Scutellarein: a review of chemistry and pharmacology.

OBJECTIVES: To get a better understanding of the scientific values of flavone scutellarein (SCT), and to encourage its applications in human health, the current review systematically summarizes the natural observation, biosynthesis, synthesis, pharmacology, pharmacokinetics, and recent synthetic advances. KEY FINDINGS: Scientific sources to search for references included Google Scholar, Scopus, Web of Science, PubMed, Sci-Finder, and journal websites. The references have been collected from the 1970s to the present. "Scutellarein" is the most meaningful keyword to search for publications, in which it was used alone or in combination with other keywords. SUMMARYS: SCT as a hydrophobic flavonoid can be found in various medicinal plants of the families Lamiaceae, Compositae, and Verbenaceae. Flavone SCT has drawn much interest due to its wide pharmacological effects, such as anticancer, anti-inflammation, antioxidant, antiobesity, and vasorelaxant. The SCT treatments also possessed a lot of positive results in the neuron, liver, heart, lung, kidney, bone, and skin protective experiments, and human sperm function enhancement. Its underlying mechanism of action may relate to the apoptotic program and cytokine inhibition by regulating a panel of the signaling pathway, e.g., NF-κB (nuclear factor kappa B)/MAPK (mitogen-activated protein kinase), IκBa (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitors alpha)/NF-κB, TRAF2 (tumor necrosis factor receptor-associated factor 2)/NF-κB, and PTEN (phosphatase and tension homologue deleted on chromosome 10)/Akt (protein kinase B)/NF-κB. In addition, the metabolic actions and synthetic derivative promotions of SCT were mostly based on the substitution of hydroxyl groups. Collectively, the studies that aim to highlight the role of scutellarein in preclinical and clinical treatments are urgently needed. More and more experiments to improve its bioavailability are expected.

A Cocktail of Natural Compounds Holds Promise for New Immunotherapeutic Potential in Head and Neck Cancer.

OBJECTIVE: To obtain detailed understanding on the gene regulation of natural compounds in altering prognosis of head and neck squamous cell carcinomas (HNSC). METHODS: Gene expression data of HNSC samples and peripheral blood mononuclear cells (PBMCs) of HNSC patients were collected from Gene Expression Omnibus (GEO). Differential gene expression analysis of GEO datasets were achieved by the GEO2R tool. Common differentially expressed gerres (DEGs) were screened by comparing DEGs of HNSC with those of PBMCs. The combination was further analyzed for regulating pathways and biological processes that were affected. RESULTS: Totally 110 DEGs were retrieved and identified to be involved in biological processes related to tumor regulation. Then 102 natural compounds were screened for a combination such that the expression of all 110 commonly DEGs was altered. A combination of salidroside, ginsenoside Rd, oridonin, britanin, and scutellarein was chosen. A multifaceted, multi-dimensional tumor regression was showed by altering autophagy, apoptosis, inhibiting cell proliferation, angiogenesis, metastasis and inflammatory cytokines production. CONCLUSIONS: This study has helped develop a unique combination of natural compounds that will markedly reduce the propensity of development of drug resistance in tumors and immune evasion by tumors. The result is crucial to developing a combinatorial natural therapeutic cocktail with accentuated immunotherapeutic potential.

Scutellarein alleviates chronic obstructive pulmonary disease through inhibition of ferroptosis by chelating iron and interacting with arachidonate 15-lipoxygenase.

Ferroptosis, an iron-dependent cell death characterized by lethal lipid peroxidation, is involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, ferroptosis inhibition represents an attractive strategy for COPD therapy. Herein, we identified natural flavonoid scutellarein as a potent ferroptosis inhibitor for the first time, and characterized its underlying mechanisms for inhibition of ferroptosis and COPD. In vitro, the anti-ferroptotic activity of scutellarein was investigated through CCK8, real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, flow cytometry, and transmission electron microscope (TEM). In vivo, COPD was induced by lipopolysaccharide (LPS)/cigarette smoke (CS) and assessed by changes in histopathological, inflammatory, and ferroptotic markers. The mechanisms were investigated by RNA-sequencing (RNA-seq), electrospray ionization mass spectra (ESI-MS), local surface plasmon resonance (LSPR), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular dynamics. Our results showed that scutellarein significantly inhibited Ras-selective lethal small molecule (RSL)-3-induced ferroptosis and mitochondria injury in BEAS-2B cells, and ameliorated LPS/CS-induced COPD in mice. Furthermore, scutellarein also repressed RSL-3- or LPS/CS-induced lipid peroxidation, GPX4 down-regulation, and overactivation of Nrf2/HO-1 and JNK/p38 pathways. Mechanistically, scutellarein inhibited RSL-3- or LPS/CS-induced Fe2+ elevation through directly chelating Fe2+ . Moreover, scutellarein bound to the lipid peroxidizing enzyme arachidonate 15-lipoxygenase (ALOX15), which resulted in an unstable state of the catalysis-related Fe2+ chelating cluster. Additionally, ALOX15 overexpression partially abolished scutellarein-mediated anti-ferroptotic activity. Our findings revealed that scutellarein alleviated COPD by inhibiting ferroptosis via directly chelating Fe2+ and interacting with ALOX15, and also highlighted scutellarein as a candidate for the treatment of COPD and other ferroptosis-related diseases.

Scutellarein regulates the PTEN/AKT/NFκB signaling pathway to reduce pirarubicin related liver inflammation.

The side effects of chemotherapy drugs have been hindering the progress of tumor treatment. The liver is the metabolic site of most drugs, which leads to the frequent occurrence of liver injury. Classical chemotherapy drugs such as pirarubicin (THP) can also cause dose­dependent hepatotoxicity, and the related mechanism is closely related to liver inflammation. Scutellarein (Sc) is a potential Chinese herbal monomer exhibiting liver protection activity, which can effectively alleviate the liver inflammation caused by obesity. In the present study, THP was used to establish a rat model of hepatotoxicity, and Sc was used for treatment. The experimental methods used included measuring body weight, detecting serum biomarkers, observing liver morphology with H&E staining, observing cell apoptosis with TUNEL staining, and detecting the expression of PTEN/AKT/NFκB signaling pathways and inflammatory genes with PCR and western blotting. However, whether Sc can inhibit the liver inflammation induced by THP has not been reported. The experimental results showed that THP led to the upregulation of PTEN and the increase of inflammatory factors in rat liver, while Sc effectively alleviated the aforementioned changes. It was further identified in primary hepatocytes that Sc can effectively inhabited PTEN, regulate AKT/NFκB signaling pathway, inhibit liver inflammation and ultimately protect the liver.

Anti-arboviral activity and chemical characterization of hispidulin and ethanolic extracts from Millingtonia hortensis L.f. and Oroxylum indicum (L.) Kurz (Bignoniaceae).

Millingtonia hortensis L.f. and Oroxylum indicum (L.) Kurz (Bignoniaceae) are native species from the Asian continent. They are popularly used in traditional medicine and their extracts are rich in flavonoids. In this work, ethanolic extracts of stems and leaves of these species were evaluated against the Chikungunya, Zika and Mayaro virus. The extracts were subjected to analysis by ultra-efficient liquid chromatography coupled to mass spectrometry. Additionally, M. hortensis leaves extract was fractionated, leading to the isolation of hispidulin. Anti-arboviral activity against the three viruses was detected for M. hortensis leaves extract with EC50 ranging from 37.8 to 134.1 µg/mL and for O. indicum stems extract with EC50 ranging from 18.6 to 55.9 µg/mL. Hispidulin inhibited viral cytopathic effect of MAYV (EC50 value 32.2 µM) and CHIKV (EC50 value 78.8 µM). In LC-DAD-ESI-MS/MS analysis we characterized 25 flavonoids confirming once again the presence of these substances in extracts of these species.

Scutellarein stimulates human sperm function by increasing the levels of intracellular calcium and tyrosine phosphorylation.

As a kind of flavonoid, scutellarein is widely used to protect against various human diseases. Although the protective effects of scutellarein have been well studied, its influence on human reproduction remains unknown. In this research, we evaluated the effect of scutellarein on human sperm functions in vitro. Three different concentrations of scutellarein (1, 10, 100 µM) were applied to ejaculated human sperm. Fertilisation-essential functions, as well as the intracellular calcium concentration ([Ca2+ ]i ) and protein-tyrosine phosphorylation, two factors which are vital for sperm function regulation, were evaluated. The results demonstrated that all concentrations of scutellarein utilised in this study could significantly increase sperm spontaneous capacitation and acrosome reaction through the enhancement of [Ca2+ ]i . Besides, the level of tyrosine phosphorylation of sperm could also be increased by scutellarein. Meanwhile, the sperm motility could be improved by 10 and 100 µM scutellarein, which also make a significant enhancement in sperm penetration ability and hyperactivation. This is one of the limited studies showing the regulation of scutellarein on human spermatozoa functions and is helpful to enrich its application.

Scutellarein attenuates atopic dermatitis by selectively inhibiting transient receptor potential vanilloid 3 channels.

BACKGROUND AND PURPOSE: Atopic dermatitis (AD) is one of the most common chronic inflammatory cutaneous diseases with unmet clinical needs. As a common ingredient found in several medicinal herbs with efficacy on cutaneous inflammatory diseases, Scutellarein (Scu) has been shown to possess anti-inflammatory and anti-proliferative activities. We aimed to evaluate the therapeutic efficacy of Scu against AD and its underlying molecular mechanism. EXPERIMENTAL APPROACH: Efficacy of Scu on AD was evaluated in 2,4-dinitrofluorobenzene (DNFB) and carvacrol-induced dermatitis mouse models. Cytokine mRNA and serum IgE levels were examined using qPCR and ELISA, respectively. Voltage clamp recordings were used to measure currents mediated by transient receptor potential (TRP) channels. In silico docking, site-direct mutagenesis, and covalent modification were used to explore the binding pocket of Scu on TRPV3. KEY RESULTS: Subcutaneous administration of Scu efficaciously suppresses DNFB and carvacrol-induced pruritus, epidermal hyperplasia and skin inflammation in wild type mice but has no additional benefit in Trpv3 knockout mice in the carvacrol model. Scu is a potent and selective TRPV3 channel allosteric negative modulator with an apparent affinity of 1.18 µM. Molecular docking coupled with site-direct mutagenesis and covalent modification of incorporated cysteine residues demonstrate that Scu targets the cavity formed between the pore helix and transmembrane helix S6. Moreover, Scu attenuates endogenous TRPV3 activity in human keratinocytes and inhibits carvacrol-induced proliferative and proinflammatory responses. CONCLUSION AND IMPLICATIONS: Collectively, these data demonstrate that Scu ameliorates carvacrol-induced skin inflammation by directly inhibiting TRPV3, and TRPV3 represents a viable therapeutic target for AD treatment.

Synthesis and biological evaluation of scutellarein derivatives as neuroprotective agents via activating Nrf2/HO-1 pathway.

Oxidative stress has been considered as the main factor of neurodegenerative diseases. Activation of the Nrf2/HO-1 pathway, as one of the most crucial endogenous protection systems, was regarded as an effective strategy to against oxidative injury. Here, a series of phosphate esters or phosphonates of scutellarein derivatives were designed, synthesized and evaluated on SH-SY5Y cell lines to examine neuroprotective effects against H2O2 induced damage. Among them, compound 16d exhibited more potent cytoprotective effect than the lead compound scutellarin. Preliminary mechanism studies showed that compound 16d could prevent H2O2 induced neuronal apoptosis, significantly decrease ROS generation, elevate SOD and reduce MDA levels in a dose-dependent manner in SH-SY5Y cell lines. Furthermore, western blot assay disclosed that compound 16d could activate Nrf2, and increase the expression of its downstream genes HO-1 in a concentration-dependent manner, thus displaying potent neuroprotective activity. Overall, these findings demonstrated that compound 16d, as a promising neuroprotective agent, deserved further development.

Scutellarein induces apoptosis and inhibits proliferation, migration, and invasion in ovarian cancer via inhibition of EZH2/FOXO1 signaling.

Scutellarein, a flavone found in the perennial herb Scutellaria baicalensis, has antitumorigenic activity in multiple human cancers. However, whether scutellarein can attenuate ovarian cancer (OC) is unclear. This study investigated the effects of scutellarein in OC. In vitro cell viability was assessed using MTT assay whereas proliferation was assessed using 5-ethynyl-2'-deoxyuridine and colony formation assays. Cell apoptosis was detected by an Annexin V-fluorescein isothiocyanate/propidium iodide assay. Wound-healing and Transwell assays were used to determine cell migration and invasion. The differential expression of enhancer of zeste homolog 2 (EZH2) and forkhead box protein O1 (FOXO1) was measured by Quantitative real-time PCR and western blot analysis. We found that scutellarein inhibited viability, migration, invasion of A2780 and SKOV-3 cells, and reduced the expression of EZH2 in OC cells. In addition, FOXO1 was downregulated in OC tissues and cells and negatively regulated by EZH2. Also, scutellarein inhibited tumor growth and metastasis in vivo. In conclusion, scutellarein alleviates OC by the regulation of EZH2/FOXO1 signaling.

Improve the Biosynthesis of Baicalein and Scutellarein via Manufacturing Self-Assembly Enzyme Reactor In Vivo.

Baicalein and scutellarein are bioactive flavonoids isolated from the traditional Chinese medicine Scutellaria baicalensis Georgi; however, there is a lack of effective strategies for producing baicalein and scutellarein. In this study, we developed a sequential self-assembly enzyme reactor involving two enzymes in the baicalein pathway with a pair of protein-peptide interactions in E. coli. These domains enabled us to optimize the stoichiometry of two baicalein biosynthetic enzymes recruited to be an enzymes complex. This strategy reduces the accumulation of intermediates and removes the pathway bottleneck. With this strategy, we successfully promoted the titer of baicalein by 6.6-fold (from 21.6 to 143.5 mg/L) and that of scutellarein by 1.4-fold (from 84.3 to 120.4 mg/L) in a flask fermentation, respectively. Furthermore, we first achieved the de novo biosynthesis of baicalein directly from glucose, and the strain was capable of producing 214.1 mg/L baicalein by fed-batch fermentation. This work provides novel insights for future optimization and large-scale fermentation of baicalein and scutellarein.

Cytotoxicity and antibacterial activity of scutellarein and carajurone-enriched fraction obtained from the hydroethanolic extract of the leaves of Fridericia chica (Bonpl.) L.G. Lohmann.

The hydroethanolic extract obtained from the dry leaves of Fridericia chica (HEFc) underwent several fractionations by different chromatographic techniques. The ethyl acetate and dichloromethane fraction were subjected to phytochemical analysis, resulting in the identification and isolation of scutellarein (1) and in a fraction rich in carajurone (2). They were tested for cytotoxicity in CHO-K1 and the antibacterial activity and mode of action by in vitro assays. The HEFc and scutellarein (1) presented no cytotoxicity. The results showed good antibacterial effect of HEFc against Streptococcus pyogenes and Staphylococcus aureus and moderate activity for Staphylococcus epidermidis, Pseudomonas aeruginosa and Salmonella typhimurium. The fraction containing the compound carajurone (2) showed good activity against Staphylococcus aureus and Staphylococcus epidermidis and moderate activity against Streptococcus pyogenes. Scutellarein (1) showed no activity against the bacteria tested. HEFc antibacterial mode of action appeared to be associated with changes in the permeability of bacterial membranes and nucleotide leakage.

Scutellarein inhibits BLM-mediated pulmonary fibrosis by affecting fibroblast differentiation, proliferation, and apoptosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease that has a poor prognosis. Scutellarein, which is extracted from the traditional Chinese medicine Erigeron breviscapus, is used to treat a variety of diseases; however, the use of scutellarein for the treatment of pulmonary fibrosis and the related mechanisms of action have not been fully explored. METHODS: This study was conducted using a well-established mouse model of pulmonary fibrosis induced by bleomycin (BLM). The antifibrotic effects of scutellarein on histopathologic manifestations and fibrotic marker expression levels were examined. The effects of scutellarein on fibroblast differentiation, proliferation, and apoptosis and on related signaling pathways were next investigated to demonstrate the underlying mechanisms. RESULTS: In the present study, we found that scutellarein alleviated BLM-induced pulmonary fibrosis, as indicated by histopathologic manifestations and the expression levels of fibrotic markers. Further data demonstrated that the ability of fibroblasts to differentiate into myofibroblasts was attenuated in scutellarein-treated mice model. In addition, we obtained in vitro evidence that scutellarein inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling, inhibited cellular proliferation by repressing PI3K/Akt signaling, and increased apoptosis of fibroblasts by affecting Bax/Bcl2 signaling. DISCUSSION: In general, scutellarein might exert therapeutic effects on pulmonary fibrosis by altering the differentiation, proliferation, and apoptosis of fibroblasts. Although scutellarein has been demonstrated to be safe in mice, further studies are required to investigate the efficacy of scutellarein in patients with IPF.

The Active Ingredients Identification and Antidiarrheal Mechanism Analysis of Plantago asiatica L. Superfine Powder.

Plantago asiatica L. is a natural medicinal plant that has been widely used for its various pharmacological effects such as antidiarrheal, anti-inflammatory, and wound healing. This study aims to explore the antidiarrheal active ingredients of Plantago asiatica L. that can be used as quality markers to evaluate P. asiatica L. superfine powder (PSP). Molecular docking experiment was performed to identify the effective components of P. asiatica L., which were further evaluated by an established mouse diarrhea model. Na+/K+-ATPase and creatine kinase (CK) activities and the Na+/K+ concentrations were determined. The gene expression of ckb and Atp1b3 was detected. PSP was prepared and evaluated in terms of the tap density and the angle of repose. The structures of PSPs of different sizes were measured by infrared spectra. The active ingredient contents of PSPs were determined by HPLC. The results indicated that the main antidiarrheal components of P. asiatica L. were luteolin and scutellarein that could increase the concentration of Na+ and K+ by upregulating the activity and gene level of CK and Na+/K+-ATPase. In addition, luteolin and scutellarein could also decrease the volume and weight of small intestinal contents to exert antidiarrheal activity. Moreover, as the PSP size decreased from 6.66 to 3.55 µm, the powder tended to be amorphous and homogenized and of good fluidity, the content of active compounds gradually increased, and the main structure of the molecule remained steady. The optimum particle size of PSP with the highest content of active components was 3.55 µm, and the lowest effective dose for antidiarrhea was 2,000 mg/kg. Therefore, the antidiarrheal active ingredients of PSP were identified as luteolin and scutellarein that exert antidiarrheal activity by binding with Na+/K+-ATPase. PSP was successfully prepared and could be used as a new dosage form for the diarrhea treatment.

Scutellarein suppresses Aß-induced memory impairment via inhibition of the NF-κB pathway in vivo and in vitro.

The flavonoid compound scutellarin (Scu) is a traditional Chinese medicine used to treat a variety of diseases; however, the use of scutellarein (Scue), the hydrolysate of Scu, and its mechanisms of action in Alzheimer's disease (AD) have not been fully elucidated. In the present study, the effects of Scue on amyloid ß (Aß)-induced AD-like pathology were investigated. An in vitro model of inflammation and an aged rat model were used to confirm the effects of Scue. In vitro MTT assays and flow cytometry were used to assess the effects of Scue on cell viability and apoptosis, respectively. A Morris water maze was used to evaluate spatial learning and memory, and the levels of Aß deposition, superoxide dismutase, malondialdehyde, apoptosis, neuro-inflammatory factors and nuclear factor-κB (NF-κB) activation in hippocampal tissues in vivo were measured to determine the effect of Scue in AD. Scue may be protective, as it decreased the apoptosis of hippocampal cells in vitro, inhibited Aß-induced cognitive impairment, suppressed hippocampal neuro-inflammation and suppressed activation of NF-κB in vivo. Therefore, Scue may be a useful agent for the treatment of Aß-associated pathology in the central nervous system through inhibition of the protein kinase B/NF-κB signaling pathway and thus, future studies are required to investigate the efficacy of Scue in patients with AD.

Autophagy as a molecular target for cancer treatment.

Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.

Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer.

Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of CD44, PROM1, SOX9, and SNAI1 genes (1.83 ± 0.34, 2.54 ± 0.51, 2.03 ± 0.15, and 6.12 ± 1.59 times) and high self-renewal capability (352 ± 55 colonies compared to 253 ± 42 for 2D). Incubation with OPE (1 mg/mL) significantly inhibited cell proliferation and modulated cancer stemness and self-renewal ability: colony formation, ALDH1 activity, and the expression of cancer stemness biomarkers PROM1 and LGR5 were significantly reduced (0.66 ± 0.15 and 0.51 ± 0.14 times, respectively). Among all PMFs, tangeretin was the most efficient in targeting the CSC population by decreasing colony formation and the expression of PROM1 and LGR5. Scutellarein tetramethylether was shown to modulate markers of mesenchymal/metastatic transition (increasing CDH1 and reducing ZEB1 and SNAI1) and nobiletin was capable of downregulating PROM1 and SNAI1 expression. Importantly, all PMFs and OPE were shown to synergistically interact with 5-fluorouracil, improving the antiproliferative response of this drug.

Production of plant-specific flavones baicalein and scutellarein in an engineered E. coli from available phenylalanine and tyrosine.

Baicalein and scutellarein are bioactive flavones found in the medicinal plant Scutellaria baicalensis Georgi, used in traditional Chinese medicine. Extensive previous work has demonstrated the broad biological activity of these flavonoids, such as antifibrotic, antiviral and anticancer properties. However, their supply from plant material is insufficient to meet demand. Here, to provide an alternative production source and increase production levels of these flavones, we engineered an artificial pathway in an Escherichia coli cell factory for the first time. By first reconstructing the plant flavonoid biosynthetic pathway genes from five different species: phenylalanine ammonia lyase from Rhodotorula toruloides (PAL), 4-coumarate-coenzyme A ligase from Petroselinum crispum (4CL), chalcone synthase from Petunia hybrida (CHS), chalcone isomerase from Medicago sativa (CHI) and an oxidoreductase flavone synthase I from P. crispum (FNSI), production of the intermediates chrysin and apigenin was achieved by feeding phenylalanine and tyrosine as precursors. By comparative analysis of various versions of P450s, a construction expressing 2B1 incorporated with a 22-aa N-terminal truncated flavone C-6 hydroxylase from S. baicalensis (F6H) and partner P450 reductase from Arabidopsis thaliana (AtCPR) was found most effective for production of both baicalein (8.5 mg/L) and scutellarein (47.1 mg/L) upon supplementation with 0.5 g/L phenylalanine and tyrosine in 48 h of fermentation. Finally, optimization of malonyl-CoA availability further increased the production of baicalein to 23.6 mg/L and scutellarein to 106.5 mg/L in a flask culture. This report presents a significant advancement of flavone synthetic production and provides foundation for production of other flavones in microbial hosts.

Scutellarein selectively targets multiple myeloma cells by increasing mitochondrial superoxide production and activating intrinsic apoptosis pathway.

OBJECTIVES: Scutellarein is a flavonoid monomer found in traditional Chinese medicine such as Scutellaria barbata. This study aimed to investigate the cytotoxic effect of scutellarein treatment on multiple myeloma (MM) cells. METHODS: circulating B lymphocytes (CBL) isolated from healthy donors' peripheral blood served as control for MM.1R and IM-9 MM cells. CLB and MM cells were treated with various concentrations of scutellarein before their cell viability and apoptosis being evaluated. Nude mice burdened with MM xenograft tumor were intravenously injected with different concentrations of scutellarein, and their tumor burden change were monitored. Apoptosis of MM cells or CBL after scutellarein treatment was assayed by measuring caspase-3, -8 and -9 activities. FADD or APAF1 gene knockdown in MM cells was achieved by lentiviral transfection. Amount of Cytochrome C in cytosol or mitochondria as well as that of Bax and Bcl-2 protein were evaluated by Western blot. Mitochondria-induced apoptosis was assayed by measuring mitochondrial membrane potential change. Production of general reactive oxygen species and mitochondrial superoxide in MM or CBL was detected after scutellarein treatment, which was reduced by MitoTEMPO or apocynin treatment, respectively. RESULTS: Scutellarein treatment showed potent cytotoxicity on MM cells but not on viable CBL, and intravenous injection of scutellarein significantly reduced MM xenograft tumor burden in nude mice. Scutellarein treatment in MM cells activated the mitochondrial-mediated intrinsic apoptosis pathway by increasing the production of mitochondrial superoxide, which was reduced to ROS by NADPH, but this effect was weakened in healthy CBL. Co-treatment with scutellarein synergized with bortezomib in inducing apoptosis in MM cells in vitro and in reducing tumor volume in MM xenografted nude mice. CONCLUSIONS: Scutellarein induced mitochondrial-mediated intrinsic apoptosis selectively on malignant cells comparing to healthy cells.

The traditional uses, phytochemistry, and pharmacology of Atractylodes macrocephala Koidz.: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodes macrocephala Koidz. (called Baizhu in China) is a medicinal plant that has long been used as a tonic agent in various ethno-medical systems in East Asia, especially in China, for the treatment of gastrointestinal dysfunction, cancer, osteoporosis, obesity, and fetal irritability. AIM OF THE REVIEW: This review aims to provide a systematic summary on the botany, traditional uses, phytochemistry, pharmacology, pharmacokinetics, and toxicology of A. macrocephala to explore the future therapeutic potential and scientific potential of this plant. MATERIALS AND METHODS: A literature search was performed on A. macrocephala using scientific databases including Web of Science, Google Scholar, Baidu Scholar, Springer, PubMed, SciFinder, and ScienceDirect. Information was also collected from classic books of Chinese herbal medicine, Ph.D. and M.Sc. dissertations, unpublished materials, and local conference papers on toxicology. Plant taxonomy was confirmed to the database "The Plant List" (www.theplantlist.org). RESULTS: More than 79 chemical compounds have been isolated from A. macrocephala, including sesquiterpenoids, triterpenoids, polyacetylenes, coumarins, phenylpropanoids, flavonoids and flavonoid glycosides, steroids, benzoquinones, and polysaccharides. Crude extracts and pure compounds of A. macrocephala are used to treat gastrointestinal hypofunction, cancer, arthritis, osteoporosis, splenic asthenia, abnormal fetal movement, Alzheimer disease, and obesity. These extracts have various pharmacological effects, including anti-tumor activity, anti-inflammatory activity, anti-aging activity, anti-oxidative activity, anti-osteoporotic activity, neuroprotective activity, and immunomodulatory activity, as well as improving gastrointestinal function and gonadal hormone regulation. CONCLUSIONS: A. macrocephala is a valuable traditional Chinese medicinal herb with multiple pharmacological activities. Pharmacological investigations support the traditional use of A. macrocephala, and may validate the folk medicinal use of A. macrocephala to treat many chronic diseases. The available literature shows that much of the activity of A. macrocephala can be attributed to sesquiterpenoids, polysaccharides and polyacetylenes. However, there is a need to further understand the molecular mechanisms and the structure-function relationship of these constituents, as well as their potential synergistic and antagonistic effects. Further research on the comprehensive evaluation of medicinal quality, the understanding of multi-target network pharmacology of A. macrocephala, as well as its long-term in vivo toxicity and clinical efficacy is recommended.

A UPLC-ESI-MS/MS Method for Simultaneous Quantitation of Chlorogenic Acid, Scutellarin, and Scutellarein in Rat Plasma: Application to a Comparative Pharmacokinetic Study in Sham-Operated and MCAO Rats after Oral Administration of Erigeron breviscapus Extract.

Erigeron breviscapus, a traditional Chinese medicine, is clinically used for the treatment of occlusive cerebral vascular diseases. We developed a sensitive and reliable ultra-performance liquid chromatography-electrospray-tandem mass spectrometry (UPLC-ESI-MS/MS) method for simultaneous quantitation of chlorogenic acid, scutellarin, and scutellarein, the main active constituents in Erigeron breviscapus, and compared the pharmacokinetics of these active ingredients in sham-operated and middle cerebral artery occlusion (MCAO) rats orally administrated with Erigeron breviscapus extract. Plasma samples were collected at 15 time points after oral administration of the Erigeron breviscapus extract. The levels of chlorogenic acid, scutellarin, and scutellarein in rat plasma at various time points were determined by a UPLC-ESI-MS/MS method, and the drug concentration versus time plots were constructed to estimate pharmacokinetic parameters. The concentration of chlorogenic acid in the plasma reached the maximum plasma drug concentration in about 15 min and was below the limit of detection after 4 h. Scutellarin and scutellarein showed the phenomenon of multiple absorption peaks in sham-operated and MCAO rats, respectively. Compared with the sham-operated rats, the terminal elimination half-life of scutellarein in the MCAO rats was prolonged by more than two times and the area under the curve of each component in the MCAO rats was significantly increased. The results showed chlorogenic acid, scutellarin, and scutellarein in MCAO rats had higher drug exposure than that in sham-operated rats, which provided a reference for the development of innovative drugs, optimal dosing regimens, and clinical rational drug use.