the TLR4 signaling pathway was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. The proliferation capacity of MOVAS cells was determined through cell counting. In a rat model, atherosclerosis was induced in femoral arteries using an improved guidewire injury method, and TLR4 expression in plaque areas was assessed using immunofluorescence. Pathological changes were examined through hematoxylin and eosin staining, as well as Oil-Red-O staining.
RESULTS: Corilagin demonstrated inhibitory effects on the TLR4 signaling pathway in MOVAS cells pre-stimulated with ox-LDL, consequently impeding the proliferative impact of ox-LDL. The modulation of TLR4 expression, either through downregulation or upregulation, similarly influenced the expression of downstream molecules. In an in vivo context, corilagin exhibited the ability to suppress TLR4 and MyD88 expression in the plaque lesion areas of rat femoral arteries, thereby alleviating the formation of atherosclerotic plaques.
CONCLUSIONS: Corilagin can inhibit the TLR4 signaling pathway in VSMCs, possibly by downregulating TLR4 expression and, consequently, relieving atherosclerosis.

UNASSIGNED: Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which significantly influences atherosclerotic progression. Recent research has identified that the olfactory receptor 2 (Olfr2) in vascular macrophages is instrumental in driving atherosclerosis through NLRP3- dependent IL-1 production.
UNASSIGNED: To investigate the effects of Corilagin, noted for its anti-inflammatory attributes, on atherosclerotic development and the Olfr2 signaling pathway, our study employed an atherosclerosis model in ApoE-/- mice, fed a high-fat, high-cholesterol diet, alongside cellular models in Ana-1 cells and mouse bone marrow-derived macrophages, stimulated with lipopolysaccharides and oxidized low-density lipoprotein.
UNASSIGNED: The vivo and vitro experiments indicated that Corilagin could effectively reduce serum lipid levels, alleviate aortic pathological changes, and decrease intimal lipid deposition. Additionally, as results showed, Corilagin was able to cut down expressions of molecules associated with the Olfr2 signaling pathway.
UNASSIGNED: Our findings indicated that Corilagin effectively inhibited NLRP3 inflammasome activation, consequently diminishing inflammation, macrophage polarization, and pyroptosis in the mouse aorta and cellular models via the Olfr2 pathway. This suggests a novel therapeutic mechanism of Corilagin in the treatment of atherosclerosis.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are characterized by uncontrolled inflammatory responses, neutrophil activation and infiltration, damage to the alveolar capillary membrane, and diffuse alveolar injury. Neutrophil extracellular traps (NETs), formed by activated neutrophils, contribute significantly to various inflammatory disorders and can lead to tissue damage and organ dysfunction. Corilagin, a compound found in Phyllanthus urinaria, possesses antioxidative and anti-inflammatory properties. In this study, we investigated the protective effects and underlying mechanisms of corilagin in hydrochloric acid (HCl)/lipopolysaccharide (LPS)-induced lung injury. Mice received intraperitoneal administration of corilagin (2.5, 5, or 10 mg/kg) or an equal volume of saline 30 min after intratracheal HCl/LPS administration. After 20 h, lung tissues were collected for analysis. Corilagin treatment significantly mitigated lung injury, as evidenced by reduced inflammatory cell infiltration, decreased production of proinflammatory cytokines, and alleviated oxidative stress. Furthermore, corilagin treatment suppressed neutrophil elastase expression, reduced NET formation, and inhibited the expression of ERK, p38, AKT, STAT3, and NOX2. Our findings suggest that corilagin inhibits NET formation and protects against HCl/LPS-induced ALI in mice by modulating the STAT3 and NOX2 signaling pathways.

UNASSIGNED: Corilagin (Cor) is reported as beiing hepatoprotective, anti-inflammatory, antibacterial, and anti-oxidant, while the effect on atrial fibrosis remains unknown. Therefore, we investigated the protective effect of Cor in angiotensin II (Ang II)-induced atrial fibrosis and atrial fibrillation (AF).
UNASSIGNED: C57BL/6 mice (male, 8-10 weeks, n = 40) were subcutaneously infused either with saline or Ang II (2.0 mg/kg/day) and Cor (30 mg/kg) intraperitoneally injected 2 hr before Ang II infusion for 4 weeks. Mice were grouped into the control group (n=8), Cor group (n=8), Ang II group (n=8), and Ang II + Cor group (n=8). Morphological, histological, and biochemical examinations were performed. In vivo, transesophageal burst pacing was used to generate AF.
UNASSIGNED: Cor treatment markedly reduced Ang II-induced AF development in mice. Ang II + Cor therapy potentially decreased the atrial fibrotic area. It significantly decreased the increase in smooth muscle alpha-actin (α-SMA), CTGF, Collagen I, and Collagen III expressions brought on by Ang II treatment. Moreover, Ang II + Cor treatment remarkably decreased the malondialdehyde (MDA) content, whereas superoxide dismutase (SOD) and catalase (CAT) activities were potentially increased (all, P<0.001). In addition, Ang II + Cor significantly reduced Ang II-induced interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) concentrations in atrial tissues. Furthermore, Cor significantly inhibited Ang II-induced p-PI3K, p-Akt, and NF-κB p-p65 protein expression in atrial tissues.
UNASSIGNED: Our data speculated that Cor could have a protective effect against Ang II-induced atrial fibrosis and AF via down-regulation of the PI3K-Akt pathway.

BACKGROUND: Stroke is one of the leading causes of death and long-term disability worldwide. Previous studies have found that corilagin has antioxidant, anti-inflammatory, anti-atherosclerotic and other pharmacological activities and has a protective effect against cardiac and cerebrovascular injury.
OBJECTIVE: The aim of this study was to investigate the protective effects of corilagin against ischemic stroke and to elucidate the underlying molecular mechanisms using network pharmacology, molecular docking, and animal and cell experiments.
METHODS: We investigated the potential of corilagin to ameliorate cerebral ischemia-reperfusion injury using in vivo rat middle cerebral artery occlusion/reperfusion (MCAO/R) and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) models.
RESULTS: Our results suggest that corilagin may exert its anti-ischemic stroke effect by interacting with 92 key targets, including apoptosis-associated proteins (Bcl-2, Bax, caspase-3) and PI3K/Akt signaling pathway-related proteins. In vivo and in vitro experiments showed that corilagin treatment improved neurological deficits, attenuated cerebral infarct volume, and mitigated neuronal damage in MCAO/R rats. Corilagin treatment also enhanced the survival of PC12 cells exposed to OGD/R, reduced the rate of LDH leakage, inhibited cell apoptosis, and activated the PI3K/Akt signaling pathway. Importantly, the effects of corilagin on the PI3K/Akt signaling pathway and apoptosis-associated proteins were reversed by the PI3K-specific inhibitor LY294002.
CONCLUSIONS: These results indicate that the molecular mechanism of the anti-ischemic effect of corilagin involves inhibiting neuronal apoptosis and activating the PI3K/Akt signaling pathway. These findings provide a theoretical and experimental basis for the further development and application of corilagin as a potential anti-ischemic stroke agent.

The aim of this study is to explore whether Nrf2 antioxidant pathway negatively regulates the ChTLR15/NLRP3 inflammatory pathway stimulated by Eimeria tenella infection. Firstly, levels of molecules in the Nrf2/HO-1 pathway in DF-1 cells pre-treated with an optimized dose of Corilagine or probiotics Levilactobacillus brevis 23017 were quantified using real-time PCR (qRT-PCR) and Western blot. Then, DF-1 cells pre-treated with Corilagine or L. brevis 23017 were stimulated with E. tenella sporozoites, and mRNA levels of molecules in Nrf2/HO-1 and ChTLR15/NLRP3 pathways, protein levels of p-Nrf2, Nrf2, HO-1, ChTLR15 and ChNLRP3, levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were quantified. Further, expression level of Nrf2 and ChTLR15 in DF-1 cells was knocked down by RNA interfering (RNAi) method, and target cells were pre-treated with Corilagine or L. brevis 23017, followed by stimulation with E. tenella sporozoites, and the expression levels of key molecules in Nrf2/HO-1 and ChTLR15/NLRP3 pathways were quantified. The results showed that mRNA and protein levels of key molecules in the Nrf2/HO-1 pathway in DF-1 cells was significantly upregulated after pretreating with 15 μM Corilagine and supernatant of L. brevis 23017. After stimulating with E. tenella sporozoites, levels of molecules in the ChTLR15/NLRP3 pathway, levels of MDA and ROS in DF-1 cells pre-treated with 15 μM Corilagine or bacterial supernatant were all significantly down-regulated. The results from the knock-down experiment also displayed that Corrigine and L. brevis 23017 inhibited the activation of the ChTLR15/ChNLRP3 inflammatory pathway stimulated by E. tenella sporozoites through activating Nrf2/HO-1 antioxidant pathway. This study provides new ideas for the development of novel anticoccidial products.

Sarcopoterium spinosum (L.) Spach is a Rosaceae shrub employed in the folk medicine in the Eastern Mediterranean basin. The previous few studies have focused on the S. spinosum roots, while the fruits have been poorly investigated. The present study aims to assess the biological properties of S. spinosum fruits collected in Lebanon and subjected to ethanolic, water or boiling water extraction. The extracts were compared for the phenol and flavonoid contents, and for the in vitro radical scavenging ability. The ethanolic extract (SEE) was selected and characterized by high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS) showing a phenolome rich in tannins (ellagitannins), flavonoids (quercetin derivatives), and triterpenes. The biological activity of SEE was tested on a cellular model of moderate steatosis consisting of lipid-loaded hepatic cells treated with increasing concentrations of SEE (1-25 μg/mL), or with corilagin or quercetin as comparison. In steatotic hepatocytes the SEE was able (i) to ameliorate the hepatosteatosis; (ii) to counteract the excess ROS and lipid peroxidation; (iii) to restore the impaired catalase activity. The results indicate that the ethanolic extract from S. spinosum fruits is endowed with relevant antisteatotic and antioxidant activities and might find application as nutraceutical product.