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Background: Inorganic polyphosphate (polyP)-targeted polyphosphate kinase 1 (PPK1) has attracted much attention by virtue of its importance in bacterial pathogenicity and persistence, as well as its exclusive presence in microorganisms. However, only very few drugs have been found to be efficacious in inhibiting the Acinetobacter baumannii (A. baumannii) PPK1 protein. Results: In this study, we identified Scutellarein (Scu), a potent PPK1 inhibitor that could significantly influence PPK1-regulated motility, biofilm formation, and bacterial persistence, which was further validated by the results of transcriptome analysis. Mechanistic explorations revealed that Scu achieved its enzyme inhibitory activity predominantly through direct engagement with the active center of PPK1. Moreover, the survival rate of Galleria mellonella larvae was increased by about 35% with 20 mg/kg of Scu treatment. The remarkable therapeutic benefits of Scu were also observed in the mouse pneumonia model, shown mainly by reduced bacterial colonization, pathological lesions, and inflammatory factors. Conclusion: Our results revealed that Scu could attenuate the pathogenicity and persistence of A. baumannii by interfering with its important kinase PPK1. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is a chronic neurological condition with various underlying mechanisms. It is known to affect a multitude of people across the globe, regardless of age and gender. Seizures associated with epilepsy involve the participation of stimulatory glutamatergic mechanisms along with inflammation and oxidative damage. Objectives: In this investigation, the anti-epileptic effect of scutellarein, a phytochemical compound isolated from Erigeron breviscapus (Vant.), has been evaluated in the pentylenetetrazol (PTZ) kindling epilepsy model in mice. Materials and Methods: The experimental mice were categorized into six groups with six animals in each. The first control group was given normal saline. The second group was provided only PTZ through an intraperitoneal route to induce seizures. The third and fourth groups received two oral doses of scutellarein (10 and 20 mg/kg) before 30 min of PTZ induction. Diazepam was intraperitoneally administered to the fifth group as a positive control. The impact of scutellarein on the duration and initiation of clonic and tonic convulsion, mortality, kindling, mobility, and immobility duration in PTZ-induced rodents was estimated. Also, the impact of scutellarein on oxidative stress markers and antioxidant and inflammatory marker levels was also evaluated. Results: Scutellarein treatment was able to reduce PTZ-induced seizures in mice. In PTZ animals, scutellarein lowered the seizure severity by suppressing the onset and duration of convulsions. Scutellarein successfully modulated the PTZ-provoked changes in gamma-aminobutyric acid (GABA), glutamate, and dopamine levels, as well as Ca2+ ATPase and Na+ K+ ATPase activity. Conclusion: Furthermore, it remarkably reduced the oxidative stress markers and decreased the contents of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in PTZ animal brain tissues, confirming its anti-convulsant potential. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • Scutellarein derivatives (11a-l) with dual activity of H 3 R antagonism and cholinesterase inhibition were synthesized. • 11l exhibited the most potent inhibition potency against hu AChE and excellent inhibition potency against Aβ 1-42 aggregation. • 11l exhibited the most potent H 3 R antagonistic activities and significantly reduced tau protein hyperphosphorylation. • 11l could ameliorate the learning and memory impairment in mice by increasing ACh levels and reducing AChE levels. • 11l had favorable druggability and pharmacokinetic properties. A series of scutellarein 7- l -amino acid carbamate-4′-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer's disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l , l -Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC 50 values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H 3 R antagonistic activities than clobenpropit, with an IC 50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu2+-induced Aβ 1–42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu2+-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ 25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood–brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and seriously threatened public health and safety. Despite COVID-19 vaccines being readily popularized worldwide, targeted therapeutic agents for the treatment of this disease remain very limited. Here, we studied the inhibitory activity of the scutellarein and its methylated derivatives against SARS-CoV-2 main protease (Mpro) by the fluorescence resonance energy transfer (FRET) assay. Among all the methylated derivatives we studied, 4′- O -methylscutellarein exhibited the most promising enzyme inhibitory activity in vitro , with the half-maximal inhibitory concentration value (IC 50) of 0.40 ± 0.03 μM. Additionally, the mechanism of action of the hits was further characterized through enzyme kinetic studies and molecular docking. Overall, our results implied that 4′- O -methylscutellarein could be a primary lead compound with clinical potential for the development of inhibitors against the SARS-CoV-2 Mpro. • There were differences in the inhibition of SARS-CoV-2 Mpro between scutellarein and its methylated derivatives. • The most potent SARS-CoV-2 Mpro inhibitor (4′- O -methylscutellarein) was identified as an antiviral candidate. • The binding mode of 4′- O -methyl scutellarin with SARS-CoV-2 Mpro was predicted and the structure-activity relationship was analyzed. [ABSTRACT FROM AUTHOR]

SUMMARY: Distant species producing the same secondary metabolites is an interesting and common phenomenon in nature. A classic example of this is scutellarein whose derivatives have been used clinically for more than 30 years. Scutellarein occurs in significant amounts in species of two different orders, Scutellaria baicalensis and Erigeron breviscapus, which diverged more than 100 million years ago. Here, according to the genome‐wide selection and functional identification of 39 CYP450 genes from various angiosperms, we confirmed that only seven Scutellaria‐specific CYP82D genes and one Erigeron CYP706X gene could perform the catalytic activity of flavone 6‐hydroxylase (F6H), suggesting that the convergent evolution of scutellarein production in these two distant species was caused by two independently evolved CYP450 families. We also identified seven Scutellaria‐specific CYP82D genes encoding flavone 8‐hydroxylase (F8H). The evolutionary patterns of CYP82 and CYP706 families via kingdom‐wide comparative genomics highlighted the evolutionary diversity of CYP82D and the specificity of CYP706X in angiosperms. Multi‐collinearity and phylogenetic analysis of CYP82D in Scutellaria confirmed that the function of F6H evolved from F8H. Furthermore, the SbaiCYP82D1A319D, EbreCYP706XR130A, EbreCYP706XF312D and EbreCYP706XA318D mutants can significantly decrease the catalytic activity of F6H, revealing the contribution of crucial F6H amino acids to the scutellarein biosynthesis of distant species. This study provides important insights into the multi‐origin evolution of the same secondary metabolite biosynthesis in the plant kingdom. Significance Statement: Here, we determined that the scutellarein accumulation in distant species from Lamiaceae and Asteraceae arose from the convergent evolution of Scutellaria‐specific CYP82D and Asteraceae‐specific CYP706X. The independent evolutionary pattern of CYP82 and CYP706 and the findings of crucial residues will provide novel insights into the convergent evolution of secondary metabolite biosynthesis in the plant kingdom. [ABSTRACT FROM AUTHOR]

Background: The problems associated with the poor water solubility of anticancer drugs are one of the most important challenges in achieving effective cancer therapy. The present study was designed to evaluate the effect of scutellarein on human colon cancer cells in vitro by using a target αvβ3 novel scutellarein (Scu)-loaded niosome nanoparticle (β-CD-CL-Scu-cRGD). Results: β-CD-CL-Scu-cRGD has a diameter of 140.2 nm and zeta potential of − 11.3 mV with constant physicochemical stability. The MTT assay showed both Scu and β-CD-CL-Scu-cRGD caused a decrease in cell proliferation and viability of LoVo, but β-CD-CL-Scu-cRGD showed better activity in vitro. Colony formation assay and flow cytometry assay showed that β-CD-CL-Scu-cRGD has a better effect on cell proliferation and apoptosis. In vivo, animal experimental results showed that β-CD-CL-Scu-cRGD can significantly inhibit tumor growth, and the bodyweight of mice decreases during the treatment of scutellarein and its derivatives. β-CD-CL-Scu-cRGD could inhibit the protein levels of Ki67 and αvβ3, thereby inhibiting tumor growth. Conclusions: Although further in vitro and in vivo studies are necessary, our results suggested that β-CD-CL-Scu-cRGD could be an outstanding carrier to deliver Scu for potential therapeutic approaches into colon cancer. [ABSTRACT FROM AUTHOR]

Background: The problems associated with the poor water solubility of anticancer drugs are one of the most important challenges in achieving effective cancer therapy. The present study was designed to evaluate the effect of scutellarein on human colon cancer cells in vitro by using a target αvβ3 novel scutellarein (Scu)-loaded niosome nanoparticle (β-CD-CL-Scu-cRGD). Results: β-CD-CL-Scu-cRGD has a diameter of 140.2 nm and zeta potential of − 11.3 mV with constant physicochemical stability. The MTT assay showed both Scu and β-CD-CL-Scu-cRGD caused a decrease in cell proliferation and viability of LoVo, but β-CD-CL-Scu-cRGD showed better activity in vitro. Colony formation assay and flow cytometry assay showed that β-CD-CL-Scu-cRGD has a better effect on cell proliferation and apoptosis. In vivo, animal experimental results showed that β-CD-CL-Scu-cRGD can significantly inhibit tumor growth, and the bodyweight of mice decreases during the treatment of scutellarein and its derivatives. β-CD-CL-Scu-cRGD could inhibit the protein levels of Ki67 and αvβ3, thereby inhibiting tumor growth. Conclusions: Although further in vitro and in vivo studies are necessary, our results suggested that β-CD-CL-Scu-cRGD could be an outstanding carrier to deliver Scu for potential therapeutic approaches into colon cancer. [ABSTRACT FROM AUTHOR]

Pirarubicin (THP) is one of the most commonly used antineoplastic drugs in clinical practice. However, its clinical application is limited due to its toxic and heart-related side effects. It has been reported that oxidative stress, inflammation and apoptosis are closely associated with cardiotoxicity caused by pirarubicin (CTP). Additionally, it has also been reported that scutellarein (Sc) exerts anti-inflammatory, antioxidant, cardio-cerebral vascular protective and anti-apoptotic properties. Therefore, the present study aimed to investigate the effect of food therapy with Sc on CTP and its underlying molecular mechanism using echocardiography, immunofluorescence, western blot, ROS staining, and TUNEL staining. The in vivo results demonstrated that THP was associated with cardiotoxicity. Additionally, abnormal changes in the expression of indicators associated with oxidative stress, ferroptosis and apoptosis were observed, which were restored by Sc. Therefore, it was hypothesized that CTP could be associated with oxidative stress, ferroptosis and apoptosis. Furthermore, the in vitro experiments showed that Sc and the NADPH oxidase 2 (NOX2) inhibitor, GSK2795039 (GSK), upregulated glutathione peroxidase 4 (GPX4) and inhibited THP-induced oxidative stress, apoptosis and ferroptosis. However, cell treatment with the ferroptosis inhibitor, ferrostatin-1, or inducer, erastin, could not significantly reduce or promote, respectively, the expression of NOX2. However, GSK significantly affected ferroptosis and GPX4 expression. Overall, the results of the present study indicated that food therapy with Sc ameliorated CTP via inhibition of apoptosis and ferroptosis through regulation of NOX2-induced oxidative stress, thus suggesting that Sc may be a potential therapeutic drug against CTP. [ABSTRACT FROM AUTHOR]

[Display omitted] • All synthesized hybrid molecules exhibited excellent neuroprotective and antiplatelet effects. • The selected compound 1e could inhibit the Gly-Sar uptake for Caco-2 cells in a dose-dependent manner. • The selected compound 1e descreased apoptosis of OGD/R PC12 cells. • The selected compound 1e showed antiplatelet through enhancing the activity of eNOS. • The selected compound 1e significantly reduced the cerebral infarction volume of MCAO/R rats. Ischemic stroke caused by insufficient blood supply to the brain may produce a sequence of cascade reactions, leading to oxidative stress and ultimately inducing nerve cell damage. Therefore, hybrid molecules with multiple therapeutic effects have irreplaceable advantages for the treatment of ischemic stroke. Based on the previous works, two types of Scutellarein and Tertramethylpyrazine hybrid molecules were designed and synthesized according to the PepT 1-based design. After systematic research, all synthesized hybrid molecules exhibited more excellent neuroprotective effect and antiplatelet activity compared to the original drugs. Among them, the selected compound 1e with superior neuroprotective and antiplatelet effects could significantly enhance the permeability on the Caco-2 monolayer membrane and inhibit the Gly-Sar uptake on Caco-2 cells. Meanwhile, the result of intestinal perfusion has also confirmed that the absorption of the selected compound 1e is indeed increased. Further, the selected compound 1e significantly reduce the cerebral infarction volume of middle cerebral artery occlusion/reperfusion rats. Especially, the cerebral infarction volume of the high-dose 1e group reduced to one fourth of the model group. Meanwhile, results of hematoxylin-eosin staining also indicated that the damage in the hippocampus CA1 region was significantly alleviated after treatment with the compound 1e. Accordingly, molecular hybridization strategy is one of the simple and feasible ways to improve the therapeutic effect of single targeted drug. [ABSTRACT FROM AUTHOR]

The polyphenolic composition and anti-inflammatory activity of selected Thymus species (T. longicaulis C. Presl, T. praecox Opiz subsp. polytrichus (A. Kerner Ex Borbás) Jalas, T. pulegioides L., T. serpyllum L. subsp. serpyllum and T. striatus Vahl) was studied in comparison with T. vulgaris, as an officinal medicinal plant, to evaluate the biomedical potential of these Croatian wild-growing species. This paper provides a first insight into the polyphenolic profiles of T. praecox subsp. polytrichus and T. striatus. Also, some flavone and hydroxycinnamic derivatives were at first identified in the other studied species by LC-DAD-ESI–MS/MS analysis. Rosmarinic acid and glycosides of scutellarein and luteolin were found to be the most abundant polyphenolic constituents. The Thymus extracts inhibited Src tyrosine kinase activity and they reduced the production of proinflammatory cytokine interleukin-6 in Balb/C mice splenocytes. The obtained results highlighted T. longicaulis as a potential source of herbal drugs with anti-inflammatory properties and/or novel functional food rich in flavonoids and phenolic acids. [ABSTRACT FROM AUTHOR]

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 β (Aβ)-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 Aβ 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 Aβ-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 Aβ-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. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • E. coli was engineered for production of bioactive flavones baicalein and scutellarein for the first time. • Flavonoid synthetic pathway was constructed from five plant enzymes. • Optimization by enzyme selection, P450 enzyme truncation and N-terminal modification. • Malonyl-CoA availability engineering improved the yield of baicalein 2.8-fold and scutellarein 2.3-fold. • Final optimized strain could produce 23.6 mg/L baicalein and 106.2 mg/L scutellarein. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • Scutellarein derivatives were designed as potential multifunctional agents for the treatment of AD. • 11e displayed excellent inhibition of self- and Cu2+-induced Aβ 1–42 aggregation and induced disassembly of Aβ fibrils. • 11e significantly reduced tau hyperphosphorylation and exhibited good inhibition of platelet aggregation. • 11e exhibited optimal Papp AP–BL desirable direct uptake values in hCMEC/D3 cell monolayer and hPepT1-MDCK cell lines. • 11e could ameliorate the learning and memory impairment by significantly reduced APP and BACE-1 expression. Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a–i , containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC 50 values of 6.72 ± 0.09 and 8.91 ± 0.08 μM, respectively. In addition, compound 11e displayed not only excellent inhibition of self- and Cu2+-induced Aβ 1–42 aggregation (91.85% and 85.62%, respectively) but also induced disassembly of self- and Cu2+-induced Aβ fibrils (84.54% and 83.49% disaggregation, respectively). Moreover, 11e significantly reduced tau protein hyperphosphorylation induced by Aβ 25–35 , and also exhibited good inhibition of platelet aggregation. A neuroprotective assay demonstrated that pre-treatment of PC12 cells with 11e significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax and caspase-3) and inhibited RSL3-induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 11e would have optimal blood–brain barrier and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11e significantly attenuated learning and memory impairment in an AD mice model. Toxicity experiments with the compound did not reveal any safety concerns. Notably, 11e significantly reduced β-amyloid precursor protein (APP) and β-site APP cleaving enzyme-1 (BACE-1) protein expression in brain tissue of scopolamine-treated mice. Taken together, these outstanding properties qualified compound 11e as a promising multi-target candidate for AD therapy, worthy of further studies. [ABSTRACT FROM AUTHOR]

Abstract To explore antitumor agents with potent efficacy and low toxicity, scutellarein derivatives with benzoic acid mustard (10a − c , 11a − c and 13a − c) were designed and synthesized. The antiproliferative activities of the target derivatives against A549, MCF-7 and Bel-7402 cancer cell lines were tested. Compound 10a showed the strongest potency with an IC 50 value of 1.50 μM against MCF-7 cell line, and displayed low toxicity against human liver L-O2 normal cells (IC 50 > 50 μM), showing specificity between normal and malignant cells. The mechanism studies revealed that 10a could induce apoptosis in MCF-7 cells, arrest MCF-7 cell cycle at the G1 phase and cause mitochondrial dysfunction in a concentration-dependant manner. Furthermore, the enhanced expression of the pro-apoptotic proteins caspase-9, caspase-3, Bax and cytochrome c , and the reduced expression of the anti-apoptotic protein Bcl-2 confirmed that 10a induced the intrinsic apoptosis pathway in MCF-7 cells. The potent antiproliferative activity and good selectivity guaranteed 10a a lead compound for the further development into anticancer therapeutics, especially for breast cancer. Graphical abstract Image 1 Highlights • Hybrids of scutellarein and benzoic acid mustard were designed and synthesized. • Some exhibited potent antiproliferative activities with low IC 50 values. • Compound 10a showed good selectivity between human normal and tumor cells. • 10a induced apoptosis and arrest cell cycle at G1 phase in MCF-7 cells. • 10a induced MCF-7 cells apoptosis via the mitochondria-dependent pathways. [ABSTRACT FROM AUTHOR]

Scutellarin is the major active flavonoid extracted from the traditional Chinese herbal medicine Erigeron breviscapus (Vant.) Hand-Mazz., which is widely used in China. Recently, accumulating evidence has highlighted the potential role of scutellarin and its main metabolite scutellarein in the treatment of cancer. To explore novel anticancer agents with high efficiency, a series of new scutellarein derivatives with a long aliphatic chain were synthesized, and the antiproliferative activities against Jurkat, HCT-116 and MDA-MB-231 cancer cell lines were assessed. Among them, compound 6a exhibited the strongest antiproliferative effects on Jurkat (IC50 = 1.80 μM), HCT-116 (IC50 = 11.50 μM) and MDA-MB-231 (IC50 = 53.91 μM). In particular, 6a even showed stronger antiproliferative effects than the positive control NaAsO2 on Jurkat and HCT-116 cell lines. The results showed that a proper long aliphatic chain enhanced the antiproliferative activity of scutellarein. [ABSTRACT FROM AUTHOR]

Scutellarin, one of natural flavonoids, is widely and clinically used for treating many diseases in China. Recently, scutellarin has demonstrated a broad spectrum of anti-proliferative activities against multiple cancer cell lines. However, the molecular mechanism of action remains to be investigated. We herein report the design and synthesis of biotinylated scutellareins as probes, which can be applied to discover scutellarein interacting proteins. Finally, we show that scutellarin directly targets pyruvate kinase M2 (PKM2) and inhibits its cytosolic activity to decrease glycolytic metabolism; on the other hand, scutellarin may also participate in regulating cell cycle and apoptotic proteins by activating MEK/ERK/PIN1 signaling pathway to promote the nuclear translocation of PKM2. [ABSTRACT FROM AUTHOR]

[Display omitted] • Scutellarein is a potent inhibitor against tyrosinase. • Integrated approaches coupling enzyme kinetics, multi-spectroscopy and computational simulation reveals scutellarein induces conformational changes. • Scutellarein effectively controlled the enzymatic browning of during food storage. Tyrosinase plays an important role in melanin synthesis. Inhibition against tyrosinase activity has been extensively focused on for pharmaceutical, food, cosmetic, and agricultural purpose. The inhibitory mechanism of scutellarein on tyrosinase was elaborated by coupling enzyme kinetics, multi-spectroscopy and computational simulation. Scutellarein remarkably inhibited tyrosinase activity with an IC 50 value of 91 μM. Scutellarein reversibly inhibited tyrosinase in a competitive manner. Fluorescence quenching validated that interaction of scutellarein with tyrosinase occurred to form a complex with a binding constant of 6.11 × 104 M−1. Thermodynamic parameters suggested that scutellarein spontaneously bound with tyrosinase via hydrogen bond and van der Waals force. Three-dimensional fluorescence spectra and circular dichroism spectra revealed that scutellarein induced an obvious conformational change in tyrosinase. Molecular docking result predicted that scutellarein mainly bound with tyrosinase via Arg268 residue. Scutellarein effectively controlled the enzymatic browning of apple slices during storage. This research could give theoretical guiding significance in various application for tyrosinase inhibitors. [ABSTRACT FROM AUTHOR]

Bacterial β-glucuronidases play key roles in the deconjugation of a variety of endogenous and drug glucuronides, thus have been recognized as important targets to modulate the enterohepatic circulation of various glucuronides. In this study, more than 30 natural flavonoids were collected and their inhibitory effects against E. coli β-glucuronidase (EcGUS) were assayed. The results demonstrated that some flavonoids including scutellarein, luteolin, baicalein, quercetin and scutellarin displayed strong to moderate inhibitory effects against EcGUS, with the IC 50 values ranging from 5.76 μM to 29.64 μM, while isoflavones and dihydroflavones displayed weak inhibitory effects against EcGUS. Further investigation on inhibition kinetics revealed that scutellarein and luteolin functioned as potent competitive inhibitors against EcGUS-mediated PNPG hydrolysis, with the K i values less than 3.0 μM. Molecular docking simulations demonstrated that scutellarein and luteolin could be well-docked into the catalytic site of EcGUS, while the binding areas of these two natural inhibitors on EcGUS were highly overlapped with that of PNPG on EcGUS. Additionally, the structure-inhibition relationships of natural flavonoids against EcGUS are also summarized, which will be very helpful for the medicinal chemists to design and develop more potent flavonoid-type inhibitors against EcGUS. [ABSTRACT FROM AUTHOR]

Scutellarin (1) has been widely used to treat acute cerebral infarction in clinic, but poor aqueous solubility decreases its bioavailability. Interestingly, scutellarin (1) could be metabolized into scutellarein (2) in vivo. In this study, a sulfonic group was introduced at position C-8 of scutellarein (2) to enhance the aqueous solubility of the obtained derivative (3). DPPH (1,1-diphenyl-2-picrylhydrazyl)-radical scavenging ability and antithrombic activity were also conducted to determine its bioactivity. The result showed that scutellarein derivate (3) could be a better agent for ischemic cerebrovascular disease treatment. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of scutellarin on the cell cycle， so as to demonstrate the mechanism of action of scutellarin in inhibiting the proliferation of tumor cells. Methods We analyzed the relative mRNA expression of cyclin dependent kinase（CDK）1，CDK2，cyclin A2，cyclin E2 and p21 in a breast cancer cell line，MDA-MB-231 under several doses of scutellarin by quantitative real-time PCR. The most important control points were G2/M and G1/S. CDK1and cyclin A2 were related toG2/M， while CDK2 and cyclinE2 were related toG1/S. Results When the dose of scutellarin was less than 25μmol/L， the relative mRNA expression of CDK1 increased apparently. The increasing trend decreased when the doses increased. The relative mRNA expression of CDK1 hardly changed when the dose reached 50μmol/L. The relative mRNA expression of cyclinA2，which regulated the G2/M phase of MDA-MB-231 cells in company with CDK1，increased apparently at the doses less than 50μmol/L. The relative mRNA expression of CDK2 decreased apparently at low doses of scutellarin， but increased apparently at low doses of 100μmol/L. The relative mRNA expression of cyclin E2，which regulated he G1/S phase of MDA-MB-231 cells in company with CDK2，increased apparently at low doses and hardly changed at the dose of 100μmol·L-1. The relative mRNA expression of p21，a cyclin dependent-kinase inhibitor， increased apparently at the dose of50μmol·L-1 and 100μmol·L-1. Conclusion Scutellarin apparently modifies CDK1，CDK2，cyclin A2，cyclin E2 and p21 in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Neoplastic cells often reside in distinctive tumor hypoxia armed with a series of adaptive responses including oxidative stress, defective apoptotic machinery and neoangiogenesis, through that further confer cell survival improvement. Plants still acts as reservoir of natural chemicals to provide newer active pharmacophores. Scutellarein is flavones which has wide range of pharmacophoral effects. In our current research, scutellarein employed for targeting oxidative stress mediated tumor angiogenesis and apoptotic nuclear fragmentation. Experimental results revealed that scutellarein has antiproliferative index against multiple cancer cell lines and diminished the oxidative stress and tumor development of murine ascitic lymphoma & inflammatory hepatocellular carcinoma. Eventual consequences lead to reduced neovessel formation by abrogating angiogeneic factors cytokine-VEGF-A, Flt-1, HIF-1α, MMP-2 and MMP-9 and reversing of evading apoptosis by activating caspase-3 activated DNA fragmentation factor (DFF-40) mediated nucleosomal degradation. In summary, our experimental evidences suggest that scutellarein has strong potentiality to attenuate the tumor development by modulating sprouting neovasculature and DFF-40 mediated apoptosis. [ABSTRACT FROM AUTHOR]

Greenhouse experiments were conducted to determine the effects of nitrogen (N), phosphorus (P), and potassium (K) fertilizer on biomass yield and flavonoid content of American skullcap (Scutellaria lateriflora). Each experiment was carried out two times and consisted of six levels of each nutrient. The regressions gave maxima for dry matter, baicalein yield, and chrysin yield at 446, 412, and 351 kg N/ha for N fertilizer, respectively. Dry matter yield exhibited linear response to P application. The yield of scutellarein, baicalin, baicalein, and chrysin increased with addition of P. The regression gave maximum for dry matter at 208 kg K/ha for K fertilizer. A linear response to K fertilization was observed for scutellarein concentration. P application had the greatest effect on the flavonoids analyzed, whereas K had least, which may be attributed in part to the presence of K in the fritted clay medium. [ABSTRACT FROM AUTHOR]

Oroxylin A and hispidulin, compounds which are abundant in both Scutellaria and liverwort species, are important lead compounds for the treatment of ischemic cerebrovascular disease. Their enzymatic synthesis requires an O-methyltransferase able to interact with the related flavonoid's 6- OH group, but such an enzyme has yet to be identified in plants. Here, the gene encoding an O-methyltransferase (designated PaF6 OMT) was isolated from the liverwort species Plagiochasma appendiculatum. A test of alternative substrates revealed that its strongest preferences were baicalein and scutellarein, which were converted into, respectively, oroxylin A and hispidulin. Allowed a sufficient reaction time, the conversion rate of these two substrates was, respectively, 90% and 100%. PaF6 OMT offers an enzymatic route to the synthesis of oroxylin A and hispidulin. [ABSTRACT FROM AUTHOR]

Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin ( 1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2O2-induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative ( 18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein ( 2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment. [ABSTRACT FROM AUTHOR]

Objective To study the antioxidant activities and chemical compositions of Thymus quinquecostatus Celak (dijiao). Methods The antioxidant activities of five polar fractions of dijiao were screened and evaluated using DPPH and ABTS free radical scavenging assays. After the chemical compositions were separated and purified by using silica gel chromatography, Sephadex LH-20 chromatography and MCI GEL CHP-20P column chromatography, the chemical compositions were identified by MS and NMR spectrometers, and records of literature. Results From the EtOAc and n-BuOH fractions which showed high antioxidant activity, total 18 compositions were separated and identified: scutellarin ("1 "short for peak No. 1, the same below), scutellarein (2), 5,6,7-trihydroxy-4′-methoxyflavone (3), xanthomicrol (4), apigenin (5), 4′-methoxyluteolin (6), luteolin-7-O-β-D-glucopyranoside (7), luteolin (8),and rutin (9), danshensu (10), vanillic acid (11), protocatechuic acid (12), chlorogenic acid (13), caffeic acid (14), ferulic acid (15), 2,6-dihydroxy-4-isopropylphenyl-β-D-glucopyranoside (16), olenolic cid (17) and daucosterol (18). Conclusion The composition 1,2, 3 and 16 were the first reported in the genus Thymus, and 4∼8, 10∼12, 14∼15 and 17∼18 were found first in dijiao. [ABSTRACT FROM AUTHOR]

Abstract: Scutellarein (2), which is an important in vivo metabolite of scutellarin (1), was synthesized from 3,4,5-trimethoxyphenol (3) in high yield in four steps. This strategy relies on acetylation, aldolization, cyclization and hydrolysis reactions, respectively [ABSTRACT FROM AUTHOR]

Scutellarin ( 1 ) could be hydrolyzed into scutellarein ( 2 ) in vivo and then converted into methylated, sulfated and glucuronidated forms. In order to investigate the biological activities of these methylated metabolites, eight methylated analogs of scutellarein ( 2 ) were synthesized via semi-synthetic methods. The antithrombotic activities of these compounds were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H 2 O 2 -induced cytotoxicity. Furthermore, the physicochemical properties of these compounds including aqueous solubility and lipophilicity were also investigated. The results showed that 6- O -methylscutellarein ( 5 ) demonstrated potent antithrombotic activity, stronger antioxidant activity and balanced solubility and permeability compared with scutellarin ( 1 ), which warrants further development of 5 as a promising lead for the treatment of ischemic cerebrovascular disease. [ABSTRACT FROM AUTHOR]

In order to improve the biological activity and water solubility of scutellarin ( 1 ), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H 2 O 2 -induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein ( 2 ), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease. [ABSTRACT FROM AUTHOR]

Flavonoids are plant pigments that have been demonstrated to exert various pharmacological effects including anti-cancer, anti-diabetic, anti-atherosclerotic, anti-bacterial, and anti-inflammatory activities. However, the molecular mechanisms in terms of exact target proteins of flavonoids are not fully elucidated yet. In this study, we aimed to evaluate the anti-inflammatory mechanism of scutellarein (SCT), a flavonoid isolated from Erigeron breviscapus, Clerodendrum phlomidis and Oroxylum indicum Vent that have been traditionally used to treat various inflammatory diseases in China and Brazil. For this purpose, a nitric oxide (NO) assay, polymerase chain reaction (PCR), nuclear fractionation, immunoblot analysis, a kinase assay, and an overexpression strategy were employed. Scutellarein significantly inhibited NO production in a dose-dependent manner and reduced the mRNA expression levels of inducible NO synthase (iNOS) and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-activated RAW264.7 cells. In addition, SCT also dampened nuclear factor (NF)-κB-driven expression of a luciferase reporter gene upon transfection of a TIR-domain-containing adapter-inducing interferon-β (TRIF) construct into Human embryonic kidney 293 (HEK 293) cells; similarly, NF-κ B nuclear translocation was inhibited by SCT. Moreover, the phosphorylation levels of various upstream signaling enzymes involved in NF-κB activation were decreased by SCT treatment in LPS-treated RAW264.7 cells. Finally, SCT strongly inhibited Src kinase activity and also inhibited the autophosphorylation of overexpressed Src. Therefore, our data suggest that SCT can block the inflammatory response by directly inhibiting Src kinase activity linked to NF-κB activation. [ABSTRACT FROM AUTHOR]

A series of 4′- N-substituted (aminomethyl)benzoate derivatives of scutellarein were designed and synthesized. Evaluation of their physiochemical properties showed that the designed target compounds 5a-e exhibit higher chemical stability and aqueous solubility than scutellarin and scutellarein. The permeability ( Papp AP to BL ) of 5c-e in Caco-2 cells were 2.8, 8.1, and 12.6 times higher than that of scutellarin and 1.3, 4.1, and 6.0 times higher than that of scutellarein; especially, 5e had the highest Papp AP to BL value (7.19 ± 0.31 × 10−6 cm/s) and the lowest ER ( Papp BL to AP / Papp AP to BL ) value of 0.17. In vitro antioxidative evaluation results revealed that 5e could protect against H2O2 -induced PC12 cells' oxidative damage by attenuating mitochondrial membrane potential loss and decreasing H2O2 -induced reactive oxygen species ( ROS) production. [ABSTRACT FROM AUTHOR]

In this paper, a new and efficient synthesis of 6-O-methylscutellarein (3), the major metabolite of the natural medicine scutellarin, is reported. Two hydroxyl groups at C-4' and C-7 in 2 were selectively protected by chloromethyl methyl ether after the reaction conditions were optimized, then 6-O-methyl-scutellarein (3) was produced in high yield after methylation of the hydroxyl group at C-6 and subsequent deprotection of the two methyl ether groups. [ABSTRACT FROM AUTHOR]

Scutellarin (1) has been used for the treatment of angina pectoris, cerebral infarction and coronary heart disease with a large market share in China. Pharmacokinetic studies on scutellarin showed that scutellarin (1) is readily converted into its metabolites in vivo. In this paper, a new and practical synthetic method for the synthesis of 6-O-methyl-scutellarein (3) (one metabolite of scutellarin in vivo) is reported. The benzyl bromide was firstly used to selectively replace the acetyl group at C-7 in 7, and was then used to protect the hydroxy groups at C-4' in 10, 6-O-methyl-scutellarein (3) is obtained in high yield through these methods. [ABSTRACT FROM AUTHOR]

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 H 2 O 2 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 H 2 O 2 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. [Display omitted] [ABSTRACT FROM AUTHOR]

A practical and economical five-step synthesis of the flavone scutellarein has been achieved in 60% overall yield using the available and cheap 2,6-dimethoxy-1,4-benzoquinone as starting material. The reaction sequence involved reduction to the corresponding quinol, Friedel-Crafts acetylation, Claisen-Schmidt condensation with p-methoxybenzaldehyde, cyclisation and demethylation. The procedure is operationally simple and amenable to scale-up synthesis. [ABSTRACT FROM AUTHOR]

Scutellaria lateriflora (American skullcap) has been used in traditional medicine to treat several medical conditions including nervous disorders and cancer. Previous studies have associated these medicinal properties to flavones present in roots and leaves of this species. In order to develop a production system and study the biosynthesis of these bioactive compounds, hairy root cultures of S. lateriflora were established and line 4 was selected for further studies based on its growth performance in a modified Murashige and Skoog’s medium supplemented with 0.5 mg/l indole-3-butyric acid. Scanning electron microscopy of the hairy roots showed a high profusion of hairs along the root. Several phenolic compounds, including verbascoside, and the flavones wogonin, baicalein, scutellarein and their respective glucuronides were identified by high performance liquid chromatography–tandem mass spectrometry in the root tissue, but not in the culture medium. Among these compounds, verbascoside accumulated at the highest levels. Interestingly, cultures incubated under continuous light and treated with 15 mM methyl-β-cyclodextrin for 24 h produced significantly higher levels of the aglycones, baicalein and wogonin, but not scutellarein, compared to cultures incubated under continuous darkness. This work demonstrates that hairy root cultures of S. lateriflora have the biosynthetic capacity to produce known Scutellaria flavones and suggest that light may have a selected regulatory effect on the synthesis or accumulation of these phenolic compounds. [ABSTRACT FROM AUTHOR]

The inclusion complexation behavior of scutellarein (SCUE) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has been investigated in both solution and in the solid state. SCUE/HP-β-CD solid system was prepared by suspension method. The formation of SCUE/HP-β-CD complex in aqueous solution was demonstrated by fluorescence spectroscopy, and the Job plot showed a maximum at a molar fraction of 0.5, indicating 1:1 inclusion complexation between SCUE and HP-β-CD. However, SCUE/HP-β-CD inclusion complex was characterized by means of XRD, DSC, 1H, and two-dimensional NMR. Through the complexation between HP-β-CD and SCUE, the water solubility and antitumor activity of SCUE were obviously increased. This satisfactory water solubility and high antitumor activity of the SCUE/HP-β-CD complex will be potentially useful for its application on human colon cancer chemotherapies. [ABSTRACT FROM AUTHOR]

To investigate the mechanism in Scutellarein-induced apoptosis of SAS human tongue cancer cells, inhibitory effects of Scutellarein on SAS cells were detected by MTT assay. Cell apoptosis was analyzed by flow cytometry. Ultrastructural changes of SAS cells were observed by transmission electron microscopy (TEM). Mitochondrial transmembrane potential (ΔΨm) were analyzed by JC-1 [5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide]. Western blotting was used to examine the expression level of Bcl-2, Bax and caspase-3 in SAS cells treated with Scutellarein. Scutellarein inhibited the proliferation of SAS cells in a time and dose-dependent manner and increased the percent of apoptotic cells. The mitochondrial cristae were swollen and had vacuolar degeneration. ΔΨm decreased when the concentration of scutellarein increased. Scutellarein effectively up-regulated the expression of mitochondrial Bax and caspase-3 and down-regulated the expression of Bcl-2. Scutellarein induces apoptosis of SAS human tongue cancer cells via activating mitochondrial signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Scutellarin had protective effects against neuronal injury, however, there are few studies on the protective effect of scutellarein, which is the main metabolite of scutellarin in vivo. This study investigated whether the neural injury by ischemia/reperfusion would be influenced by different doses of scutellarin and scutellarein. Male Wistar rats were orally administered with scutellarin and scutellarein at the doses of 0.09, 0.17, 0.35, 0.70, 1.40mmol/kg, respectively; then after six consecutive days, they were subjected to global ischemia by occlusion of the bilateral common carotid arteries (BCCAO). After reperfusion for about 21h, neurological and histological examinations were performed. The present results showed that scutellarein attenuated neuronal cell damage, reduced cerebral water content, regulated the expression of glutamic acid (Glu), aspartic acid (Asp), glycine (Gly), γ-aminobutyric acid (GABA) and taurine (Tau), and improved the Ca2+-ATPase and Na+,K+-ATPase activity. Meanwhile, significant difference was found among various doses of scutellarin and scutellarein. Our studies indicated that scutellarin and scutellarein could improve neuronal injury, and scutellarein had better protective effect than scutellarin in rat cerebral ischemia. [Copyright &y& Elsevier]

[Display omitted] • Spectroscopic properties of scutellarein have been studied in methanol, acetonitrile and N,N-dimethylformamide. • Significant time-dependent spectral changes have been observed in the case of N,N-dimethylformamide solution. • The rising absorption in the 500–750 nm wavelength range can be explained by the isomerization of scutellarein. • The quantum-chemical calculations have shown the possibility of ESIPT in scutellarein. In this work, the spectroscopic properties of scutellarein (6-hydroxyapigenin) were studied in three organic solvents (methanol, acetonitrile and N,N-dimethylformamide) taking into account possible ionization and isomerization (tautomerization) processes. Significant visible colour changes were reported in the case of scutellarein in N,N-dimethylformamide. It was shown that isomerization processes can be one of the reasons for the observed changes in absorption spectrum, because some scutellarein isomers have an absorption band at about 623 nm while other forms of scutellarein show no absorption in this region. Moreover, spectroscopic properties were studied for cases of scutellarein in acetonitrile and methanol. The molar extinction coefficient has been found in the case of methanol solution which could be used to determine scutellarein concentration in this solvent using spectroscopic methods in future studies. The quantum-chemical calculations were performed for neutral and anionic forms and for two types of possible isomers of scutellarein in each solvent. The results help explain the experimentally observed rising absorption in the 500–750 nm wavelength range. Another important result of the quantum-chemical calculations is a prediction of excited state intramolecular proton transfer (ESIPT) in scutellarein. This result has been obtained for free molecule in vacuum and in the cases of methanol, acetonitrile and N,N-dimethylformamide solution. It was found that the excited state energy of the normal molecular form is higher than the excited state energy of the tautomer form of scutellarein. [ABSTRACT FROM AUTHOR]

A field experiment was conducted in Alabama to determine the effect of timing and frequency of harvest on shoot yield and flavonoid content of American skullcap. In the first year (2008), harvesting twice gave 36% higher yield than harvesting once. In the second year (2009), plant die-off late in the season prevented a comparison of two and three harvests, so only the effects of early and late harvest were compared. There was no difference in yield between early or late harvesting. Plant height and density, percent dry matter, and shoot yield were higher in the first harvest than the second harvest. In 2008, the yield and concentration of flavonoid baicalein was the highest. In 2009, the yield and concentration of baicalin was the highest, followed by baicalein and apigenin. There were no differences in flavonoid yield between early and late harvest. Flavonoid yield in 2009 was 58% higher in the first harvest than in the second. [ABSTRACT FROM PUBLISHER]

Abstract: Based on metabolic mechanism of scutellarin in vivo that scutellarin could be hydrolyzed into scutellarein by β-glucuronide enzyme, some glucose-containing scutellarein derivatives were designed and synthesized through the introduction of glucose moiety at C-7 position of scutellarein via a glucosidic bond. Biological activity evaluation showed that these glucose-containing scutellarein derivatives exhibited potent DPPH radical scavenging activities. Furthermore, the improvement of physicochemical properties such as anticoagulant and neuroprotective activities alongside with the water solubility was achieved by introducing glucose. These findings suggest that the introduction of the glucose moiety to scutellarein wattants further development of this kind of compounds as neuroprotective agents. [Copyright &y& Elsevier]

Abstract: Two series of 8-aminomethylated derivatives were prepared by Mannich reaction of scutellarein (2) with appropriate aliphatic amines, alicyclic amines and formaldehyde. All the compounds were tested for their thrombin inhibition activity through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay method and the solubility were assessed by ultraviolet (UV). The results showed that morpholinyl aminomethylene substituent derivative (3d) demonstrated stronger anticoagulant activity, better water solubility and good antioxidant activity compared with scutellarein (2), which warrants further development as a agent for ischemic cerebrovascular disease treatment. [Copyright &y& Elsevier]

Abstract: Severe acute respiratory syndrome (SARS) was the first pandemic in the 21st century to claim more than 700 lives worldwide. However, effective anti-SARS vaccines or medications are currently unavailable despite being desperately needed to adequately prepare for a possible SARS outbreak. SARS is caused by a novel coronavirus, and one of its components, a viral helicase, is emerging as a promising target for the development of chemical SARS inhibitors. In the following review, we describe the characterization, family classification, and kinetic movement mechanisms of the SARS coronavirus (SCV) helicase—nsP13. We also discuss the recent progress in the identification of novel chemical inhibitors of nsP13 in the context of our recent discovery of the strong inhibition of the SARS helicase by natural flavonoids, myricetin and scutellarein. These compounds will serve as important resources for the future development of anti-SARS medications. [Copyright &y& Elsevier]

Scutellarein, the main metabolite of scutellarin in vivo, has relatively better solubility, bioavailability and bio-activity than scutellarin. However, compared with scutellarin, it is very difficult to obtain scutellarein from Nature. Therefore, the present study focused on establishing an efficient route for the synthesis of scutellarein by hydrolyzing scutellarin. Neurological deficit score and cerebral infarction volume with the administration of scutellarein were then used to compare its neuroprotective effects on focal cerebral ischemia/reperfusion in rats induced by middle cerebral artery occlusion (MCAO) with those of scutellarin. The results showed that scutellarein had better protective effect on focal cerebral ischemia/reperfusion than scutellarin, which laid the foundation for further research and development of scutellarein as a promising candidate for ischemic cerebro-vascular disease. [ABSTRACT FROM AUTHOR]

Abstract: Severe acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there are no natural or synthetic compounds currently available that can inhibit SARS-CoV. We examined the inhibitory effects of 64 purified natural compounds against the activity of SARS helicase, nsP13, and the hepatitis C virus (HCV) helicase, NS3h, by conducting fluorescence resonance energy transfer (FRET)-based double-strand (ds) DNA unwinding assay or by using a colorimetry-based ATP hydrolysis assay. While none of the compounds, examined in our study inhibited the DNA unwinding activity or ATPase activity of human HCV helicase protein, we found that myricetin and scutellarein potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity, but not the unwinding activity, nsP13. In addition, we observed that myricetin and scutellarein did not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Our study demonstrates for the first time that selected naturally-occurring flavonoids, including myricetin and scultellarein might serve as SARS-CoV chemical inhibitors. [Copyright &y& Elsevier]

Scutellarein, the main metabolite of scutellarin in vivo, has relatively better solubility, bioavailability and bio-activity than scutellarin. However, it is very difficult to obtain scutellarein in nature compared with scutellarin. Therefore, the present study focused on establishing an efficient route for the synthesis of scutellarein by hydrolyzing scutellarin. The in vitro antioxidant activities of scutellarein were evaluated by measuring its scavenging capacities toward DPPH, ABTS+•, *hellip;H free radicals and its protective effect on H2O2-induced cytotoxicity in PC12 cells using MTT assay method. The results showed that essential point to the synthesis was the implementation of H2SO4 in 90% ethanol in N2 atmosphere; scutellarein had stronger antioxidant activity than scutellarin. The results have laid the foundation for further research and the development of scutellarein as a promising candidate for ischemic cerebrovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: The application of near-infrared (NIR) spectroscopy for in-line monitoring of extraction process of scutellarein from Erigeron breviscapus (vant.) Hand-Mazz was investigated. For NIR measurements, two fiber optic probes designed to transmit NIR radiation through a 2mm pathlength flow cell were utilized to collect spectra in real-time. High performance liquid chromatography (HPLC) was used as a reference method to determine scutellarein in extract solution. Partial least squares regression (PLSR) calibration model of Savitzky–Golay smoothing NIR spectra in the 5450–10,000cm−1 region gave satisfactory predictive results for scutellarein. The results showed that the correlation coefficients of calibration and cross validation were 0.9967 and 0.9811, respectively, and the root mean square error of calibration and cross validation were 0.044 and 0.105, respectively. Furthermore, both the moving block standard deviation (MBSD) method and conformity test were used to identify the end point of extraction process, providing real-time data and instant feedback about the extraction course. The results obtained in this study indicated that the NIR spectroscopy technique provides an efficient and environmentally friendly approach for fast determination of scutellarein and end point control of extraction process. [Copyright &y& Elsevier]