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Osteoarthritis (OA), the most prevalent type of arthritis, is characterised by permanent damage to the articular cartilage. The progression of OA is mediated by the disruption of extracellular matrix (ECM) homeostasis and the overactivation of the inflammatory response. Herbal extracts, with their safety and multi‐targeting properties, have demonstrated unique advantages in inhibiting inflammation, delaying cartilage degeneration and regulating the joint microenvironment. The PI3K/AKT signalling and NF‐kB signalling pathways, two classical inflammatory signalling pathways, mediate the occurrence and development of osteoarthritis by regulating the inflammatory response. Pulchinenoside C (PC, also known as Anemoside B4), derived from Pulsatilla chinensis, contains the highest concentration of triterpenoid saponins. PC exerts definite anti‐inflammatory effects. However, its ability to delay the progress of OA by regulating the classical inflammatory signalling pathway remains to be clarified. This study aimed to elucidate the mechanism through which PC prevented the progression of OA in vitro and in vivo. In vitro, PC exerted significant anti‐inflammatory effects on IL‐1β‐induced inflammatory responses in the ATDC5 cells. Notably, PC also inhibited matrix metalloproteinase expression and successfully protected the extracellular matrix of chondrocytes. In vivo, PC prevented the development of OA in a C57BL/6 mouse model of OA caused by medial meniscus (DMM) instability by inhibiting the activation of the PI3K/AKT/NF‐κB pathway. These findings suggest that PC is a potentially safe and successful therapeutic agent for OA.

Aims Alzheimer's disease (AD) is a neurodegenerative disorder with limited treatment options. This study aimed to investigate the therapeutic effects of Ginkgo biloba leaf extract (GBE) on AD and explore its potential mechanisms of action. Methods Key chemical components of GBE, including quercetin, luteolin, and kaempferol, were identified using network pharmacology methods. Bioinformatics analysis revealed their potential roles in AD through modulation of the PI3K/AKT/NF‐κB signaling pathway. Results Mouse experiments demonstrated that GBE improved cognitive function, enhanced neuronal morphology, and reduced serum inflammatory factors. Additionally, GBE modulated the expression of relevant proteins and mRNA. Conclusion GBE shows promise as a potential treatment for AD. Its beneficial effects on cognitive function, neuronal morphology, and inflammation may be attributed to its modulation of the PI3K/AKT/NF‐κB signaling pathway. These findings provide experimental evidence for the application of Ginkgo biloba leaf in AD treatment and highlight its potential mechanisms of action. The Ginkgo biloba leaf extract (GBE) study demonstrates its promise as an Alzheimer's treatment, significantly improving cognitive function and neuronal morphology. The effects are mediated through modulation of the PI3K/AKT/NF‐κB signaling pathway, which impacts inflammation and neuronal health, offering a potential new avenue for therapeutic intervention in neurodegenerative disorders.

In Traditional Chinese medicine (TCM) theory, ulcerative colitis (UC) is associated with damp-heat, blood stasis, and intestinal vascular ischemia. Kuijieyuan decoction (KD) is a traditional Chinese medicine based on the above theory and used clinically to alleviate UC injury. The main components of KD were analyzed by using high-pressure liquid chromatography (HPLC) and confirmed by UPLC-MS/MS. A UC model was established in rats by using dextran sulfate sodium (DSS) and dead rats (caused by DSS) were excluded from the study. Forty-eight rats were divided into 6 groups, health control (CG), UC model (UG), sulfasalazine (SG), low-dose KD (LG), middle-dose KD (MG), and high-dose KD (HG) groups. UC damage was assessed by hematoxylin and eosin staining and scan electron microscopy. We measured Toll-like receptor 4 (TLR4), p-phosphatidylinositol 3-kinase (PI3K), PI3K, p-Protein kinase B (AKT), AKT, p-nuclear factor kappa B (NF-κB), NF-κB, oxidative stress marker (superoxidase dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), and malondialdehyde) and inflammatory markers (tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6 and IL-10) in UC tissues. Gut microbiota was analyzed through16S rRNA sequencing. The main components of KD consist of gallic acid, paeoniflorin, emodin, berberine, coptisine, palmatine, jatrorrhizine, baicalein and baicalin. The UC model was successfully established by causing intestinal barrier injury with the loss of intestinal villi and destructed mitochondria of intestinal epithelial cells. Both sulfasalazine and KD treatment repaired UC injury, reduced the levels of malondialdehyde, TNFα, IL-1, IL-6, TLR4, p-PI3K, p-AKT, and p-NF-κB, and increased the levels of SOD, GPx, CAT, and IL-10. KD showed a protective function for the UC model in a dose-dependent way. The serum levels of paeoniflorin and baicalin had a strong relationship with the levels of inflammatory and oxidative stress biomarkers. KD treatment increased the proportion of Alloprevotella, Treponema, Prevotellaceae, and Prevotella, and reduced the proportion of Escherichia_Shigella and Desulfovibrio in gut microbiota. KD improved intestinal barrier injury of ulcerative colitis, antioxidant and anti-inflammatory properties by affecting TLR4-dependent PI3K/AKT/NF-κB signaling possibly through the combination of its main compounds, and improving gut microbiota.

Background Prenatal stress (PNS) is a significant risk factor impacting the lifelong health of offspring, and it has been widely recognized as being closely linked to the increased prevalence of neurodevelopmental disorders and psychiatric illnesses. However, effective pharmacological interventions to mitigate its detrimental effects remain limited. Melatonin (Mel), an endogenous hormone, has demonstrated considerable potential in treating neurological diseases due to its anti‐inflammatory, antioxidant, and neuroprotective properties, as well as its favorable safety profile and broad clinical applicability. Objective This study aims to investigate the protective effects and mechanisms of melatonin on neurodevelopmental and behavioral abnormalities in offspring induced by prenatal stress. Methods Using a prenatal stress mouse model, we evaluated the effects of melatonin on emotional and cognitive deficits in offspring. Neurogenesis and synaptic development were assessed, and RNA sequencing was performed to analyze microglial gene enrichment and immune‐related pathways. Both in vivo and in vitro experiments were conducted to validate the findings, focusing on the PI3K/AKT/NF‐κB signaling pathway in microglia. Results Melatonin administration alleviated emotional and cognitive deficits in offspring mice exposed to prenatal stress, addressing abnormalities in neurogenesis and synaptic development. Additionally, RNA sequencing revealed that melatonin suppresses microglial gene enrichment and the upregulation of immune‐related pathways. Both in vivo and in vitro validation indicated that melatonin modulates the PI3K/AKT/NF‐κB signaling pathway in microglia, reducing the elevated expression of CXCL10 in the dentate gyrus, thereby restoring normal neuro‐supportive functions and optimizing the neurodevelopmental environment. Conclusion These findings suggest that melatonin significantly improves neurodevelopmental disorders and behavioral abnormalities caused by prenatal stress by inhibiting pathological microglial activation and promoting hippocampal neurogenesis and synaptic plasticity. This provides new insights into melatonin's potential as a neuroprotective agent for treating prenatal stress‐related disorders. Prenatal stress increases the risk of neurodevelopmental disorders and psychiatric illnesses in offspring. This study demonstrates that melatonin alleviates emotional and cognitive deficits in offspring exposed to prenatal stress. By modulating the PI3K/AKT/NF‐κB signaling pathway in microglia and reducing the elevated expression of CXCL10 in the dentate gyrus, melatonin promotes neurogenesis and synaptic plasticity.

Mycoplasma gallisepticum (MG) mainly infects chickens to initiate chronic respiratory disease (CRD). microRNAs (miRNAs) play vital roles according to previously reported studies. Our previous study showed that gga-miR-16-5p, in MG-infected lungs of chicken embryo, was upregulated by Illumina sequencing. The study aimed to reveal what role gga-miR-16-5p plays in CRD progression. gga-miR-16-5p was upregulated in MG-infected fibroblast cells (DF-1). Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was demonstrated as the target gene of gga-miR-16-5p. Furthermore, PIK3R1 expression was lower in MG-infected groups than it in noninfected controls measured by qPCR. Additionally, overexpressed gga-miR-16-5p could downregulate PIK3R1 and phosphorylated serine/threonine kinase (p-Akt) to express protein, whereas there is an opposite effect on inhibition. Overexpressed gga-miR-16-5p resulted in decreased activity of tumor necrosis factor alpha (TNF-α) and the nuclear factor-kappaB (NF-κB) by qPCR. Furthermore, overexpressed gga-miR-16-5p restricted cell multiplication, cycle progression, and increased apoptosis of MG-infected DF-1 cells, whereas inhibited gga-miR-16-5p led to the opposite effect. Collectively, upregulated gga-miR-16-5p could decrease multiplication, cycle progression, and increase apoptosis of MG-infected DF-1 cells, at least partly through directly targeting PIK3R1 and inhibiting PI3K/Akt/NF-κB pathway to exert an anti-inflammatory effect. Our results will provide more experimental evidence to bring pathogenesis of MG infection to light.

Scutellarein (SCU) is a well-known flavone with a broad range of biological activities against several cancers. Human hepatocellular carcinoma (HCC) is major cancer type due to its poor prognosis even after treatment with chemotherapeutic drugs, which causes a variety of side effects in patients. Therefore, efforts have been made to develop effective biomarkers in the treatment of HCC in order to improve therapeutic outcomes using natural based agents. The current study used SCU as a treatment approach against HCC using the HepG2 cell line. Based on the cell viability assessment up to a 200 μM concentration of SCU, three low-toxic concentrations of (25, 50, and 100) μM were adopted for further investigation. SCU induced cell cycle arrest at the G2/M phase and inhibited cell migration and proliferation in HepG2 cells in a dose-dependent manner. Furthermore, increased PTEN expression by SCU led to the subsequent downregulation of PI3K/Akt/NF-κB signaling pathway related proteins. In addition, SCU regulated the metastasis with EMT and migration-related proteins in HepG2 cells. In summary, SCU inhibits cell proliferation and metastasis in HepG2 cells through PI3K/Akt/NF-κB signaling by upregulation of PTEN, suggesting that SCU might be used as a potential agent for HCC therapy.

Osteoarthritis (OA) is a chronic progressive articular illness which commonly affects older-aged adults, presenting with cartilage inflammation and degradation. Rutaecarpine (RUT) has been shown to exert promising anti-inflammatory effects; however, the efficacy of RUT in the treatment of OA is debatable. The present study investigated the potential of RUT in alleviating OA in a mouse model. Treatment with RUT inhibited the inflammatory response and extracellular matrix degradation by suppressing process regulators in interleukin (IL)-1β-stimulated chondrocytes. Moreover, treatment with RUT in vitro upregulated the gene expression of anabolic agents, such as collagen type II, aggrecan and SRY-box transcription factor 9, indicating that RUT contributed to cartilage repair. Additionally, flow cytometric assays, and the measurement of β-galactosidase levels, autophagic flux and related protein expression revealed that RUT effectively attenuated IL-1β-induced chondrocyte apoptosis, senescence and autophagy impairment. In addition, bioinformatics analysis and in vitro experiments demonstrated that RUT protected cartilage by mediating the phosphoinositide-3-kinase (PI3K)/Akt/nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. The ameliorative effects of RUT on IL-1β-stimulated chondrocytes were abrogated when siRNA was used to knock down integrin αVβ3. Furthermore, the results of immunohistochemical analysis and microcomputed tomography confirmed the in vivo therapeutic effects of RUT in mice with OA. On the whole, the present study demonstrates that RUT attenuates the inflammatory response and cartilage degradation in mice with OA by suppressing the activation of the PI3K/AKT/NF-κB and MAPK pathways. Integrin αVβ3 may play a pivotal role in these effects.

Background Sepsis-associated acute kidney injury (SA-AKI) is marked by systemic inflammation and organ dysfunction. Ubiquitin-specific protease 18 (USP18) is a regulator in immune responses and apoptosis. Objectives To explore USP18's role in inflammatory pathways and apoptosis in SA-AKI, particularly its interactions with the PI3K-AKT-NF-κB pathway. Design A combination of animal experiments and cellular models was employed to investigate the expression and regulatory functions of USP18 in both in vivo and in vitro settings. Methods We established SA-AKI models in mice and HK-2 cells using LPS. Gene expression was analyzed via RNA-seq, and Cr, BUN, and inflammatory factors were measured using biochemical assays and ELISA. Kidney pathology was assessed with HE staining, mRNA levels with qRT-PCR, protein expression with Western blots, and cell apoptosis with flow cytometry. Results In SA-AKI mice model and HK-2 cell lines, upregulated USP18 was linked to increased activity in the PI3K-AKT-NF-κB pathway and heightened inflammation. Conversely, USP18 downregulation decreased early cell apoptosis and raised levels of inflammatory proteins. Elevated USP18 levels were also found in SA-AKI patients’ blood and urine. Conclusion USP18 enhances in vitro and in vivo responses by modulating inflammation and apoptosis through the PI3K-AKT-NF-κB pathway, presenting a potential target for SA-AKI therapy.

Introduction: Asparagus ( Asparagus officinalis ) is a perennial flowering plant species. Its main components have tumor-prevention, immune system-enhancement, and anti-inflammation effects. Network pharmacology is a powerful approach that is being applied increasingly to research of herbal medicines. Herb identification, study of compound targets, network construction, and network analysis have been used to elucidate how herbal medicines work. However, the interaction of bioactive substances from asparagus with the targets involved in multiple myeloma (MM) has not been elucidated. We explored the mechanism of action of asparagus in MM through network pharmacology and experimental verification. Methods: The active ingredients and corresponding targets of asparagus were acquired from the Traditional Chinese Medicine System Pharmacology database, followed by identification of MM-related target genes using GeneCards and Online Mendelian Inheritance in Man databases, which were matched with the potential targets of asparagus. Potential targets were identified and a target network of traditional Chinese medicine was constructed. The STRING database and Cytoscape were utilized to create protein–protein interaction (PPI) networks and further screening of core targets. Results: The intersection of target genes and core target genes of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was enriched, the top-five core target genes were selected, and the binding affinity of corresponding compounds to the top-five core targets was analyzed using molecular docking. Network pharmacology identified nine active components of asparagus from databases based on oral bioavailability and drug similarity, and predicted 157 potential targets related to asparagus. Enrichment analyses showed that “steroid receptor activity” and the “PI3K/AKT signaling pathway” were the most enriched biological process and signaling pathway, respectively. According to the top-10 core genes and targets of the PPI pathway, AKT1, interleukin (IL)-6, vascular endothelial growth factor (VEGF)A, MYC, and epidermal growth factor receptor (EGFR) were selected for molecular docking. The latter showed that five core targets of the PI3K/AKT signaling pathway could bind to quercetin, among which EGFR, IL-6, and MYC showed strong docking, and the diosgenin ligand could bind to VEGFA. Cell experiments showed that asparagus, through the PI3K/AKT/NF-κB pathway, inhibited the proliferation and migration of MM cells, and caused retardation and apoptosis of MM cells in the G0/G1 phase. Discussion: In this study, the anti-cancer activity of asparagus against MM was demonstrated using network pharmacology, and potential pharmacological mechanisms were inferred using in vitro experimental data.