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Osteoarthritis (OA), a joint disease that is associated with inflammatory processes is involved in joint destruction. Scutellarein (Scu), a component of the medicinal herbs Scutellaria barbata D. Don and Erigeron breviscapus (vant) Hand Mass, has anti‐inflammatory effects. We explored the role of Scu in the development of OA and the underlying mechanisms. CCK‐8 assays, Calcein‐AM/PI and EdU staining were used to determine chondrocyte viability after Scu exposure. Western blot, qPCR, as well as ELISA were utilized to measure extracellular matrix (ECM) degradation and inflammation. Immunofluorescence (IF), western blot and luciferase assays were used to examine the NF‐kappaB (NF‐κB) pathway. Scu interacting proteins were predicted using network pharmacology analysis and molecular docking. X‐ray, H&E, Safranin O‐Fast Green(S‐O), toluidine blue, and immunohistochemistry analysis were used to examine the therapeutic effects of Scu in OA using destabilization of medial meniscus (DMM) models. Scu demonstrated inhibitory effects on ECM degradation and pro‐inflammatory factor levels in chondrocytes treated with IL‐1β. Mechanistically, Scu inhibited the IL‐1β‐induced activation of the PI3K/Akt/ NF‐κB signaling pathway cascades. Furthermore, Scu has been shown to have significant binding capacities to PI3K. Additionally, Scu ameliorated the OA progression in DMM models. Our findings suggest that Scu may contribute to the amelioration of OA progression by targeting the PI3K/Akt/NF‐κB signaling pathway, implying Scu possesses promising therapeutic potential for the treatment of OA. [ABSTRACT FROM AUTHOR]

Scutellarein is a key active constituent present in many plants, especially in Scutellaria baicalensis Georgi and Erigeron breviscapus (vant.) Hand-Mazz which possesses both anti-inflammatory and anti-oxidative activities. It also is the metabolite of scutellarin, with the ability to relieve LPS-induced acute lung injury (ALI), strongly suggesting that scutellarein could suppress respiratory inflammation. The present study aimed to investigate the effects of scutellarein on lung inflammation by using LPS-activated BEAS-2B cells (a human bronchial epithelial cell line) and LPS-induced ALI mice. The results showed that scutellarein could reduce intracellular reactive oxygen species (ROS) accumulation through inhibiting the activation of NADPH oxidases, markedly downregulating the transcription and translation of pro-inflammatory cytokines, including interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand (CXCL) 8 in LPS-activated BEAS-2B cells. The mechanism study revealed that it suppressed the phosphorylation and degradation of IκBα, consequently hindering the translocation of p65 from the cytoplasm to the nucleus and its subsequent binding to DNA, thereby decreasing NF-κB-regulated gene transcription. Notably, scutellarein had no impact on the activation of AP-1 signaling. In LPS-induced ALI mice, scutellarein significantly decreased IL-6, CCL2, and tumor necrosis factor-α (TNF-α) levels in the bronchoalveolar lavage fluid, attenuated lung injury, and inhibited neutrophil infiltration. Our findings suggest that scutellarein may be a beneficial agent for the treatment of infectious pneumonia by virtue of its anti-oxidative and anti-inflammatory activities. [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]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Scutellarein is a key active constituent present in many plants, especially in Scutellaria baicalensis Georgi and Erigeron breviscapus (vant.) Hand-Mazz which possesses both anti-inflammatory and anti-oxidative activities. It also is the metabolite of scutellarin, with the ability to relieve LPS-induced acute lung injury (ALI), strongly suggesting that scutellarein could suppress respiratory inflammation. The present study aimed to investigate the effects of scutellarein on lung inflammation by using LPS-activated BEAS-2B cells (a human bronchial epithelial cell line) and LPS-induced ALI mice. The results showed that scutellarein could reduce intracellular reactive oxygen species (ROS) accumulation through inhibiting the activation of NADPH oxidases, markedly downregulating the transcription and translation of pro-inflammatory cytokines, including interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand (CXCL) 8 in LPS-activated BEAS-2B cells. The mechanism study revealed that it suppressed the phosphorylation and degradation of IκBα, consequently hindering the translocation of p65 from the cytoplasm to the nucleus and its subsequent binding to DNA, thereby decreasing NF-κB-regulated gene transcription. Notably, scutellarein had no impact on the activation of AP-1 signaling. In LPS-induced ALI mice, scutellarein significantly decreased IL-6, CCL2, and tumor necrosis factor-α (TNF-α) levels in the bronchoalveolar lavage fluid, attenuated lung injury, and inhibited neutrophil infiltration. Our findings suggest that scutellarein may be a beneficial agent for the treatment of infectious pneumonia by virtue of its anti-oxidative and anti-inflammatory activities.

To screen natural product inhibitors targeting the SARS-CoV-2 main protease, this paper takes the main peoteases of SARS-Cov-2 as the research object, and 16 potential inhibitors were preliminarily screened by computer-aided drug screening method and tested for enzyme activity in vitro. Among them, the IC50 of scutellarin against SARS-CoV-2 main protease was (10.79 ± 2.116) µmol/L. The IC50 of (-)-Gallocatechin gallate against SARS-CoV-2 main protease was (2.104 ± 0.346) µmol/L. Finally, molecular dynamics simulations were performed on the two natural products and Mpro. It was found that the RMSD of the complexes of (-)-Gallocatechin gallate and Scutellarein with Mpro was around 0.22 A, indicating that the two natural products were stable in binding with Mpro and could be used as inhibitors or lead compounds of Mpro in SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Today, Alzheimer's disease (AD)—the most common neurodegenerative disorder, which affects 50 million people—remains incurable. Several studies suggest that one of the main pathological hallmarks of AD is the accumulation of abnormal amyloid beta (Aβ) aggregates; therefore, many therapeutic approaches focus on anti-Aβ aggregation inhibitors. Taking into consideration that plant-derived secondary metabolites seem to have neuroprotective effects, we attempted to assess the effects of two flavones—eupatorin and scutellarein—on the amyloidogenesis of Aβ peptides. Biophysical experimental methods were employed to inspect the aggregation process of Aβ after its incubation with each natural product, while we monitored their interactions with the oligomerized Aβ through molecular dynamics simulations. More importantly, we validated our in vitro and in silico results in a multicellular organismal model—namely, Caenorhabditis elegans—and we concluded that eupatorin is indeed able to delay the amyloidogenesis of Aβ peptides in a concentration-dependent manner. Finally, we propose that further investigation could lead to the exploitation of eupatorin or its analogues as potential drug candidates. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this paper was to develop a sensitive, reproducible Reverse Phase High Performance Liquid Chromatography (RP-HPLC) for extraction and quantitative estimation of Scutellarein, major flavone glycoside from leaves of Triumfetta rhomboidea. Materials and Methods: To optimize best solvent system and ideal extraction methodology, various leaves extract was prepared by using different solvent systems such as ethanol, ethanol: water (50:50) and water through different extraction methodologies includes, maceration, Soxhlet assisted extraction (SAE), Ultrasound Assisted Extraction (UAE) and Accelerated Solvent Extraction (ASE). Chromatographic separation of Scutellarein was performed on C18 column. Results: The results showed that the highest concentration of Scutellarein was found to be 1.547 ng in ethanolic extract. This study states about, existence of flavone glucocidic content in leaves extract of Triumfetta rhomboidea which can be extracted using ethanol as best solvent system and ASE as optimized extraction methodology. Conclusion: Extracts from T. rhomboidea obtained by maceration, SAE, UAE and ASE methods were analysed by HPLC-ESI-MS/MS to quantify flavonoid scutellarein contents. Ethanol was found to be a promising solvent system and Accelerated Solvent Extraction methodology was found to be the promising methodology for the extraction of Scutellarein from leaves of Triumfetta rhomboidea. [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]

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]

Background: The growth of several cancers can be inhibited by naturally occurring medicinal plants. A flavone called Scutellarein found in the perennial herb Scutellaria lateriflora does have a wide range of biological functions. Scutellarein was studied to determine whether it could induce apoptosis and cause cytotoxicity. Methods: On oral squamous cell carcinoma KB cell lines, Scutellarein's cytotoxic activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Scutellarein was added to KB cells at concentrations ranging from 25 to 125 g/mL for 24 h. The real-time polymerase chain reaction was also used to investigate apoptotic induction potential in Scutellarein-incubated KB cell lines by analyzing Bcl-2 protein and gene expression. Results: In KB-cell lines treated with scutellarein, cytotoxicity and anticancer effects were observed, as well as inhibit the growth of cancer cells. In comparison to the cells not treated with scutellarein, KB cells that had been exposed to scutellarein displayed reduced Bcl-2 expression. Conclusion: KB cells were treated with scutellarein to induce apoptosis, suggesting its potential as a chemo preventative agent. This activity appears to be mediated through the modulation of Bcl-2, a cytotoxic gene.

Abstract 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.

Scutellarein is a flavonoid from Scutellaria baicalensis Georgi that has been shown to have a variety of pharmacological activities. This review aims to summarize the pharmacological and pharmacokinetic studies on scutellarein and provide useful information for relevant scholars. Pharmacological studies indicate that scutellarein possesses a diverse range of pharmacological properties, including but not limited to anti-inflammatory, antioxidant, antiviral, neuroprotective, hypoglycemic, hypolipidemic, anticancer, and cardiovascular protective effects. Further investigation reveals that the pharmacological effects of scutellarein are driven by multiple mechanisms. These mechanisms encompass the scavenging of free radicals, inhibition of the activation of inflammatory signaling pathways and expression of inflammatory mediators, inhibition of the activity of crucial viral proteins, suppression of gluconeogenesis, amelioration of insulin resistance, improvement of cerebral ischemia-reperfusion injury, induction of apoptosis in cancer cells, and prevention of myocardial hypertrophy, among others. In summary, these pharmacological studies suggest that scutellarein holds promise for the treatment of various diseases. It is imperative to conduct clinical studies to further elucidate the therapeutic effects of scutellarein. However, it is worth noting that studies on the pharmacokinetics reveal an inhibitory effect of scutellarein on uridine 5'-diphosphate glucuronide transferases and cytochrome P450 enzymes, potentially posing safety risks., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Ficus viren has been traditionally used to treat diabetes, and its extract inhibits carbohydrate/lipid metabolism and possesses anti-hyperglycemic potential. However, there is conflicting investigation related to F. viren extract effect on carbohydrate metabolism. Thus, bioactive and mechanism behind its antidiabetic potential is still scanty. This study explored F. viren's anti-diabetic property by identifying potential phytoconstituents and mechanism. A sequential in-silico approach was used i.e., druglikeness, molecular docking, post-docking MM-GBSA, ADMET studies, molecular dynamic simulation (MDS), and post-MDS MM-GBSA. We screened ∼32 phytoconstituents and twelve potential organ-specific diabetic targets (O.S.D.Ts i.e., IR, DPP-4, ppar-γ, ppar-α, ppar-δ, GLP-1R, SIRT-1, AMPK, GSK-3β, RAGE, and AR). Drug likeness study identified 18 druggable candidates among 32 phytoconstituents. K3A, quercetin, scutellarein, sorbifolin, and vogeline J identified as potential ligands from druggable ligands, using IR as the standard target. Subsequently, potential ligands docked with remaining O.S.D.Ts. and data showed that K3A binds strongly with AMPK, ppar-δ, DPP-4, and GSK-3β, while scutellarein binds with AR and ppar-α. Sorbifolin, quercetin, and vogeline J binds with ppar-α, ppar-γ, and RAGE, respectively. Post-docking MM-GBSA data (∆G Bind ) also depicted potential ligand's strong binding affinities with their corresponding targets. Thereafter, simulation data revealed that only scutellarein and sorbifolin showed dynamic stability with their respective targets, i.e., AR/ppar-α and ppar-α, respectively. Interestingly, post-MDS MM-GBSA revealed that only scutellarein exhibited strong ∆G Bind of -55.08 kcal/mol and -75.48 kcal/mol with AR and ppar-α, respectively. Though, collective computational analysis supports antidiabetic potential of F. viren through AR and ppar-α modulation by scutellarein., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Today, Alzheimer’s disease (AD)—the most common neurodegenerative disorder, which affects 50 million people—remains incurable. Several studies suggest that one of the main pathological hallmarks of AD is the accumulation of abnormal amyloid beta (Aβ) aggregates; therefore, many therapeutic approaches focus on anti-Aβ aggregation inhibitors. Taking into consideration that plant-derived secondary metabolites seem to have neuroprotective effects, we attempted to assess the effects of two flavones—eupatorin and scutellarein—on the amyloidogenesis of Aβ peptides. Biophysical experimental methods were employed to inspect the aggregation process of Aβ after its incubation with each natural product, while we monitored their interactions with the oligomerized Aβ through molecular dynamics simulations. More importantly, we validated our in vitro and in silico results in a multicellular organismal model—namely, Caenorhabditis elegans—and we concluded that eupatorin is indeed able to delay the amyloidogenesis of Aβ peptides in a concentration-dependent manner. Finally, we propose that further investigation could lead to the exploitation of eupatorin or its analogues as potential drug candidates.

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]

[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]

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]

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: Scutellarein, a widely studied ingredient of scutellaria herbs, has higher bioavailability and solubility than that of scutellarin. Although the scutellarein had been reported to modulate numerous biological functions, its ability in suppressing cardiac hypertrophy remains unclear. Hence, the present study attempted to investigate whether scutellarein played critical roles in preventing phenylephrine (PE)-induced cardiac hypertrophy. Methods and results: Immunocytochemistry (ICC) was employed for evaluating the morphology of the treated cardiomyocytes. Real-time PCR and western blot were respectively applied to assess the mRNA levels and protein expression of the relevant molecules. Bioinformatics analyses were carried out to investigate the potential mechanisms by which scutellarein modulated the PE-induced cardiac hypertrophy. The results showed that Scutellarein treatment significantly inhibited PE-induced increase in H9c2 and AC16 cardiomyocyte size. Besides, scutellarein treatment also dramatically suppressed the expression of the cardiac hypertrophic markers: ANP, BNP and β-MHC. Furthermore, the effects of scutellarein on attenuating the cardiac hypertrophy might be mediated by suppressing the activity of TRAF2/NF-κB signaling pathway. Conclusions: Collectively, our data indicated that scutellarein could protect against PE-induced cardiac hypertrophy via regulating TRAF2/NF-κB signaling pathway using in vitro experiments. [ABSTRACT FROM AUTHOR]

Background: The growth of several cancers can be inhibited by naturally occurring medicinal plants. A flavone called Scutellarein found in the perennial herb Scutellaria lateriflora does have a wide range of biological functions. Scutellarein was studied to determine whether it could induce apoptosis and cause cytotoxicity. Methods: On oral squamous cell carcinoma KB cell lines, Scutellarein's cytotoxic activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Scutellarein was added to KB cells at concentrations ranging from 25 to 125 g/mL for 24 h. The real-time polymerase chain reaction was also used to investigate apoptotic induction potential in Scutellarein-incubated KB cell lines by analyzing Bcl-2 protein and gene expression. Results: In KB-cell lines treated with scutellarein, cytotoxicity and anticancer effects were observed, as well as inhibit the growth of cancer cells. In comparison to the cells not treated with scutellarein, KB cells that had been exposed to scutellarein displayed reduced Bcl-2 expression. Conclusion: KB cells were treated with scutellarein to induce apoptosis, suggesting its potential as a chemo preventative agent. This activity appears to be mediated through the modulation of Bcl-2, a cytotoxic gene. [ABSTRACT FROM AUTHOR]

AIM: To investigate the alleviation of scutellarein (SN) against inner blood-retinal-barrier (iBRB) dysfunction in microglia cells stimulated by hyperglycemia and to elucidate the engaged mechanism. METHODS: Microglia BV2 cells were stimulated by using 25 mmol/L D-glucose. The same concentration of mannitol (25 mmol/L) was applied as an isotonic contrast. Real-time PCR, Western-blot assay and immunofluorescence staining assay was performed. The dysfunction of iBRB in vitro was detected by using transendothelial electrical resistance (TEER) assay. Additionally, the leakage of fluorescein isothiocyanate (FITC)-conjugated dextran (70 kDa) was detected. RESULTS: SN abrogated microglia BV2 cells activation and reduced the phosphorylated activation of extracellular signal-regulated protein kinase (ERK)1/2. SN also decreased the transcriptional activation of nuclear factor κB (NFκB) and the elevated expression of tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-1β in BV2 cells treated with D-glucose (25 mmol/L). SN attenuated iBRB dysfunction in human retinal endothelial cells (HRECs) or choroid-retinal endothelial RF/6A cells when those cells were treated with TNFα, IL-1β or IL-6, or co-cultured with microglia cells stimulated by D-glucose. Moreover, SN restored the decreased protein expression of tight junctions (TJs) in TNFα-treated HRECs and RF/6A cells. CONCLUSION: SN not only alleviate iBRB dysfunction via directly inhibiting retinal endothelial injury caused by TNFα, IL-1β or IL-6, but also reduce the release of TNFα, IL-1β and IL-6 from microglia cells by abrogating hyperglycemia-mediated the activation of microglia cells.

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. [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]

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. [ABSTRACT FROM AUTHOR]

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

[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]

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.

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.

The multi-target effects of natural products allow us to fight complex diseases like cancer on multiple fronts. Unlike docking techniques, network-based approaches such as genome-scale metabolic modelling can capture multi-target effects. However, the incompleteness of natural product target information reduces the prediction accuracy of in silico gene knockout strategies. Here, we present a drug selection workflow based on context-specific genome-scale metabolic models, built from the expression data of cancer cells treated with natural products, to predict cell viability. The workflow comprises four steps: first, in silico single-drug and drug combination predictions; second, the assessment of the effects of natural products on cancer metabolism via the computation of a dissimilarity score between the treated and control models; third, the identification of natural products with similar effects to the approved drugs; and fourth, the identification of drugs with the predicted effects in pathways of interest, such as the androgen and estrogen pathway. Out of the initial 101 natural products, nine candidates were tested in a 2D cell viability assay. Bruceine D, emodin, and scutellarein showed a dose-dependent inhibition of MCF-7 and Hs 578T cell proliferation with IC50 values between 0.7 to 65 μM, depending on the drug and cell line. Bruceine D, extracted from Brucea javanica seeds, showed the highest potency.

• Scutellarein has a novel pharmacological effect: anti-insulin resistance. • Anti-oxidant stress may be one of the important mechanisms of Sc in improving IR. • TThe underlying mechanisms might be related to the activation of insulin signaling pathway and AMPKα. • Our results advance the understanding of the pharmacological actions of scutellarein. • Our results provide a role for scutellarein in effective management of diabetes mellitus. Scutellarein (Sc), a natural compound and an active ingredient of Erigeronbrevis-capus (Vant.) , shows anti-obesity, anti-inflammation and lipid-lowering properties in our previous study. However, no previous in vivo and vitro has been conducted to assess the effects of Sc in insulin resistance (IR). This study investigated the effects of Sc on IR and oxidative stress and explored the underlying mechanisms of action in vivo and vitro. A well-established mouse model of IR, induced by high-fat diet (HFD) feeding, was applied in this study. The effects of Sc were evaluated on obesity, glycometabolism disorder and oxidative stress. The anti-IR effect was assessed using blood glucose, serum insulin, HOMA index, intraperitoneal glucose tolerance tests (IPGTT), intraperitoneal insulin tolerance tests (IPITT), and glucose-regulating enzyme activity. The insulin signaling pathways and AMPKα expressions were tested by Western blot. The primary culture of hepatocytes was prepared and used for confirming the above signaling pathways. Obesity, IR and oxidative stress developed in HFD mice. Administration of Sc at a dose of 50 mg/kg for 16 weeks effectively attenuated these changes. Further studies revealed the antagonistic effect of Sc on IR was a result of the activation of the insulin signaling pathway and AMPKα. The primary hepatocyte test, stimulated by high glucose, further confirmed that SC exerts anti-IR through the above signaling pathway and key protein. These results suggested that Sc possesses not only an important novel anti-IR effect but also an anti-oxidative stress effect. These favorable effects were causally associated with weight loss and the improved glycometabolism. The underlying mechanisms might associated with the activation of the insulin signaling pathway and AMPKα. Our study promotes the understanding of the pharmacological actions of Sc, and plays a role for Sc in the effective treatment of diabetes mellitus. [ABSTRACT FROM AUTHOR]

Scutellarein (SCU) is a well-known flavone with a broad range of biological activities against several cancers. Human hepatocellular carcinoma (HCC) is major cancer type due to its poor prognosis even after treatment with chemotherapeutic drugs, which causes a variety of side effects in patients. Therefore, efforts have been made to develop effective biomarkers in the treatment of HCC in order to improve therapeutic outcomes using natural based agents. The current study used SCU as a treatment approach against HCC using the HepG2 cell line. Based on the cell viability assessment up to a 200 μM concentration of SCU, three low-toxic concentrations of (25, 50, and 100) μM were adopted for further investigation. SCU induced cell cycle arrest at the G2/M phase and inhibited cell migration and proliferation in HepG2 cells in a dose-dependent manner. Furthermore, increased PTEN expression by SCU led to the subsequent downregulation of PI3K/Akt/NF-κB signaling pathway related proteins. In addition, SCU regulated the metastasis with EMT and migration-related proteins in HepG2 cells. In summary, SCU inhibits cell proliferation and metastasis in HepG2 cells through PI3K/Akt/NF-κB signaling by upregulation of PTEN, suggesting that SCU might be used as a potential agent for HCC therapy.

Aims: Scutellarein (Sc), a natural compound and an active ingredient of Erigeron breviscapus (vant.), shows anti-inflammatory and antioxidant properties and has the potential for obesity treatment. However, no previous in vivo study has been conducted to assess the role of Sc in obesity. This study investigated the effects of Sc on obesity and associated hyperlipidemia and fatty liver and explores the underlying mechanisms of action in a mouse model. Methods: The study was conducted using a well-established mouse model of obesity induced by high-fat diet (HFD) feeding. Anti-obesity effects were assessed using body weight, abdominal circumference, white adipose tissue, adiposity index, and fatty liver index. Lipid lowering and liver protective effects were examined by blood sample analysis. Lipid dystopia deposition was confirmed by liver pathological sections. The signaling pathways of lipid metabolism and cytokine/inflammatory mediator were evaluated using Real-Time PCR and Western blot. Results: Central obesity, dyslipidemia, inflammation, and hepatic steatosis were developed in mice fed with HFD. Administration of Sc at a dose of 50 mg/kg for 16 weeks effectively attenuated all obesity indicators tested. Further studies revealed the antagonistic effect of Sc on hyperlipidemia was a result of the repression of the lipid synthesis pathway, de novo pathway, HMGCR, promoting fatty acid oxidation (PPARα, CPT-1a) and increased cholesterol output (PPARγ-LXRα-ABCA1). The anti-inflammatory effect was attributed to blocking the expression of inflammatory genes, including TNF-α, IL-6, NF-κB. Conclusions: These results suggest that Sc possesses important novel anti-obesity effects accompanying lipid lowering and anti-inflammation-based liver protective effects. These favorable effects are causally associated with the suppression of gene expression of inflammatory cytokines and fine regulation of genes responsible for energy metabolism. Our results advance the understanding of the pharmacological actions of Sc, and provides a role for Sc in effective management of obesity.

Fairer skin is preferred in many Asian countries and there is a high demand for skin whitening and lightening products. However, in recent years, problems related to the safety of using whitening agents have emerged. This study demonstrates that plant-derived scutellarein effectively inhibits melanogenesis in B16 melanoma cells. However, baicalein, which is similar to scutellarein in its chemical structure, does not show any inhibitory effect on melanogenesis. Cellular tyrosinase activity is decreased by scutellarein in a dose-dependent manner. No cytotoxicity is observed at the effective concentration range. Additionally, both the protein and mRNA levels of tyrosinase are significantly decreased by scutellarein. Further, the risk of leukoderma development also is determined by evaluating the production of free hydroxyl radicals (˙OH); scutellarein treatment does not induce ˙OH production. Scutellarein shows no risk of causing leukoderma. Our results suggest that scutellarein or plant extracts containing high concentrations of scutellarein have the potential to inhibit melanin production and serve as cosmetic skin-lightening agents.

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]

To search novel therapy for human colon cancer, scutellarein identified from Scutellaria barbata was investigated using HCT116 cells. As a result, scutellarein can induce apoptosis of HCT116 cells. Further investigation for the mechanism has revealed scutellarein can increase the production of intracellular ROS and lead to the collapse of mitochondrial membrane potential. Meanwhile, the activity of caspase-3 in HCT116 cells was elevated by scutellarein. Moreover, down-regulated Bcl-2 and up-regulated Bax were observed. Additionaly, scutellarein resulted in cytochrome c release from mitochondria. These results indicated the apoptosis induction of HCT116 cells by scutellarein was implemented through ROS-mediated mitochondria-dependent pathway. [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]

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]

[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]

[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]