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Several plant bioactive compounds have exhibited functional activities that suggest they could play a remarkable role in preventing a wide range of chronic diseases. The largest group of naturally-occurring polyphenols are the flavonoids, including apigenin. The present work is an updated overview of apigenin, focusing on its health-promoting effects/therapeutic functions and, in particular, results of in vivo research. In addition to an introduction to its chemistry, nutraceutical features have also been described. The main key findings from in vivo research, including animal models and human studies, are summarized. The beneficial indications are reported and discussed in detail, including effects in diabetes, amnesia and Alzheimer’s disease, depression and insomnia, cancer, etc. Finally, data on flavonoids from the main public databases are gathered to highlight the apigenin’s key role in dietary assessment and in the evaluation of a formulated diet, to determine exposure and to investigate its health effects in vivo.

Cancer is a serious public health concern worldwide, and nervous system (NS) cancers are among the most life-threatening malignancies. Efforts have been devoted to introduce natural anticancer agents with minimal side effects. Apigenin is an edible flavonoid that is abundantly found in many vegetables and fruits. Various pharmaceutical activities, including anti-inflammatory, antioxidative, antimicrobial, and anticancer effects have been reported for apigenin. This review provides insights into the therapeutic effects of apigenin and flavonoids with similar structure on glioblastoma and neuroblastoma. Current evidence indicates that apigenin has the unique ability to cross the blood-brain barrier, and its antioxidative, anti-inflammatory, neurogenic, and neuroprotective effects have made this flavonoid a great option for the treatment of neurodegenerative disorders. Meanwhile, apigenin has low toxicity on normal neuronal cells, while induces cytotoxicity on NS cancer cells via triggering several signal pathways and molecular targets. Anticancer effects of apigenin have been contributed to various mechanisms such as induction of cell cycle arrest and apoptosis, and inhibition of migration, invasion, and angiogenesis. Although apigenin is a promising pharmaceutical agent, its low bioavailability is an important issue that must be solved before introducing to clinic. Recently, nano-delivery of apigenin by liposomes and poly lactic-co-glycolide nanoparticles has greatly improved functionality of this agent. Hence, investigating pharmaceutical effects of apigenin-loaded nanocarriers on NS cancer cell lines and animal models is recommended for future studies.

The skin is the main barrier between the body and the environment, protecting it from external oxidative stress induced by ultraviolet rays. It also prevents the entrance of infectious agents such as viruses, external antigens, allergens, and bacteria into our bodies. An overreaction to these agents causes severe skin diseases, including atopic dermatitis, pruritus, psoriasis, skin cancer, and vitiligo. Members of the flavonoid family include apigenin, quercetin, luteolin, and kaempferol. Of these, apigenin has been used as a dietary supplement due to its various biological activities and has been shown to reduce skin inflammation by downregulating various inflammatory markers and molecular targets. In this review, we deal with current knowledge about inflammatory reactions in the skin and the molecular mechanisms by which apigenin reduces skin inflammation.

Microglial activation underpins the methotrexate (MTX)-induced neurotoxicity; however, the precise mechanism remains unclear. This study appraised the potential impact of apigenin (Api), a neuroprotective flavonoid, in MTX-induced neurotoxicity in rats in terms of microglial activation through targeting the miR-15a/Rho-associated protein kinase-1 (ROCK-1)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Male Sprague Dawley rats were randomly divided into 4 groups: Normal control (saline i.p. daily and i.v. on days 8 and 15); Api control (20 mg/kg, p.o.) daily for 30 days; MTX-alone (75 mg/kg, i.v.) on days 8 and 15, then four i.p. injections of leucovorin (LCV): 6 mg/kg after 18 h, then three doses (3 mg/kg) every 8 h post-MTX; and Api co-treated (20 mg/kg/day, p.o.) throughout the model for 30 days, with administration of MTX and LCV as in group 3. MTX administration elevated hippocampal ionized calcium-binding adaptor protein-1 (Iba-1) immunostaining, indicating microglial activation. This was accompanied by neuroinflammation, oxidative stress, and enhanced apoptosis manifested by elevated hippocampal interleukin-1β, malondialdehyde, and caspase-3, and decreased reduced glutathione levels. Concurrently, abated miR-15a expression, overexpression of its target ROCK-1, diminished downstream ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation, and decreased hippocampal brain-derived neurotrophic factor (BDNF) levels were observed. Api mitigated the MTX-induced neurotoxicity by reversing the biochemical, histopathological, and behavioral derangements tested by novel object recognition and Morris water maze tests. Conclusively, Api lessens MTX-induced neuroinflammation, oxidative stress, and apoptosis and boosts cognitive function through inhibiting microglial activation via modulating the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway. Graphical Abstract Graphical abstract showing the effects of methotrexate and apigenin co-treatment in MTX-induced neurotoxicity model. On the left, methotrexate (MTX) administration to rats resulted in hippocampal miR-15a downregulation, which triggered an enhanced expression of its target ROCK-1, consequently inhibiting the downstream ERK1/2/CREB/BDNF pathway, instigating a state of microglial activation, neuroinflammation, oxidative stress, and apoptosis. On the other hand, apigenin (Api) co-treatment restored miR-15a, inhibited ROCK-1 expression, and activated the ERK1/2/CREB/BDNF pathway, leading to diminished hippocampal microglial activation, neuroinflammation, and apoptosis, and restoration of the redox balance, along with improvement in memory and cognitive function of the MTX-treated rats.

Apigenin (4′,5,7-trihydroxyflavone, flavonoid) is a phenolic compound that is known to reduce the risk of chronic disease owing to its low toxicity. The first study on apigenin analyzed its effect on histamine release in the 1950s. Since then, anti-mutation and antitumor properties of apigenin have been widely reported. In the present study, we evaluated the apigenin-mediated amelioration of skin disease and investigated its applicability as a functional ingredient, especially in cosmetics. The effect of apigenin on RAW264.7 (murine macrophage), RBL-2H3 (rat basophilic leukemia), and HaCaT (human immortalized keratinocyte) cells were analyzed. Apigenin (100 μM) significantly inhibited nitric oxide (NO) production, cytokine expression (interleukin (IL)-1β, IL6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase [iNOS]), and phosphorylation of mitogen-activated protein kinase (MAPK) signal molecules, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK) in RAW264.7 cells. Apigenin (30 μM) also inhibited the phosphorylation of signaling molecules (Lyn, Syk, phospholipase Cγ1, ERK, and JNK) and the expression of high-affinity IgE receptor FcεRIα and cytokines (tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-6, IL-13, and COX-2) that are known to induce inflammation and allergic responses in RBL-2H3 cells. Further, apigenin (20 μM) significantly induced the expression of filaggrin, loricrin, aquaporin-3, hyaluronic acid, hyaluronic acid synthase (HAS)-1, HAS-2, and HAS-3 in HaCaT cells that are the main components of the physical barrier of the skin. Moreover, it promoted the expression of human β-defensin (HBD)-1, HBD-2, HBD-3, and cathelicidin (LL-37) in HaCaT cells. These antimicrobial peptides are known to play an important role in the skin as chemical barriers. Apigenin significantly suppressed the inflammatory and allergic responses of RAW264.7 and RBL cells, respectively, and would, therefore, serve as a potential prophylactic and therapeutic agent for immune-related diseases. Apigenin could also be used to improve the functions of the physical and chemical skin barriers and to alleviate psoriasis, acne, and atopic dermatitis.

This study aims to develop a self-nanoemulsifying drug delivery system (SNEDDS) to solve the limited oral bioavailability problem of apigenin, a bioactive flavonoid. Apigenin-loaded SNEDDS consisting of Gelucire 44/14, Tween 80, and PEG 400 in the mass ratios of 25:37.5:37.5 and 30:35:35 were prepared, and designated as GTP2575 and GTP3070, respectively. The physicochemical stability at 30 and 40 ºC for 6 months was evaluated and a good stability was found. The in vitro transport of apigenin across Caco-2 monolayers from the SNEDDS and the in vivo pharmacokinetics in rats were investigated and compared with apigenin intact form. The in vitro permeation results demonstrated an increased transcellular permeability compared to the apigenin coarse powder ( p  < 0.05), while there was comparable permeation of apigenin in GTP2575 and GTP3070 formulations, with the permeability constants (P app ) being 2.97 × 10 -5 and 3.13 × 10 -5 , respectively ( p  > 0.05). The pharmacokinetic analysis in rats revealed that the pharmacokinetic parameters, such as C max , AUC 0-24 , and AUC 0−∞ , were significantly higher with apigenin-loaded SNEDDS than with apigenin coarse powder ( p  < 0.05). Apigenin’s oral relative bioavailability increased by 3.8 and 3.3 times for GTP2575 and GTP3070, respectively, due to SNEDDS’s effect on solubilization and transcellular permeability. The in vivo acute oral toxicity according to OECD 425 was evaluated and revealed low toxicity with an LD 50 exceeding 2,000 mg/kg in all apigenin’s formulations. These findings suggest that apigenin-loaded SNEDDS may represent a promising strategy for improving the oral delivery of apigenin.

This review summarizes the latest advancements in phytochemicals as functional antiviral agents. We focused on flavonoids, like apigenin, vitexin, quercetin, rutin and naringenin, which have shown a wide range of biological effects including antiviral activities. The molecular mechanisms of their antiviral effects mainly consist in the inhibition of viral neuraminidase, proteases and DNA/RNA polymerases, as well as in the modification of various viral proteins. Mixtures of different flavonoids or combination of flavonoids with antiviral synthetic drugs provide an enhancement of their antiviral effects. Recent strategies in drug delivery significantly contribute to overcoming the low bioavailability of flavonoids. Frequent viral infections worldwide have led to the need for new effective antiviral agents, which can be identified among the various phytochemicals. In this light, screening the antiviral activities of a cocktail of flavonoids would be advantageous in order to prevent viral infections and improve current antiviral therapies.

Cancer remains one of the leading global health challenges, driving extensive research into natural dietary compounds with potential preventive and therapeutic benefits. This review data from preclinical research on the significance of a diet abundant in flavonoids in reducing cancer risk. An increasing number of experimental studies suggest that flavonoids play a protective role by modulating diverse mechanisms associated with cancer, including carcinogen activation, cellular signaling, cell cycle control, inflammation, angiogenesis, and oxidative damage. The aim of this review is to discuss apigenin and its related forms, focusing on their therapeutic potential. It explores the biological effects of apigenin and its sugar-based derivatives, along with evidence from studies suggesting their possible role in cancer prevention. Apigetrin, a glycoside form of apigenin found in many foods and medicinal herbs, shows several health benefits, including antioxidant, anti-inflammatory, anticancer, pain-relieving, and brain-protective effects. The article highlights recent advancements in research on the anti-tumor properties of apigenin, vitexin, and apigetrin, along with their potential mechanisms. It provides a comprehensive summary of their anticancer actions, offering insights and references for cancer treatment strategies. Results obtained from both cell-based and animal studies indicate that apigenin, vitexin, and apigetrin possess protective effects against cancer development, demonstrating anticancer activity by promoting apoptosis and/or autophagy.

Hypoxia is a major obstacle to gastric cancer (GC) therapy and leads to chemoresistance as GC cells are frequently exposed to the hypoxia environment. Apigenin, a flavonoid found in traditional medicine, fruits, and vegetables and an HDAC inhibitor, is a powerful anti-cancer agent against various cancer cell lines. However, detailed mechanisms involved in the treatment of GC using APG are not fully understood. In this study, we investigated the biological activity of and molecular mechanisms involved in APG-mediated treatment of GC under hypoxia. APG promoted autophagic cell death by increasing ATG5, LC3-II, and phosphorylation of AMPK and ULK1 and down-regulating p-mTOR and p62 in GC. Furthermore, our results show that APG induces autophagic cell death via the activation of the PERK signaling, indicating an endoplasmic reticulum (ER) stress response. The inhibition of ER stress suppressed APG-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further show that APG induces ER stress- and autophagy-related cell death through the inhibition of HIF-1α and Ezh2 under normoxia and hypoxia. Taken together, our findings indicate that APG activates autophagic cell death by inhibiting HIF-1α and Ezh2 under hypoxia conditions in GC cells.

Background The PD-L1/PD-1 pathway blockade-mediated immune therapy has shown promising efficacy in the treatment of multiple cancers including melanoma. The present study investigated the effects of the flavonoid apigenin on the PD-L1 expression and the tumorigenesis of melanoma. Methods The influence of flavonoids on melanoma cell growth and apoptosis was investigated using cell proliferation and flow cytometric analyses. The differential IFN-γ-induced PD-L1 expression and STAT1 activation were examined in curcumin and apigenin-treated melanoma cells using immunoblotting or immunofluorescence assays. The effects of flavonoid treatment on melanoma sensitivity towards T cells were investigated using Jurkat cell killing, cytotoxicity, cell viability, and IL-2 secretion assays. Melanoma xenograft mouse model was used to assess the impact of flavonoids on tumorigenesis in vivo. Human peripheral blood mononuclear cells were used to examine the influence of flavonoids on PD-L1 expression in dendritic cells and cytotoxicity of cocultured cytokine-induced killer cells by cell killing assays. Results Curcumin and apigenin showed growth-suppressive and pro-apoptotic effects on melanoma cells. The IFN-γ-induced PD-L1 upregulation was significantly inhibited by flavonoids, especially apigenin, with correlated reductions in STAT1 phosphorylation. Apigenin-treated A375 cells exhibited increased sensitivity towards T cell-mediated killing. Apigenin also strongly inhibited A375 melanoma xenograft growth in vivo, with enhanced T cell infiltration into tumor tissues. PD-L1 expression in dendritic cells was reduced by apigenin, which potentiated the cytotoxicity of cocultured cytokine-induced killer cells against melanoma cells. Conclusions Apigenin restricted melanoma growth through multiple mechanisms, among which its suppression of PD-L1 expression exerted a dual effect via regulating both tumor and antigen presenting cells. Our findings provide novel insights into the anticancer effects of apigenin and might have potential clinical implications.