Gout is the second largest metabolic disease worldwide after diabetes, with acute gouty arthritis as most common symptom. Xanthine oxidase (XOD) and the NOD like receptor-3 (NLRP3) inflammasome are the key targets for acute gout treatment. Chlorogenic acid has been reported with a good anti-inflammatory activity, and Apigenin showed an excellent potential in XOD inhibition. Therefore, a series of chlorogenic acid-apigenin (CA) conjugates with varying linkers were designed and synthesized as dual XOD/NLRP3 inhibitors, and their activities both in XOD and NLRP3 inhibition were evaluated. An in vitro study of XOD inhibitory activity revealed that the majority of CA conjugates exhibited favorable XOD inhibitory activity. Particularly, the effects of compounds 10c and 10d, with an alkyl linker on the apigenin moiety, were stronger than that of allopurinol. The selected CA conjugates also demonstrated a favorable anti-inflammatory activity in RAW264.7 cells. Furthermore, compound 10d, which showed the optimal activity both in XOD inhibition and anti-inflammatory, was chosen and its inhibitory ability on NLRP3 and related proinflammatory cytokines was further tested. Compound 10d effectively reduced NLRP3 expression and the secretion of interluekin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) with an activity stronger than the positive control isoliquiritigenin (ISL). Based on these findings, compound 10d exhibits dual XOD/NLRP3 inhibitory activity and, therefore, the therapeutic effects on acute gout is worthy of further study.

Apigenin, a dietary flavonoid, has gained increasing attention for its potential therapeutic applications in radiation protection and radiosensitization. Ionizing radiation (IR) can harm healthy cells, but as radiotherapy remains crucial in cancer treatment. Owing to the remarkable application of radiotherapy in the treatment of cancers, it is vital to protect healthy cells from radiation hazards while increasing the sensitivity of cancer cells to radiation. This article reviews the current understanding of apigenin\'s radioprotective and radiosensitive properties with a focuses on the involved signaling pathways and key molecular targets. When exposed to irradiation, apigenin reduces inflammation via cyclooxygenase-2 inhibition and modulates proapoptotic and antiapoptotic biomarkers. Apigenin\'s radical scavenging abilities and antioxidant enhancement mitigate oxidative DNA damage. It inhibits radiation-induced mammalian target of rapamycin activation, vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP), and STAT3 expression, while promoting AMPK, autophagy, and apoptosis, suggesting potential in cancer prevention. As a radiosensitizer, apigenin inhibits tumor growth by inducing apoptosis, suppressing VEGF-C, tumor necrosis factor alpha, and STAT3, reducing MMP-2/9 activity, and inhibiting cancer cell glucose uptake. Cellular and animal studies support apigenin\'s radioprotective and anticancer potential, making it a potential candidate for further research. Investigation into apigenin\'s therapeutic efficacy in diverse cancer types and radiation damage is essential.

Apigenin is a flavone-kind of flavonoid present in fruits and vegetables. Apigenin exhibits biological activities including neuropharmacological effects against different neurological disorders. In this study, we summarize and discuss the molecular mechanisms of the anti-neuroinflammatory effects of apigenin in neurological disorders. A systematic review was conducted by searching Google Scholar, Web of Science, Scopus and PubMed. A total of 461 records were retrieved from the search. After screening of the records based on the inclusion criteria, 16 articles were selected and discussed in this study. The results from the selected studies showed that apigenin exhibited anti-neuroinflammatory effect in preclinical studies. The anti-neuroinflammatory mechanisms exhibited by apigenin include inhibition of overproduction of pro-inflammatory cytokines, attenuation of microglia activation via reduction of CD-11b-positive cells, inhibition of ROCK-1 expression and upregulation of miR-15a, p-ERK1/2, p-CREB, and BDNF, downregulation of NLRP3 inflammasome, iNOS and COX-2 expression, reduction of Toll-like receptor-4 expression and inhibition of nuclear factor-kappa B (NF-kB) activation. Overall, apigenin inhibited neuroinflammation which suggests it confers neuroprotective effect against neuronal degeneration in some neurodegenerative conditions. This review provides important neuropharmacological information on the neuroprotective mechanisms of apigenin against neuroinflammation which may be useful for future preclinical and clinical studies.

Inducing browning in white adipocytes has emerged as a promising therapeutic approach for addressing obesity. Bioactive that modulate the WAT microenvironment to induce trans browning in white adipocytes have been explored as a strategy to control unregulated lipid storage. However, relying on a single bioactive for modulating lipid metabolism has proven insufficient in obese individuals during human trials, because these compounds primarily activate a single biochemical pathway in promoting browning. Consequently, there is a growing emphasis on targeting multiple pathways to ensure a safe and effective browning process. The present study investigated the combinatorial effect of bioactives namely Apigenin and Resveratrol for activating multiple pathways for effective trans-browning of white adipocytes. The combination was seen to promote the browning more effectively than the single bioactive, as the combination simultaneously activated multiple signaling pathways to induce angiogenesis-mediated browning in primary white adipocytes isolated from obese mice. Activation of PI3K signaling via estrogen receptor-α-dependent pathway resulted in simultaneous activation of angiogenesis and trans browning in white adipocytes. The study provides valuable insights into the potential use of bioactives in combination with therapeutic intervention to improve the overall health of obese subjects by enhancing lipid metabolism by activating trans-differentiation of white adipocytes.

Non-alcoholic fatty liver disease (NAFLD) constitutes one of major worldwide health problem which typically progressively results in non-alcoholic steatohepatitis (NASH) and eventually cirrhosis and liver cancer. Liver-specific deletion of INSIG1 promotes SREBP1 nuclear translocation to activate downstream lipogenic genes expression, leading to lipid accumulation. However, the underlying pathogenesis of NAFLD, and particularly involved in miRNA participation are still to be thoroughly explored. Here, we found that miR-363-3p was significantly overexpressed in high-fat, high-cholesterol (HFHC) diet mice liver tissue and fatty acid-induced steatosis cells. miR-363-3p directly targets INSIG1 to inhibit its expression, thereby facilitating the cleavage of SREBP and nuclear translocation to activate subsequent transcription of lipogenic genes in vitro and in vivo. In addition, we identified apigenin, a natural flavonoid compound, inhibited miR-363-3p expression to up-regulate INSIG1 and suppress nuclear translocation of SREBP1, thereby down-regulated lipogenic genes expression in steatosis cells and HFHC diet mice liver tissues. Taken together, our results demonstrated that miR-363-3p as a key regulator of hepatic lipid homeostasis targeted INSIG1, and apigenin alleviated NAFLD through the miR-363-3p/INSIG1/SREBP1 pathway. This indicates that reduction of miR-363-3p levels as a possible treatment of hepatic steatosis and provides a potential new therapeutic strategy for targeting miRNA to ameliorate NAFLD.

Flavonoids, a class of natural compounds with anticancer activity, exhibit varying biological activities and potencies based on their structural differences. Acylation, including acetylation of flavonoids, generally increases their structural diversity, which is closely related to the diversity of bioactivity within this group of compounds. However, it remains largely unknown how acetylation affects the bioactivity of many flavonoids. Based on our previous findings that O-acetylation enhances quercetin\'s bioactivity against various cancer cells, we synthesized 12 acetylated flavonoids, including seven novel compounds, to investigate their anticancer activities in the MDA-MB-231, HCT-116, and HepG2 cell lines. Our results showed that acetylation notably enhanced the cell proliferation inhibitory effect of quercetin and kaempferol across all cancer cell lines tested. Interestingly, while the 5,7,4\'-O-triacetate apigenin (3Ac-A) did not show an enhanced the effect of inhibition of cell proliferation through acetylation, it exhibited significantly strong anti-migration activity in MDA-MB-231 cells. In contrast, the 7,4\'-O-diacetate apigenin (2Ac-Q), which lacks acetylation at the 5-position hydroxy group, showed enhanced cell proliferation inhibitory effect but had weaker anti-migration effects compared to 3Ac-A. These results indicated that acetylated flavonoids, especially quercetin, kaempferol, and apigenin derivatives, are promising for anticancer applications, with 3Ac-A potentially having unique anti-migration pathways independent of apoptosis induction. This study highlights the potential application of flavonoids in novel chemopreventive strategies for their anti-cancer activity.

Cancer, a major challenge to global health and healthcare systems, requires the study of alternative and supportive treatments due to the limitations of conventional therapies. This review examines the chemopreventive potential of three natural compounds: rosmarinic acid, apigenin, and thymoquinone. Derived from various plants, these compounds have demonstrated promising chemopreventive properties in in vitro, in vivo, and in silico studies. Specifically, they have been shown to inhibit cancer cell growth, induce apoptosis, and modulate key signaling pathways involved in cancer progression. The aim of this review is to provide a comprehensive overview of the current research on these phytochemicals, elucidating their mechanisms of action, therapeutic efficacy, and potential as adjuncts to traditional cancer therapies. This information serves as a valuable resource for researchers and healthcare providers interested in expanding their knowledge within the field of alternative cancer therapies.

Whey protein (WP) is often used as a delivery carrier due to its superior biological activity and nutritional value. Covalent binding of WP to epigallocatechin gallate (EGCG) can significantly improve the performance of WP in encapsulated materials. Nevertheless, the preparation of WP-EGCG covalent complexes still suffers from low grafting rates. Studies have shown that calcium ions (Ca2+) can modify the structure of proteins. We therefore explored the effect of calcium chloride (CaCl2) on the free radical grafting of EGCG and WP. The experimental results showed that the grafting rate of free radicals increased by 17.89% after adding Ca2+. Furthermore, the impact of WP-EGCG-Ca2+ covalent complex on the entrapment efficiency of apigenin (AP) was further examined, and the results revealed that the entrapment rate could reach 93.66% at an apigenin concentration of 0.2 mg/mL. Simulated gastrointestinal digestion showed that WP-EGCG-Ca2+ covalent complex could significantly improve the bioavailability of AP. The study provides new ideas to broaden the application of WP as a carrier for delivering bioactive substances.

Revealing the interaction mechanism of proteins with bioactive molecules and the location of their binding pockets is crucial for predicting the structure-function relationship of proteins in drug discovery and design. Despite some published papers on the interaction of β-casein with small bioactive molecules, the ambiguity of the location and constituent amino acids of β-casein binding pockets prompted us to identify them by in silico simulation of its interaction with three polyphenols, chrysin, apigenin, and luteolin. Molecular docking revealed that the primary β-casein binding pocket for chrysin consists of five nonpolar amino acids (Leu73, Phe77, Pro80, Ile89, and Pro196), three polar neutral amino acids (Ser137, Gln138, and Gln197), and two polar charged amino acids (Glu136, and Arg198). For β-casein/apigenin and β-casein/luteolin complexes, Asn83 also contributes to forming the pocket. Molecular dynamics provided more details, such as the relative contribution of determinative amino acids and the role of various forces. For example, we found that Glu210, Glu132, and Glu35 are the most destructive residues in the binding of chrysin, apigenin, and luteolin to β-casein, respectively. Also, we observed that hydrophobic forces mainly stabilize β-casein/chrysin and β-casein/apigenin, and polar solvation (including hydrogen bonds) stabilizes β-casein/luteolin, all by spontaneous processes.

PANoptosis is manifested with simultaneous activation of biomarkers for both pyroptotic, apoptotic and necroptotic signaling via the molecular platform PANoptosome and it is involved in pathologies of various inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). Scutellarin is a flavonoid isolated from herbal Erigeron breviscapus (Vant.) Hand.-Mazz. and has been shown to possess multiple pharmacological effects, but it is unknown whether scutellarin has any effects on PANoptosis and related inflammatory diseases. In this study, we found that scutellarin inhibited cell death in bone marrow-derived macrophages (BMDMs) and J774A.1 cells treated with TGF-β-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (OXO) plus lipopolysaccharide (LPS), which has been commonly used to induce PANoptosis. Western blotting showed that scutellarin dose-dependently inhibited the activation biomarkers for pyroptotic (Caspase-1p10 and GSDMD-NT), apoptotic (cleaved Casp3/8/9 and GSDME-NT), and necroptotic (phosphorylated MLKL) signaling. The inhibitory effect of scutellarin was unaffected by NLRP3 or Caspase-1 deletion. Interestingly, scutellarin blocked the assembly of PANoptosome that encompasses ASC, RIPK3, Caspase-8 and ZBP1, suggesting its action on upstream signaling. Consistent with this, scutellarin inhibited mitochondrial damage and mitochondrial reactive oxygen species (mtROS) generation in cells treated with OXO+LPS. Further, mito-TEMPO that can scavenge mtROS significantly inhibited OXO+LPS-induced PANoptotic cell death. In line with the in vitro results, scutellarin markedly alleviated systemic inflammation, multiple organ injury, and activation of PANoptotic biomarkers in mice with HLH. Collectively, our data suggest that scutellarin can inhibit PANoptosis by suppressing mitochondrial damage and mtROS generation and thereby mitigating multiple organ injury in mice with inflammatory disorders.