Asthma is a chronic airway inflammation that is considered a serious public health concern worldwide. Nobiletin (5,6,7,8,3′,4′-hexamethyl flavonoid), an important compound isolated from several traditional Chinese medicines, especially Citri Reticulatae Pericarpium, is widely used for a number of indications, including cancer, allergic diseases, and chronic inflammation. However, the mechanism by which nobiletin exerts its anti-asthmatic effect remains unclear. In this research, we comprehensively demonstrated the anti-asthmatic effects of nobiletin in an animal model of asthma. It was found that nobiletin significantly reduced the levels of inflammatory cells and cytokines in mice and alleviated airway hyperresponsiveness. To explore the target of nobiletin, we identified PDE4B as the target of nobiletin through pharmacophore modeling, molecular docking, molecular dynamics simulation, SPR, and enzyme activity assays. Subsequently, it was found that nobiletin could activate the cAMP-PKA-CREB signaling pathway downstream of PDE4B in mouse lung tissues. Additionally, we studied the anti-inflammatory and anti-airway remodeling effects of nobiletin in LPS-induced RAW264.7 cells and TGF-β1-induced ASM cells, confirming the activation of the cAMP-PKA-CREB signaling pathway by nobiletin. Further validation in PDE4B-deficient RAW264.7 cells confirmed that the increase in cAMP levels induced by nobiletin depended on the inhibition of PDE4B. In conclusion, nobiletin exerts anti-asthmatic activity by targeting PDE4B and activating the cAMP-PKA-CREB signaling pathway.

As the primary bioactive flavonoid in Coreopsis tinctoria, okanin has emerged as a promising antioxidant compound of substantial pharmacological interest. However, its efficacy against UVA-mediated photoaging remains unexplored. This research investigated the molecular mechanism underlying the photoprotective activity of okanin against UVA-mediated photoaging. Network pharmacology was employed to predict the pharmacological mechanism of Coreopsis tinctoria in skin photoaging, which was then validated through in vivo and in vitro studies. In vitro experiments indicated that treatment with okanin alleviated oxidative damage, apoptosis and mitochondrial dysfunction in HaCaT cells exposed to UVA radiation. In addition, the interaction between okanin and SIRT3 was confirmed using molecular docking, SPR and DARTS assays. However, silencing SIRT3 with siRNA abolished the promoting effects of okanin on mitophagy genes, confirming that okanin protects HaCaT cells against UVA damage through SIRT3 regulation. In in vivo, okanin enhanced the expression of SIRT3 and FOXO3a in dorsal skin, mitigating UV-mediated skin damage. Taken together, our results suggest the protective effects of okanin against UV radiation in both HaCaT cells and mice induced, at least in part, by regulating SIRT3/FOXO3a/PINK1/Parkin signaling pathway. These findings highlight the potential of okanin for use in skin care products aimed at promoting skin repair following UVA exposure.

Polysaccharides derived from green algae have garnered significant attention owing to their distinctive structural characteristics and biological activities. In particular, sulfated polysaccharides from these algae represent a promising frontier in the discovery of novel therapeutic agents. In this present study, a sulfated galactan from Caulerpa taxifolia, designated SGC, was obtained by dilute alkali extraction and chromatographic purification. On the basis of chemical and spectroscopic analyses, the backbone of SGC was constituted by a backbone of →3)-β-d-Galp-(1→ with sulfate substitution at the C-2 and a branch on C-6. The side chains contained →6)-β-d-Galp(2SO₄)-(1→, →6)-β-d-Galp(3OMe)-(1→ and →3)-β-d-Galp(4,6-Pyr)-(1→ units. SGC possessed strong hypoglycemic activity in vitro, as evaluated by an assay of α-amylase inhibition. The anti-diabetic activity of SGC in vivo was further investigated using T2DM mice induced by high-fat diet combined with streptozotocin. The results indicated that SGC markedly restored body weight, reduced fasting blood glucose and possessed a significant glucose-regulating effect. Furthermore, SGC effectively increased insulin sensitivity and mitigated insulin resistance. Additionally, SGC effectively regulated lipid metabolism and alleviated oxidative stress. Notably, SGC ameliorated liver and pancreas damage induced by high-fat diet combined with streptozotocin. The investigation demonstrates that SGC is a unique sulfated galactan and has potential as a novel anti-diabetic agent.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disorder with a globally increasing prevalence. Current therapeutic strategies are limited by drug resistance and safety concerns. Studies suggest that inhibiting the secretion of inflammatory cytokines represents a promising approach for COPD treatment. Phosphodiesterase-4 (PDE4) inhibitors have emerged as potent anti-inflammatory agents for respiratory diseases. In this study, we integrated a marine-derived natural product with computer-aided drug design to develop 32 novel PDE4 inhibitors. Compound B7 exhibited potent PDE4 inhibitory activity and a favorable safety profile. In rat model of COPD, B7 significantly reduced inflammatory cell infiltration and cytokine levels, ameliorated pathological changes in the lung, decreased the percentage of goblet cell positivity, and reduced expiratory resistance. Furthermore, in vitro mechanistic studies revealed that B7 exerts its anti-inflammatory effects by activating the cAMP-PKA-CREB signaling pathway and suppressing the NF-κB pathway in RAW264.7 cells. In conclusion, B7 demonstrates potential as a safe and effective PDE4-targeted candidate for the treatment of COPD.