Plant Flavone Research Articles

The effects of plant flavones on the membrane boundary potential and lipid packing stress

Here we have revealed the effects of different plant flavones on the physicochemical properties of model lipid membranes. We have demonstrated that baicalein increases the boundary potential of membranes composed of phosphatidylcholine, while wogonin does not affect it. Other flavones tested reduce membrane boundary potential, with this ability increasing among scutellarein, chrysin, apigenin, morin, fisetin, and luteolin. Molecular dynamics simulations demonstrate connection of alteration in boundary potential with the preferential orientation of intrinsic flavone dipole moments in membranes. We have also shown that flavones reduce the melting point of phosphatidylcholine, and this ability increases in the series of luteolin, morin, wogonin, scutellarein, apigenin, baicalein, chrysin, and fisetin. The introduction of baicalein, chrysin and fisetin also leads to a significant decrease in the sharpness of the lipid phase transition. We have hypothesized that the localization of flavones in the glycerol backbone or in the C1-C8 methylene region of lipid hydrocarbon chains leads to an increase in the area per lipid and, as a consequence, to an expansion of the lipid melting peak. Replacement of neutral phosphatidylcholine with negatively charged phosphatidylserine affects the membrane-modifying activity of flavones which given the externalization of phosphatidylserine on the surface of cancer cells may be crucial in the flavone anticancer effects.

The interaction of plant flavones with amphotericin B: Consequences for its pore-forming ability

The growth of antibiotic resistance to antifungal drugs contributes to the search for new ways to enhance their effectiveness and reduce toxicity. The undeniable advantage of polyene macrolide antibiotic amphotericin B (AmB) which ensures low pathogen resistance is its mechanism of action related to the formation of transmembrane pores in target lipid membranes. Here, we investigated the effects of plant flavones, chrysin, wogonin, baicalein, apigenin, scutellarein, luteolin, morin and fisetin on the pore-forming activity of AmB in the sterol-enriched membranes by electrophysiological assays. Сhrysin, wogonin, baicalein, apigenin, scutellarein, and luteolin were shown to decrease the AmB pore-forming activity in the bilayers composed of palmitoyloleylphosphocholine independently of their sterol composition. Morin and fisetin led to the increase and decrease in the AmB pore-forming activity in the ergosterol- and cholesterol-containing bilayers respectively. Differential scanning microcalorimetry of the gel-to-liquid crystalline phase transition of membrane forming lipids, molecular dynamics simulations, and absorbance spectroscopy revealed the possibility of direct interactions between AmB and some flavones in the water and/or in the lipid bilayer. The influence of these interactions on the antibiotic partitioning between aqueous solution and membrane and/or its transition between different states in the bilayer was discussed.

Experimental evidence for anti-metastatic actions of apigenin: a mini review.

Cancer metastasis is responsible for the majority of cancer-related deaths. Accordingly, to reduce metastasis remains a vital challenge in clinical practice, and phytochemicals have taken an attention as anti-metastatic agents. Apigenin, a plant flavone, showed anti-cancer effects against in various animal models, moreover its potentials inhibiting tumor metastasis have been reported. Herein, we analyzed the overall features at what apigenin inhibited metastasis and its action modes. We searched for articles in MEDLINE (Pubmed), EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) through March 2023. Total 6 animal studies presented anti-metastatic effects of apigenin using 5 difference experimental models, while the mechanisms involved modulations of epithelial-mesenchymal transition (EMT), matrix metalloproteinases (MMPs), angiogenesis, and various metastasis-related signaling pathways. This review provides an overall potential of apigenin as a candidate reducing the risk of cancer metastasis.

Apigenin enhances sorafenib anti-tumour efficacy in hepatocellular carcinoma

BackgroundThe “one drug-one target” paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore. MethodsWe used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 μM) and Sorafenib (1-10 μM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done. ResultsThe results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4. ConclusionsIn conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.

ROOT SPECIFIC METHYLATED FLAVONES PROTECT OF SCUTELLARIA BAICALENSIS

Plant specialized metabolites are small molecules known for their role in abiotic and biotic stress tolerance. Understanding of the individual functions of most of these metabolites remains unknown. A border of the root of annual plants is especially attractive to clarity how the plant roots withstand biotic and abiotic challenges. A main part of the metabolites in the root the plant Scutellaria baicalensis consists of the wide variety of methylated flavones. Eight most abundant of its, mono- and polymethylated, which present the beginning and end of the plant flavone biosynthesis pathway, respectively, were detected as phenoxide-ions over the root organs (bark, cambium, xylem and decayed core) by LС-MS. This inspection recovers their location within cambium and bark. The disposition of mono-methylated wogonin and oroxylin A with it’s the putative potency to form the o-quinon anions (reductants) provide chemical protection of the root from reactive oxygen species. The tetra- and penta-methylated flavones arrange a passive hydrophobic physical barrier of the root bark. Environment threats necessitate the plant to produce the methylated flavones, which resistance mechanisms are embedded in the structures of their molecules.

Luteolin inhibits herpes simplex virus 1 infection by activating cyclic guanosine monophosphate-adenosine monophosphate synthase-mediated antiviral innate immunity

BackgroundThe successive outbreaks of large-scale infectious diseases due to virus infection have been a major threat to human health in recent decades. Herpes simplex virus I (HSV-1) is a widely-disseminated DNA virus that infects the central nervous system to cause herpes labialis, keratitis and herpes simplex virus encephalitis (HSE), resulting in recurrent lifelong clinical or subclinical episodes. Luteolin is a plant flavone that has been extensively used in the treatment of various human diseases, including carcinogenesis, inflammation and chronic degenerative diseases. PurposeThe aim of this study was to investigate the antiviral molecular mechanism of luteolin against HSV-1 infection in vitro and in vivo. MethodsThe antiviral effect of luteolin in cell lines was examined by viral plaque assay, RT-qPCR, Western blot and time-of-addition assay. The interaction between luteolin and cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was evaluated by molecular modeling and semi-denaturing detergent agarose gel electrophoresis. The efficacy of luteolin on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. Cytokine expression and protein levels were examined by RT-qPCR, Western blot and ELISA. ResultsLuteolin inhibited the early process of HSV-1 infection, without affecting the infection of acyclovir-resistant HSV-1 strains. In addition, luteolin enhanced antiviral type I interferon production and activated the cytoplasmic DNA-sensing cGAS-stimulator of interferon gene (STING) pathway. Luteolin directly bound the active substrate binding site and promoted the oligomerization of cGAS. Luteolin also inhibited HSE-related weight loss, neurodegeneration and neuroinflammation in mice caused by HSV-1 infection. Furthermore, luteolin enhanced type I interferon expression and stimulated the cGAS-STING signaling pathway in vivo. ConclusionLuteolin inhibited the post-entry process of HSV-1 by activating the cGAS-STING pathway to promote antiviral interferon production. These results provided the rationale for luteolin as a potent cGAS activator and antiviral agent.

Possible anti-inflammatory, antioxidant, and neuroprotective effects of apigenin in the setting of mild traumatic brain injury: an investigation*

Objective Apigenin is a plant flavone proven with biological properties such as anti-inflammatory, antioxidant, and antimicrobial effects. This study, it was aimed to examine the possible anti-inflammatory, antioxidant, and neuroprotective effects of apigenin in the setting of the mild traumatic brain injury (TBI) model. Methods Wistar albino male rats were randomly assigned to groups: control (n = 9), TBI (n = 9), TBI + vehicle (n = 8), and TBI + apigenin (20 and 40 mg/kg, immediately after trauma; n = 6 and n = 7). TBI was performed by dropping a 300 g weight from a height of 1 m onto the skull under anesthesia. Neurological examination and tail suspension tests were applied before and 24 h after trauma, as well as Y-maze and object recognition tests, after that rats were decapitated. In brain tissue, luminol- and lucigenin-enhanced chemiluminescence levels and cytokine ELISA levels were measured. Histological damage was scored. Data were analyzed with one-way ANOVA. Results After TBI, luminol (p < .001) and lucigenin (p < .001) levels increased, and luminol and lucigenin levels decreased with apigenin treatments (p < .01–.001). The tail suspension test score increased with trauma (p < .01). According to the pre-traumatic values, the number of entrances to the arms (p < .01) in the Y-maze decreased after trauma (p < .01). In the object recognition test, discrimination (p < .05) and recognition indexes (p < .05) decreased with trauma. There was no significant difference among trauma apigenin groups in behavioral tests. Interleukin (IL)-10 levels, one of the anti-inflammatory cytokines, decreased with trauma (p < .05), and increased with 20 and 40 mg apigenin treatment (p < .001 and p < .01, respectively). The histological damage score in the cortex was decreased in the apigenin 20 mg treatment group significantly (p < .05), but the decrease observed in the apigenin 40 mg group was not significant. Conclusion The results of this study revealed that apigenin 20 and 40 mg treatment may have neuroprotective effects in mild TBI via decreasing the level of luminol and lucigenin and increasing the IL-10 levels. Additionally, apigenin 20 mg treatment ameliorated the trauma-induced cortical tissue damage.

Apigenin alleviates cancer drug Sorafenib induced multiple toxic effects in Swiss albino mice via anti-oxidative stress

Sorafenib is an FDA-approved chemotherapeutic drug used as standard therapy for advanced-stage cancers. However, Sorafenib-induced multiple adverse effects are a major limitation that directly impacts patients' physical and physiological well-being. Therefore, it is vital to identify agents that can lessen the associated adverse effects and enhance efficacy. Apigenin, a dietary plant flavone, is a bioactive-compound present in fruits and vegetables having anti-oxidant, anti-inflammatory, and anti-cancer properties. Our study aimed to investigate Sorafenib-induced toxic effects at genomic, cellular, and tissue level and the potential protective effects of Apigenin. To achieve our goal, we treated Swiss albino mice with Apigenin (50 mg/kg bw) alone or in combination with Sorafenib (40 mg/kg bw). Next, we performed DNA interaction, genotoxicity, oxidative damages, anti-oxidant activities, liver enzyme levels, and histopathological studies. We demonstrated that Apigenin and Sorafenib bind DNA via electrostatic interaction. Further, Sorafenib induces genetic, oxidative, and tissue damages characterized by an increase in chromosomal aberrations and micronucleus, reactive oxygen species (ROS) and reactive nitrogen species (RNS), oxidative and DNA damage, lipid peroxidation, and hepato-renal damages, and a decrease in antioxidant-enzymes. Interestingly, the Sorafenib-induced adverse effects were ameliorated by Apigenin. Our findings indicate that Apigenin has protective effects against Sorafenib-induced toxicity and could be combined with Sorafenib to lessen its adverse effects and enhance its efficacy. However, further pre-clinical and clinical studies are required to evaluate Apigenin's effectiveness with Sorafenib.

Abstract 2594: Reactivation of maspin by plant flavone apigenin through inhibition of class I HDACs and increase in p53 transcriptional activity in prostate cancer cells

Abstract Loss of tumor suppressors leads to acquisition of metastatic capability during prostate cancer progression leading to higher mortality. Maspin (SERPINB5) is a unique member of the serpin (serine protease inhibitor) family shown to regulate cell motility, migration and invasiveness. Loss of maspin is frequently identified in clinical prostate cancer specimens and prostate cancer cell lines, therefore novel therapeutic approaches to restore its expression are needed. We recently demonstrated that knockdown of class I HDACs increase maspin expression in prostate cancer cells [Mol Carcinog. 59(8):955-966, 2020]. Apigenin (4', 5, 7-trihydroxyflavone), a plant flavone has shown to possess anticancer properties and alters pathways that regulate tumor cell invasion and metastasis, however, the molecular basis of these effects remains unclear. We investigated whether apigenin has ability to restore maspin expression and contribute to the inhibition of metastasis. Treatment of human prostate cancer LNCaP and 22Rv1 cells, both harboring wild type p53, with 1-40 µM apigenin for 72 h resulted in a dose- and time- dependent decrease in cell invasion and migration with concurrent increase in maspin expression in the nuclear compartment. Since, p53 activates maspin promoter by binding directly to p53 consensus-binding site, we studied the effect of apigenin in potentially restoring p53-mediated maspin levels. Exposure of LNCaP and 22Rv1 cells with 5-20 μM of apigenin resulted in dose-dependent increase in maspin expression and p53 activation through acetylation at the Lys305 residue. These effects were associated with the inhibition of class I HDAC levels. Furthermore, apigenin withdrawal resulted in the loss of maspin expression and p53 acetylation in LNCaP cells. The increased apigenin-mediated p53 acetylation enhanced its binding on maspin promoter, which was associated with decrease in cell invasion and migration. Apigenin treatment also caused accumulation of acetylated histone H3 in total cellular chromatin, increasing accessibility to bind with the promoter sequences of maspin, consistent with the effects elicited by HDAC inhibitor, Tricostatin A. Similar observations of inhibition of class I HDACs and increase in p53 transcriptional activity were noted after feeding apigenin at 20- and 50- µg/day to 22Rv1 tumor xenograft implanted in athymic nude mice. Our results demonstrate that apigenin-mediated increase in maspin expression together with downregulation of class I HDACs, increases p53 activation resulting in decreased invasiveness and migration capabilities in prostate cancer. Citation Format: Eswar Shankar, Albert Lee, Rajnee Kanwal, Sanjay Gupta. Reactivation of maspin by plant flavone apigenin through inhibition of class I HDACs and increase in p53 transcriptional activity in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2594.

Does Oral Apigenin Have Real Potential for a Therapeutic Effect in the Context of Human Gastrointestinal and Other Cancers?

Apigenin (4′, 5, 7-trihydroxyflavone) is a plant flavone that has been found to have various actions against cancer cells. We evaluated available evidence to determine whether it is feasible for apigenin to have such effects in human patients.Apigenin taken orally is systemically absorbed and recirculated by enterohepatic and local intestinal pathways. Its bioavailability is in the region of 30%. Once absorbed from the oral route it reaches maximal circulating concentration (Cmax) after a time (Tmax) of 0.5–2.5h, with an elimination half-life (T1/2) averaging 2.52 ± 0.56h.Using a circulating concentration for efficacy of 1–5μmol/L as the target, we evaluated data from both human and rodent pharmacokinetic studies to determine if a therapeutic concentration would be feasible. We find that oral intake of dietary materials would require heroic ingestion amounts and is not feasible. However, use of supplements of semi-purified apigenin in capsule form could reach target blood levels using amounts that are within the range currently acceptable for other supplements and medications. Modified formulations or parenteral injection are suitable but may not be necessary.Further work with direct studies of pharmacokinetics and clinical outcomes are necessary to fully evaluate whether apigenin will contribute to a useful clinical strategy, but given emerging evidence that it may interact beneficially with chemotherapeutic drugs, this is worthy of emphasis. In addition, more effective access to intestinal tissues from the oral route raises the possibility that apigenin may be of particular relevance to gastrointestinal disorders including colorectal cancer.

Plant flavones enrich rhizosphere Oxalobacteraceae to improve maize performance under nitrogen deprivation.

Beneficial interactions between plant roots and rhizosphere microorganisms are pivotal for plant fitness. Nevertheless, the molecular mechanisms controlling the feedback between root architecture and microbial community structure remain elusive in maize. Here, we demonstrate that transcriptomic gradients along the longitudinal root axis associate with specific shifts in rhizosphere microbial diversity. Moreover, we have established that root-derived flavones predominantly promote the enrichment of bacteria of the taxa Oxalobacteraceae in the rhizosphere, which in turn promote maize growth and nitrogen acquisition. Genetic experiments demonstrate that LRT1-mediated lateral root development coordinates the interactions of the root system with flavone-dependent Oxalobacteraceae under nitrogen deprivation. In summary, these experiments reveal the genetic basis of the reciprocal interactions between root architecture and the composition and diversity of specific microbial taxa in the rhizosphere resulting in improved plant performance. These findings may open new avenues towards the breeding of high-yielding and nutrient-efficient crops by exploiting their interaction with beneficial soil microorganisms.

Plant flavone Chrysin as an emerging histone deacetylase inhibitor for prosperous epigenetic-based anticancer therapy.

Aberrations in epigenetic mechanisms provide a fertile platform for tumour initiation and progression. Thus, agents capable of modulating the epigenetic environment of neoplasms will be a valuable addition to the anticancer therapeutics. Flavones are emerging as befitting anticancer agents due to their inherent antioxidant activity and the ability to restrain epi-targets namely histone deacetylases (HDACs). HDACs have broader implications in pathogenesis of various cancers. Chrysin, a flavone possessing the ability to inhibit HDACs could prove as a potential anticancer drug. Thus, in this article we focussed on Chrysin and its distinct antineoplastic effect against bellicose malignancies including lung, colorectal, cervical, gastric, melanoma, hepatocellular carcinoma and breast cancer. The underlying signalling cascades triggered by Chrysin for inducing cytotoxic effect in these cancer models are discussed. Importantly, approaches towards combinatorial treatments by Chrysin and commercial anticancer agents are taken into account. The downstream molecular mechanism aroused by combined therapy for abrogating onerous cancer chemoresistance is delineated as well. Moreover, the nano-combinatorial approach involving co-encapsulation of Chrysin with other herbal and non-herbal agents for clinical excellence is elucidated.

LC-MS/MS Determination of Apigenin in Rat Plasma and Application to Pharmacokinetic Study.

Apigenin, a natural plant flavone, has been shown to possess a variety of biological properties. In this report, a highly selective and sensitive LC-MS/MS method was developed and validated for the determination of apigenin in rat plasma. Analysts were separated on the HSS T3 column (1.8 μm 2.1×100 mm) using acetonitrile and 0.1% formic acid in 2mM ammonium acetate buffer at a supply rate of 0.200 mL/min as eluent in gradient model. Plasma samples were treated by protein precipitation using acetonitrile for the recovery ranging from 86.5% to 90.1% for apigenin. The calibration curves followed linearity in the concentration range of 0.50-500ng/mL. The inter-day and intra-day precisions at different QC levels within 13.1% and the accuracies ranged from -10.6% to 8.6%. The assay has been successfully applied to the pharmacokinetic study of apigenin in rats.

Apigenin, A Plant Flavone Playing Noble Roles in Cancer Prevention Via Modulation of Key Cell Signaling Networks.

Cancer is a global health problem and the continuous rise in incidence and mortality due to cancer carries a real economic burden to all countries. Accumulation of genetic mutation, exposure of environmental carcinogens and food habits due to change in lifestyles are the key reasons for cancer. Targeting cancer cells, we need a multitargeting molecule with low/no toxicity. To review the current update of the research status of chemopreventive/therapeutic molecule, Apigenin. Compare the results of the published articles and granted patents on this compound. We also discuss the pros and cons of the present research and future direction. Cancer cells have characteristic alterations and dysregulation of various cell signaling pathways that control cell homeostasis, proliferation, motility, and survival in normal cells. Natural flavonoids are the compounds well known for their anti-inflammatory, anti-oxidant, and anti-cancerous properties. Apigenin, along with several other physiological effects, has a very low intrinsic toxicity and striking effects on the proliferation of cancer cells. Interestingly, this multitargeting molecule is getting wide acceptance among researchers. It is evident from the recent patents filed in this compound. At present, three patents have been granted only on the anticancer properties of apigenin. This mini-review will explain the present research status of apigenin and will further shine some light on how apigenin performs its anti-cancerous actions by interfering with the key cellsignaling pathways.

Comparative Analysis of Luteolin and Luteolin-7-O-Glucoside on anti-Atherogenesis in ApoE Knockout Mice with Hyperhomocysteinemia

AbstractLuteolin is a naturally occurring flavone that reportedly has anti-inflammatory effect. Flavones in plants are usually present in the form of glucosides, although occasionally they are found as aglycones. The bioavailability of flavones may differ when consumed as either aglycones or glucosides. Nonetheless, numerous studies focused on the biological activity of flavonoid aglycones or that in vitro. These findings are supporting reason to compare the anti-atherogenic effect of aglycone and glucoside forms of flavones in vivo. Male ApoE knockout mice (n = 28, 6-week-old) were divided randomly into 4 groups of 7 mice: negative control group, homocysteine control group, luteolin and luteolin7-O-glucoside groups with homocysteine. All animals were fed by a high-fat diet, modified by AIN-93, containing 0.5% of cholesterol and 45% of fat. Luteolin and luteolin-7-O-glycoside were given daily by gavage for 5 weeks (50 mg/kg BW, respectively). To induce hyperhomocysteinemia, homocysteine was provided as a drinking water (0.9g/L). Administration of homocysteine did not affect body weight gain, feed intake and feed efficiency ratio among groups. Homocysteine feeding sharply increased serum concentrations of homocysteine and triglyceride as well as adhesion molecules including monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1, which were attenuated by the administration of luteolin and luteolin-7-O-glucoside (p &lt; 0.05). Homocysteine administration produced development of atherosclerotic process by the induction of hepatic inducible nitric oxide synthase and cyclooxygenase-2 as well as aortic intercellular adhesion molecule expressions along with diminished expressions of antioxidative enzymes, such as hepatic glutathione reductase (GR), aortic GR and glutathione peroxidase (p &lt; 0.05). Administration of both flavones down-regulated expressions of inflammatory mediators and adhesion molecules as well as up-regulated expressions of antioxidative enzymes (p &lt; 0.05). These data were in accordance with the histopathological observations which were analyzed by hematoxylin and eosin (H&amp;E) stain and immunohistochemistry. In a comparison of both agents, luteolin more potently attenuated inflammation and oxidative stress than luteolin-7-O-glucoside. These results exhibit that luteolin and luteolin-7-O-glycoside ameliorated atherogenic processes through the regulation of inflammation and oxidative stress in ApoE knockout mice with hyperhomocysteinemia. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government of MOE (No 201704340001).

The regulation of protein kinase casein kinase II by apigenin is involved in the inhibition of ultraviolet B-induced macrophage migration inhibitory factor-mediated hyperpigmentation.

Ultraviolet (UV) radiation elicits melanogenesis and pigmentation in the skin. Apigenin (4',5,7-trihydroxyflavone [AGN]) is a plant flavone contained in various herbs, fruits, and vegetables. We herein investigated antimelanogenic properties of AGN and the molecular mechanisms of the action of AGN. In UVB-treated mice, AGN inhibited cutaneous hyperpigmentation and macrophage migration inhibitory factor (MIF) expression as a melanogenesis-related key factor. In mouse keratinocytes, AGN inhibited the expression of MIF and also the related factors (e.g., stem cell factor and proteinase-activated receptor 2) induced by MIF. In addition to ellagic acid as a casein kinase II (CK2) inhibitor, AGN suppressed CK2 enzymatic activity and UVB-induced CK2 expression and subsequent phosphorylation of IκB and MIF expression. These results suggest that AGN inhibits UVB-induced hyperpigmentation through the regulation of CK2-mediated MIF expression in keratinocytes.

Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives

Mammalian Sirtuin 6 (Sirt6) is an NAD+-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an alternative binding site at the active site entrance. Based on these insights, we identified isoquercetin as a ligand that can discriminate both sites and thus activates Sirt6 with increased specificity. Furthermore, we find that quercetin derivatives that inhibit rather than activate Sirt6 exploit the same general Sirt6 binding site as the activators, identifying it as a versatile allosteric site for Sirt6 modulation. Our results thus provide a structural basis for Sirtuin effects of quercetin-related compounds and helpful insights for Sirt6-targeted drug development.

Chrysoeriol mediates mitochondrial protection via PI3K/Akt pathway in MPP+ treated SH-SY5Y cells

Chrysoeriol is a plant flavone extracted from the roots and leaves of the genus Phyllanthus. Although many biological properties of chrysoeriol have been reported, such as its antioxidant and anti-inflammatory activities, the effects of chrysoeriol on the cellular models of Parkinson's disease (PD) have not yet been elucidated. In the present study, we aimed to investigate whether chrysoeriol prevents neurotoxicity induced by 1-methyl-4-phenylpyridinium iodide (MPP+) in SH-SY5Y cells, a typical in vitro PD model. The cell viability was measured by MTT assay. The morphological changes of apoptotic cell nuclei were observed by Hoechst 33,342 staining. The expression of Bax, Bcl-2 and Caspase-3 were detected by western blot analysis. The mitochondria location in the cells was observed by Mitotracker staining. Mitochondrial membrane potential was evaluated by the JC-10 assay. Treatment with MPP+ significantly caused a decrease in the viability of cells and an increase in apoptosis, as evidenced by the upregulation of apoptotic cells, caspase-3 activity and antiapoptotic ratio. These effects were all reversed by pretreatment with chrysoeriol in SH-SY5Y cells. Moreover, pretreatment with chrysoeriol markedly mitigated the MPP+-caused increases in the levels of the prosurvial signaling proteins, phosphorylated Akt and phosphorylated mTOR. The presence of a specific PI3K inhibitor, wortmannin, particularly abolished the chrysoeriol-induced activation of Akt phosphorylation and prevented the chrysoeriol-induced survival effect. These results indicate that the neuroprotective effect of chrysoeriol against MPP+ treatment requires the activation of PI3K/Akt pathway. Ultimately, chrysoeriol could be a promising therapeutic agent for the further experiment on the treatment of PD.

Biosynthesis of cannflavins A and B from Cannabis sativa L

In addition to the psychoactive constituents that are typically associated with Cannabis sativa L., there exist numerous other specialized metabolites in this plant that are believed to contribute to its medicinal versatility. This study focused on two such compounds, known as cannflavin A and cannflavin B. These prenylated flavonoids specifically accumulate in C. sativa and are known to exhibit potent anti-inflammatory activity in various animal cell models. However, almost nothing is known about their biosynthesis. Using a combination of phylogenomic and biochemical approaches, an aromatic prenyltransferase from C. sativa (CsPT3) was identified that catalyzes the regiospecific addition of either geranyl diphosphate (GPP) or dimethylallyl diphosphate (DMAPP) to the methylated flavone, chrysoeriol, to produce cannflavins A and B, respectively. Further evidence is presented for an O-methyltransferase (CsOMT21) encoded within the C. sativa genome that specifically converts the widespread plant flavone known as luteolin to chrysoeriol, both of which accumulate in C. sativa. These results therefore imply the following reaction sequence for cannflavins A and B biosynthesis: luteolin ► chrysoeriol ► cannflavin A and cannflavin B. Taken together, the identification of these two unique enzymes represent a branch point from the general flavonoid pathway in C. sativa and offer a tractable route towards metabolic engineering strategies that are designed to produce these two medicinally relevant Cannabis compounds.

The roles of synovial hyperplasia, angiogenesis and osteoclastogenesis in the protective effect of apigenin on collagen-induced arthritis

Apigenin (API) is a plant flavone that is known to exert a protective effect in rheumatoid arthritis (RA), which is a chronic autoimmune disease. However, the molecular mechanism for API's protective effect against RA is still unclear. Here, a collagen-induced arthritis (CIA) mouse model was used to assess the protective effect of API on RA. Histomorphological studies, immunohistochemistry, RT-PCR, and western blot were conducted to elucidate the roles of synovial hyperplasia, angiogenesis, and osteoclastogenesis in the protective effect of API on RA. Fibroblast-like synoviocytes (FLSs) were isolated to measure the effect of API on FLS proliferation and apoptosis. API exhibited a significant protective effect in CIA mice in a dose- and time-dependent manner. An increase in apoptosis and decrease in proliferation were observed after the API treatment in FLSs, suggesting that API might inhibit synovial hyperplasia. Moreover, CIA angiogenesis was repressed by API via down-regulation of VEGF and VEGFR. Furthermore, API regulated the osteoclastogenesis-associated RANKL/RANK/OPG system in CIA mice. Therefore, API inhibits CIA by repressing synovial hyperplasia, angiogenesis, and osteoclastogenesis. This suggested that API might be a putative low toxicity candidate drug for RA treatment.