內(nèi)容: Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities. Axillaridine A (AA) is a newly discovered steroidal alkaloid. However, whether AA could suppress osteoclastogenesis and alleviate ovariectomy-induced bone loss in mice remains unknown. In vitro, AA significantly suppressed the receptor activator of nuclear factor-?κB (NF-?κB) ligand (RANKL)?-induced osteoclast differentiation via downregulating the expression of osteoclastogenesis-related marker genes, proteins, and transcriptional regulators, including tartrate-resistant acid phosphatase (TRAP), c-Src, matrix metallopeptidase-9 (MMP-9), cathepsin K, nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and c-Fos. This was achieved by blocking RANKL-RANK interaction and inhibiting RANKL-mediated RANK signaling pathways, including NF?-?κB, AKT, and mitogen-activated protein kinases (MAPKs) in osteoclast precursors. In vivo, AA significantly inhibited the ovariectomized (OVX)?-induced body weight gain and blood glucose increase in mice. AA did not adversely affect the histomorphologies, weights, and indices of the kidney and liver in OVX mice. AA effectively ameliorated bone loss in OVX mice by inhibiting osteoclastogenesis. AA significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b (TRACP-5b) and C-telopeptide of type I collagen (CTX-?I). AA significantly inhibited the OVX-induced expression of osteoclastogenesis-related marker genes and proteins in the femur. In summary, AA alleviates ovariectomy-induced bone loss in mice by suppressing osteoclastogenesis via inhibition of RANKL-mediated RANK signaling pathways and could be potentially used for the prevention and treatment of osteoclast-related diseases such as osteoporosis.

內(nèi)容: Salidroside (Sal), is one of the important food supplements from the traditional Chinese medicine Integripetal rhodiola herb, encapsulating significant anti-oxidative stress, anti-ferroptosis, and neuroprotective attributes. Notwithstanding these latent virtues, the ramifications of Sal on retinal ganglion cells (RGCs) impairment during the incipient stages of diabetic retinopathy (DR) remain equivocal. The purpose of this study was to investigate inhibitory effect of Sal on ferroptosis of RGCs in db/db mice. Within the research conducted, Sal was administered via gavage, and observations were made 8 weeks post-treatment. Retinal samples were collected for analysis. The results evidenced that Sal ameliorated blood glucose levels, attenuated RGCs destruction, and augmented visual functionality in db/db mice. Additionally, Sal exerted an anti-ferroptosis impact on the RGCs in the db/db mice. Successive discoveries have outlined the involvement of the HIF-1α/HO-1 signaling pathway in this protective mechanism. Ferroptosis of RGCs has a contributory effect on the development of DR, in part through the HIF-1α/HO-1 pathway. Intriguingly, Sal reversed the alterations in the HIF-1α/HO-1 pathway in db/db mice and displayed prospective advantageous effects on DR. Sal mitigated RGCs ferroptosis by reducing blood sugar and impeding the HIF-1α/HO-1 signaling pathway, thereby improving DR. Thus, Sal shows potential for use as a pharmaceutical and nutraceutical for DR.

內(nèi)容: Vascular oxidative stress serves as a pathological foundation for various vascular injury-related diseases, including atherosclerosis, hypertension, restenosis, and abdominal aortic aneurysms. Recent studies have indicated that intestinal flora-derived metabolites, especially phenylacetylglutamine (PAGln) and phenylacetylglycine (PAGly), may contribute to the promotion of thrombosis, heart failure, and other related conditions. Aucubin (AU), an iridoid glycoside, has been shown to exhibit anti-cardiovascular properties. Nevertheless, the precise role and underlying mechanisms by which AU mitigates PAGly-induced vascular injury remain poorly understood. Our results indicated that PAGln/PAGly promoted oxidative stress in vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in vitro and in vivo. Network pharmacology suggest that AU may possess the capacity to regulate lipid and atherosclerosis, and reactive oxygen species (ROS) processes. We found that AU penetrated the blood vessels and mitigated oxidative stress induced by PAGln/PAGly. Mechanistically, combining the results from intersection analysis between the targets of AU and vascular diseases and molecular docking, we found that tumor necrosis factor (TNF) may be the potential target of AU. Further DARTS and molecular docking analysis demonstrated that AU bound to recombinant TNF-α, and AU could interact with multiple amino acid residues of TNF-α, including Asn-92 and Phe-144. Additionally, PAGly upregulated the level of soluble TNF-α (sTNF-α) in mouse VSMCs and plasma, and promoted the interaction between sTNF-α and TNF receptor 1 (TNFR1), whereas AU inhibited this interaction. Both AU and Infliximab, a specific monoclonal antibody of TNF-α, inhibit TNF-α-induced ROS production. In summary, our results revealed that TNF-α is a cellular target of AU, and the interaction between AU and sTNF-α may mitigate PAGln/PAGly-induced vascular oxidative stress by inhibiting the interaction of TNF-α-TNFR1. Keywords

內(nèi)容: Sepsis-induced acute lung injury (ALI) is a major clinical challenge, with limited treatment options and high mortality. Ginsenoside Rb1, a bioactive compound derived from ginseng, has shown promising anti-inflammatory and antioxidative effects. This study is the first to systematically investigate the metabolites of ginsenoside Rb1, specifically F2 and CK, in the context of sepsis-induced ALI modeled by lipopolysaccharide (LPS) administration, a widely used preclinical approach to mimic key inflammatory features of clinical sepsis. Unlike other studies, which primarily focus on ginsenoside Rb1 itself, our research specifically emphasizes the role of its metabolites in this process. We demonstrated that ginsenoside Rb1 significantly improved lung histopathological damage, reduced inflammation, and inhibited cell apoptosis in a sepsis-induced ALI mouse model. Metabolomics and proteomics analyses revealed that Rb1 is metabolized into F2 and CK, which activate the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) signaling pathway. This activation promotes Forkhead Box O1 (FOXO1) deacetylation, inhibiting its cytoplasmic translocation and enhancing mitochondrial unfolded protein response (mtUPR) gene transcription. In vitro experiments confirmed that ginsenoside Rb1 protected alveolar type Ⅱ (AT2) cells from oxidative stress and senescence, while restoring mitochondrial function. Blocking the AMPK/SIRT1 pathway or silencing FOXO1 reversed these protective effects, highlighting their crucial roles in Rb1's mitigation of ALI. Our findings provide new insights into the molecular mechanisms by which ginsenoside Rb1 alleviates sepsis-induced ALI and offer a potential therapeutic approach for treating sepsis-related lung injuries.