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The pecan nutshell [Carya illinoinensis (Wangenh) C. Koch] (PNS) is a source of bioactives with important beneficial properties for the human health. PNS represents between 40-50 % of total mass of the nut, resulting as waste without any added value for the food industry. Even though a variety of methods were already developed for bioactive extraction from this waste, unconventional methodologies, or those which apart from green chemistry principles, were discarded considering the cost of production, the sustainable development goals of United Nations and the feasibility of real inclusion of the technology in the food chain. Then, to add-value to this waste, a low-cost, green and easy-scalable extraction methodology was developed based on the determination of seven relevant factors by means of a factorial design and a Response Surface Methodology, allowing the extraction of bioactives with antioxidant capacity. The pecan nutshell extract had a high concentration of phenolic compounds (166 mg gallic acid equivalents-GAE/g dry weight-dw), flavonoids (90 mg catechin equivalent-CE/g dw) and condensed tannins (189 mg CE/g dw) -related also to the polymeric color (74.6 %)-, with high antioxidant capacities of ABTS +. radical inhibition (3665 µmol Trolox Equivalent-TE/g dw) and of iron reduction (1305 µmol TE/g dw). Several compounds associated with these determinations were identified by HPLC-ESI-MS/MS, such as [Epi]catechin-[Epi]catechin-[Epi]gallocatechin, myricetin, dihydroquercetins, dimers A and B of protoanthocyanidins, ellagitannins and ellagic acid derivatives. Hence, through the methodology developed here, we obtained a phenolic rich extract with possible benefits for human health, and of high industrial scalability for this co-product transformation., 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.)

Epimedium, a traditional Chinese medicine commonly used as a dietary supplement, contains polysaccharides and flavonoids as its main bioactive ingredients. In this study, a neutral homogeneous polysaccharide (EPSN-1) was isolated from Epimedium brevicornu Maxim. EPSN-1 was identified as a glucan with a backbone of →4)-α-D-Glcp-(1→, branched units comprised α-D-Glcp-(1→6)-α-D-Glcp-(1→, β-D-Glcp-(1→6)-β-D-Glcp-(1→ and α-D-Glcp-(1→ connected to the C6 position of backbone. The conformation of EPSN-1 in aqueous solution indicated its potential to form nanoparticles. This paper aims to investigate the carrier and pharmacodynamic activity of EPSN-1. The findings demonstrated that, on the one hand, EPSN-1, as a functional ingredient, may load Icariin (ICA) through non-covalent interactions, improving its biopharmaceutical properties such as solubility and stability, thereby improving its intestinal absorption. Additionally, as an effective ingredient, EPSN-1 could help maintain the balance of the intestinal environment by increasing the abundance of Parabacteroides, Lachnospiraceae UGG-001, Anaeroplasma, and Eubacterium xylanophilum group, while decreasing the abundance of Allobaculum, Blautia, and Adlercreutzia. Overall, this dual action of EPSN-1 sheds light on the potential applications of natural polysaccharides, highlighting their dual role as carriers and contributors to biological activity., 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.)

This study explores the impact of processing techniques on the bioactive composition and antioxidant properties of Bambusa nutans shoots, an underutilized superfood. Boiling resulted in a significant reduction of total phenols (39.52%), flavonoid (8.07%), and tannin (27.77%). Conversely, fermentation increased total phenols (25.92%), tannin (34.72%), and phytosterol (75.39%). Antioxidant activities were notably higher in fermented-shoots, as indicated by DPPH and FRAP assays, and in-vivo experiments demonstrated increased GSH (31.85%) and decreased LPO levels (11.12%) post-administration of fermented-shoots extract. Spectral analysis revealed an increased diversity of compounds in fermented shoots, with GC/MS identifying hexadecane-1-ol in significantly higher proportions and 11 characteristic bands in FTIR spectra. HPLC analysis demonstrated changes in phenolic acids and flavonoid content, with fermentation enhancing 3,4,5-trihydroxybenzoic acid, 4'-hydroxycinnamic acid, benzene-1,2-diol, and luteolin contents. This study underscores the dynamic nature of B. nutans shoots, highlighting the potential for enhanced bioactivity and antioxidant properties through fermentation, offering promising avenues for culinary and pharmaceutical developments., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pomaces obtained from three San Marzano tomato genotypes including the wild type (WT), Sun Black (SB), and colorless fruit epidermis (CL) were dried at 50 °C and analyzed for nutritional composition, total polyphenol (TPC), flavonoid (TFC) content, polyphenol qualitative profile, total antioxidant capacity (TAC), and antimicrobial activity. Commercial dried tomato powder (CTRP) was included as a control. No differences were detected nutritionally, in TPC and antimicrobial activity, but significant changes were observed for TFC and TAC, underlying variation in the phenolic profile. SB pomace (SBP) had the highest TFC and TAC. LC-HRMS analysis showed a flavonoid-enriched profile in SBP besides the exclusive presence of anthocyanins, with petanin and negretein as the most abundant. Among flavonoids, quercetin-hexose-deoxyhexose-pentose, naringenin, and rutin were the major. Overall, we showed the potential of dried tomato pomace, especially SBP, as an extremely valuable waste product to be transformed into a functional ingredient, reducing the food industry waste., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AM is participating as inventors in owing the trademark “Sun Black” and the rights on the registered variety “Solenero.” The ownership is the University of Tuscia, Viterbo, Italy., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this study, an ultrasonic-assisted natural deep eutectic solvent (NaDES) was used to extract flavonoids from Perilla frutescens (L.) Britt. leaves. Of 10 tested NaDESs, that comprising D-(+)-glucose and glycerol exhibited the best total flavonoid extraction rate. Response surface methodology (RSM) was used for extraction modeling and optimization, and the total flavonoid content reached 87.48 ± 1.61 mg RE/g DW, which was a significant increase of 5.36% compared with that of 80% ethanol extraction. Morphological changes in P. frutescens leaves before and after extraction were analyzed by scanning electron microscopy (SEM), and the mechanism of NaDES formation was studied by Fourier transform infrared (FT-IR) spectroscopy. Furthermore, 10 flavonoids were identified by UPLC-Q-TOF-MS. In addition, the NaDES extract had better biological activity according to five kinds of antioxidant capacity measurements, cyclooxygenase-2 (COX-2) and hyaluronidase (Hyal) inhibition experiments. Moreover, the stability test revealed that the total flavonoid loss rate of the NaDES extract after four weeks was 37.75% lower than that of the ethanol extract. These results indicate that the NaDES can effectively extract flavonoids from P. frutescens leaves and provide a reference for further applications in the food, medicine, health product and cosmetic industries., 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.)

Based on in vitro digestion, micellar synthesis, and Caco-2 cell model, this study investigated the effects of typical flavonoids in citrus (naringenin, naringin, hesperetin, hesperidin, quercetin, and rutin) at different doses on the micellization and cellular uptake of β -carotene. In in vitro digestion, low-dose flavonoids enhanced β -carotene bioaccesssibility by regulating the stability and dispersibility of the intestinal medium, particularly quercetin, which significantly increased the bioaccessibility by 44.6% ( p < 0.05). Furthermore, naringenin, hesperetin, hesperidin, and quercetin enhanced the micellar incorporation rate of β -carotene; however, naringin and rutin exhibited an opposite effect, particularly naringin, which significantly reduced it by 71.3% ( p < 0.05). This phenomenon could be attributed to the high solubility of naringin and rutin in micelles, resulting in a competitive inhibitory effect on β -carotene. Besides, all treatments significantly enhanced β -carotene cellular uptake ( p < 0.05) by promoting the expression of scavenger receptor class B type I and Niemann-Pick C1-Like 1.

Huanglongbing (HLB), associated with the psyllid-vectored phloem-limited bacterium, Candidatus Liberibacter asiaticus (CLas), is a disease threat to all citrus production worldwide. Currently, there are no sustainable curative or prophylactic treatments available. In this study, we utilized mass spectrometry (MS)-based metabolomics in combination with 3D molecular mapping to visualize complex chemistries within plant tissues to explore how these chemistries change in vivo in HLB-infected trees. We demonstrate how spatial information from molecular maps of branches and single leaves yields insight into the biology not accessible otherwise. In particular, we found evidence that flavonoid biosynthesis is disrupted in HLB-infected trees, and an increase in the polyamine, feruloylputrescine, is highly correlated with an increase in disease severity. Based on mechanistic details revealed by these molecular maps, followed by metabolic modeling, we formulated and tested the hypothesis that CLas infection either directly or indirectly converts the precursor compound, ferulic acid, to feruloylputrescine to suppress the antimicrobial effects of ferulic acid and biosynthetically downstream flavonoids. Using in vitro bioassays, we demonstrated that ferulic acid and bioflavonoids are indeed highly bactericidal to CLas, with the activity on par with a reference antibiotic, oxytetracycline, recently approved for HLB management. We propose these compounds should be evaluated as therapeutics alternatives to the antibiotics for HLB treatment. Overall, the utilized 3D metabolic mapping approach provides a promising methodological framework to identify pathogen-specific inhibitory compounds in planta for potential prophylactic or therapeutic applications., (© 2024. The Author(s).)

Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α-synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO-A and MAO-B, responsible for the oxidation of monoamines such as dopamine. Increased MAO-B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD-like manifestations. Inhibitors of MAO-B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO-B inhibitors such as selegiline, L-deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO-B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO-B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO-B inhibitors. The discussion encompasses both in vitro and in vivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO-B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD-like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO-B inhibitory activity and additionally multi-targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches., (© 2024 John Wiley & Sons Ltd.)

Computer-aided drug discovery plays a vital role in developing novel medications for various diseases. The COVID-19 pandemic has heightened the need for innovative approaches to design lead compounds with the potential to become effective drugs. Specifically, designing promising inhibitors of the SARS-CoV-2 main protease (Mpro) is crucial, as it plays a key role in viral replication. Phytochemicals, primarily flavonoids and flavonols from medicinal plants, were screened. Fifty small molecules were selected for molecular docking analysis against SARS-CoV-2 Mpro (PDB ID: 6LU7). Binding energies and interactions were analyzed and compared to those of the anti-SARS-CoV-2 inhibitor Nirmatrelvir. Using these 50 structures as a training set, a QSAR model was built employing simple, reversible topological descriptors. An inverse-QSAR analysis was then performed on 2⁹ = 512 hydroxyl combinations at nine possible positions on the flavone and flavonol scaffold. The model predicted three novel, promising compounds exhibiting the most favorable binding energies (-8.5 kcal/mol) among the 512 possible hydroxyl combinations: 3,6,7,2',4'-pentahydroxyflavone (PF9), 6,7,2',4'-tetrahydroxyflavone (PF11), and 3,6,7,4'-tetrahydroxyflavone (PF15). Molecular dynamics (MD) simulations demonstrated the stability of the PF9/Mpro complex over 300 ns of simulation. These predicted structures, reported here for the first time, warrant synthesis and further evaluation of their biological activity through in vitro and in vivo studies., 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.)

Exploring antioxidant potential of flavonoid derivatives after ESIPT process provides a theoretical basis for discovering compounds with higher antioxidant capacity. In this work, employing the density functional theory (DFT) and time-dependent density functional theory (TD-DFT) methods, the antioxidant potential of two citrus-derived naringenin flavonoids after ESIPT process is explored. Based on studies of ESIPT process including IMHB intensity variations, potential energy curves, and transition state, these molecules exist only in enol and keto ⁎ forms due to ultra-fast ESIPT. The HOMOs are utilized to explore electron-donating capacity, demonstrating that the molecules in keto ⁎ form is stronger than that in enol form. Furthermore, the atomic dipole moment corrected Hirshfeld population (ADCH) and Fukui functions indicate that the sites attacked by the electrophilic free radical of the two molecules in the keto ⁎ form are O 3 and O 5' respectively, and both are more active than in the enol form. Overall, a comprehensive consideration of the ESIPT process and antioxidant potential of flavonoid derivatives will facilitate the exploration and design of substances with higher antioxidant capacity., 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 B.V. All rights reserved.)

The inhibitory potential of 17 flavonoids on lactate dehydrogenase A (LDHA), a key enzyme in the downstream process of aerobic glycolysis in cancer cells, is investigated. Fisetin exhibited excellent inhibitory activity (IC 50  = 0.066 µM). Quercetin 3-β-D-glucoside, quercetin 3-galactoside, luteolin, neoeriocitrin, and luteolin 7-O-β-D-glucoside showed good inhibitory activity (IC 50  = 1.397-15.730 µM). Biochanin A, baicalein, quercetin, scutellarein-7-glucuronide, diosmetin, baicalein 7-O-β-D-glucuronide, and apigenin 7-apioglucoside demonstrated moderate inhibitory activity (IC 50  = 33.007-86.643 µM). Eriodictyol, quercetin 7-O-β-D-glucoside, apigenin 7-O-β-D-glucoside, and epicatechin were inactive. The Lineweaver-Burk plot showed that fisetin competitively inhibits NADH binding (K i  = 0.024 µM). K i values for other compounds were calculated using the Cheng-Prusoff equation (K i  = 0.2799-2.1661 µM). The study revealed that the inhibitory effect of flavonoids varies with the number and position of OH groups and bound sugars. Molecular docking analyses indicated that flavonoids exhibited strong interactions with the NADH binding site of LDHA through hydrophobic interactions and hydrogen bonds. Molecular dynamic simulations tested the stability of the fisetin-LDHA complex over 100 ns and showed fisetin's high binding affinity to LDHA, maintaining strong hydrogen bonds. The binding energy of fisetin with LDHA was -33.928 kcal/mol, indicating its effectiveness as an LDHA inhibitor. Consequently, flavonoids identified as strong inhibitors could be potential cancer treatment sources through LDHA inhibition., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated blood glucose levels, posing a significant global health concern due to its increasing prevalence. Insulin resistance (IR) plays a major role in the development of T2DM and is often linked to factors such as obesity, physical inactivity, and a sedentary lifestyle. Recently, there has been growing interest in exploring the potential of natural products for improving insulin sensitivity and glucose metabolism. Among these, Cynomorium songaricum Rupr., an edible parasitic plant, has shown promising antidiabetic effects. However, research on its beneficial effects on IR is still nascent. Therefore, this study aims to investigate the application of a Cynomorium songaricum flavonoid-enriched fraction (CSF) in the treatment of IR in T2DM, along with elucidating the chemical and biochemical mechanisms involved., Method: First, UHPLC/ESI-LTQ-Orbitrap-MS was utilized to perform a chemical profiling of CSF. Subsequently, glycogen synthesis, gluconeogenesis and glucose consumption assays were conducted on HepG2 cells with a high glucose high insulin-induced IR model to illustrate the favorable impacts of CSF on IR. Then, an innovative network pharmacology analysis was executed to predict the potential chemical components and hub genes contributing to CSF's protective effect against IR. To further elucidate molecular interactions, molecular docking studies were performed, focusing on the binding interactions between active constituents of CSF and crucial targets. Additionally, an RNA-sequencing assay was employed to uncover the underlying biochemical signaling pathway responsible for CSF's beneficial effects. To validate these findings, western blot and qPCR assays were employed to verify the pathways related to IR and the potential signaling cascades leading to the amelioration of IR., Results: The UHPLC/ESI-LTQ-Orbitrap-MS analysis successfully identified a total of thirty-six flavonoids derived from CSF. Moreover, CSF was shown to significantly improve glycogen synthesis and glucose consumption as well as inhibit gluconeogenesis in HepG2 cells of IR. An innovative network pharmacology analysis unveiled key hub genes-AKT1 and PI3K-integral to metabolic syndrome-related signaling pathways, which contributed to the favorable impact of CSF against IR. Noteworthy active ingredients including quercetin, ellagic acid and naringenin were identified as potential contributors to these effects. The results of western blot and qPCR assays provided compelling evidence that CSF improved insulin sensitivity by modulating the PI3K-Akt signaling pathway. Subsequent RNA-sequencing analysis, in tandem with western blot assays, delved deeper into the potential mechanisms underlying CSF's advantageous effects against IR, potentially associated with the enhancement of endoplasmic reticulum (ER) proteostasis., Conclusion: CSF exhibited a remarkable ability to enhance insulin sensitivity in the IR model of HepG2 cells. This was evident through enhancements in glycogen synthesis and glucose consumption, along with its inhibitory impact on gluconeogenesis. Furthermore, CSF demonstrated an improvement in the insulin-mediated PI3K-Akt signaling pathway. The potential active constituents were identified as quercetin, ellagic acid and naringenin. The underlying biochemical mechanisms responsible for CSF's beneficial effects against IR were closely linked to its capacity to mitigate ER stress, thereby offering a comprehensive understanding of its protective action., 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. Published by Elsevier GmbH.)

The long-term stability in real and accelerated time for galenic oils based on full-spectrum cannabis has been studied, using sesame oil as a dilutant. Sesame oil is one of the most used vehicles in the cannabis pharmaceutical industry due to the costs and increased oral bioavailability of cannabinoids. The real-time assays conducted at 25 °C over twelve months demonstrated high stability and showed no significant changes in the composition of cannabinoids, total polyphenols, flavonoids, or antioxidant capacity. In these studies, it was observed that there was no development of microorganisms compromising the stability of the oils over a year. The three oil varieties exhibited a high bactericidal capacity against E. coli, S. aureus, and P. larvae., Competing Interests: Declaration of competing interest Authors declares that there is no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nineteen flavonoids were isolated from the fruits of Psoralea corylifolia L., including a novel flavanol (3) and three novel isoflavones (12-14). Their chemical structures were unequivocally determined through comprehensive spectral data analysis. The anti-proliferative effect of the isolated flavonoids was assessed in vitro using the MTT assay. Molecular docking and ELISA were employed to determine the inhibitory effects of the active compounds on ALK5. Isobavachalcone was found to inhibit TGF-β 1 induced EMT in A549 cells by Wound healing assay and Transwell chamber assay. Immunofluorescence assay and Western blot assay showed that IBC could inhibit cytoskeleton rearrangement, reduce the phosphorylation of ALK5, ERK, and Smad, down-regulate Snail expression, and up-regulate E-cadherin expression in TGF-β 1 induced A549 cells, thereby exerting the potential inhibitory effects on epithelial-mesenchymal transition (EMT) process in A549 cells. The findings presented herein establish a fundamental basis for investigating the anti-proliferative and anti-metastatic properties of psoralen flavonoids in human non-small cell lung cancer., 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. Published by Elsevier Inc.)

Epimedium is a traditional Chinese medicine with a wide range of clinical applications; however, there have been numerous reports of adverse reactions in recent years. The most common side effect of Epimedium is liver injury. In this study, the liquid chromatography-mass spectrometry (LC-MS) method has been established to study the components of Epimedium and to identify the components absorbed into the blood of rats. Bioinformatics was used to screen out potential toxic components, and the integrating metabolomics method was used to explore the molecular mechanism of Epimedium-induced liver injury. The chemical constituents of Epimedium were identified by LC-MS, and 62 compounds were obtained, including 57 flavonoids, four organic acids and one alkaloid. The toxicity network of "Epimedium-component-target-liver injury" was constructed using bioinformatics research methods, and then the key hepatotoxic component icaritin was identified. Integrating metabolomics was used to investigate the changes in the metabolic profile of L-02 cells with different durations of icaritin administration compared with the control group, and 106 different metabolites were obtained. A total of 14 potential biomarkers significantly associated with cell survival were screened by Pearson correlation analysis combined with the L-02 cell survival rate. Our study preliminarily revealed the mechanism of hepatotoxicity induced by Epimedium., (© 2024 John Wiley & Sons Ltd.)

Morus alba L. is a plant with a long history of dietary and medicinal uses. We hypothesized that M. alba possesses a significant biological potential. In that sense, we aimed to generate the chemical, antimicrobial, toxicological, and molecular profile of M. alba leaf and fruit extracts. Our results showed that extracts were rich in vitamin C, phenols, and flavonoids, with quercetin and pterostilbene concentrated in the leaf, while fisetin, hesperidin, resveratrol, and luteolin were detected in fruit. Extracts exhibited antimicrobial activity against all tested bacteria, including multidrug-resistant strains. The widest inhibition zones were in Staphylococcus aureus ATCC 33591. The values of the minimum inhibitory concentration ranged from 15.62 μg/ml in Enterococcus faecalis to 500 μg/ml in several bacteria. Minimum bactericidal concentration ranged from 31.25 μg/ml to 1000 μg/ml. Extracts impacted the biofilm formation in a concentration-dependent and species-specific manner. A significant difference in the frequency of nucleoplasmic bridges between the methanolic extract of fruit (0.5 μg/ml, 1 μg/ml, 2 μg/ml), as well as for the frequency of micronuclei between ethanolic extract of leaf (2 μg/ml) and the control group was observed. Molecular docking suggested that hesperidin possesses the highest binding affinity for multidrug efflux transporter AcrB and acyl-PBP2a from MRSA, as well as for the SARS-CoV-2 Mpro. This study, by complementing previous research in this field, gives new insights that could be of great value in obtaining a more comprehensive picture of the Morus alba L. bioactive potential, chemical composition, antimicrobial and toxicological features, as well as molecular profile., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Psoriasis is a chronic inflammatory disease and is difficult to cure. In this work, a series of novel chrysin derivatives have been designed and prepared while evaluating anti-inflammatory activities in vitro and in vivo. In vitro, RAW264.7 cells were used to detect the inflammatory activities at first, and compounds 4h, 4k, and 4o significantly decreased the levels of NO, TNF-α, and IL-6. In particular, compound 4o showed superior anti-inflammatory activities than other compounds. Moreover, compound 4o decreased the level of IL-17A in LPS-induced HaCaT cells in vitro. The effect and mechanism of anti-inflammatory activities on psoriasis were determined by imiquimod (IMQ)-induced psoriasis-like mice in vivo. Compound 4o deduced the level of IL-6, IL-17A, IL-22, IL-23, and TNF-α, and showed potent anti-psoriasis activity. Further mechanism study suggested that compound 4o could improve the skin inflammation of psoriasis by inhibiting the NF-κB and STAT3 signaling pathways., 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 Inc. All rights reserved.)

This paper explores the potential of flavonoid alkaloids, a unique class of compounds that contain both flavonoid and alkaloid structures, as emerging targets for drug discovery. These compounds exhibit diverse biological activities, such as anti-inflammatory, anti-cancer, and anti-diabetic effects, which are attributed to the combination of different flavonoid scaffolds and alkaloid groups. Flavonoid alkaloids have attracted researchers' attention due to their diverse structures and important bio-activities. Therefore, this review summarizes recent advances in the extraction, purification, structural characterization, synthesis pathways and biological activities of flavonoid alkaloids from natural sources. Finally, the potential prospects and challenges associated with this class of compounds in pharmacological research are discussed along with details of a mechanistic investigation and future clinical applications in this research field., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Effective control of postprandial blood glucose (PBG) level is essential for the prevention and treatment of diabetes and its complications. Several flavonoids have attracted much attention due to their significant PBG-lowering effects. However, there is still a certain gap in the in vivo hypoglycemic activity of most flavonoids compared to first-line drugs available on the market, and are still lack of the PBG-lowering effects of 8-hydroxyflavones and their structure-activity relationship., Purpose: Evaluate hypoglycemic effects of 8-hydroxyflavones from Rhodiola crenulata in vitro and in vivo, especially comparatively analyze the relationship between hypoglycemic effects and flavonoid configuration and reveal the possible mechanism of 8-hydroxyflavones in lowering hyperglycemia., Methods: Starch, maltose, sucrose, and glucose tolerance tests in both diabetic and normal mice were used to evaluate and compare the hypoglycemic effects of 8-hydroxyflavones rhodiosin (RHS), rhodionin (RHN), and herbacetin (HBT). Molecular docking, enzyme kinetics, and immunofluorescence analysis were used to research the possible hypoglycemic mechanisms of 8-hydroxyflavones., Results: RHS (5 and 10 mg/kg) could efficiently decrease PBG levels in both normal and diabetes mice. Moreover, RHS, RHN, and HBT all had significant PBG-lowering effects in transgenic diabetes mice, and the effects were equivalent to or stronger than acarbose. Further mechanism research indicated that 8-hydroxyflavones achieved PBG-lowering effects by inhibiting both the activity and production of glycosidase. Notably, we have innovatively discovered that inhibiting the expression of glycosidases rather than just their activities may be a new target for hypoglycemic drugs., Conclusion: We have firstly comprehensively and systematically clarified PBG-lowering effects of 8-hydroxyflavones from Rhodiola crenulata, and revealed their structure-activity relationships and hypoglycemic mechanisms. The study demonstrated that the substitution of 8-hydroxy groups in flavonoids could significantly enhance their hypoglycemic effects, which were equivalent to or stronger than commercially available drug acarbose. 8-Hydroxyflavones could be used as therapeutic or health drugs with significant potential to reduce postprandial hyperglycemia., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Phenylarsine oxide (PAO) is a known environmental pollutant and skin keratinocytes are most seriously affected. Baicalin (BCN) was reported to have antioxidant and anti-inflammatory effects, but its protective effect against PAO toxicity is unknown. This study aimed at exploring whether baicalin can reverse the toxicity of human epidermal keratinocytes that are subjected to PAO exposure and underlying mechanisms. In silico analysis from a publicly accessible HaCaT cell transcriptome dataset exposed to chronic Arsenic showed significant differential expression of several genes, including the genes related to DNA replication. Later, we performed in vitro experiments, in which HaCaT cells were exposed to PAO (500 nM) in the existence of BCN (10-50 µM). Treatment of PAO alone induces the JNK, p38 and caspase-3 activation, which were engaged in the apoptosis induction, while the activity of AKT was significantly inhibited, which was engaged in the suppression of apoptosis. PAO suppressed SIRT3 expression and induced intracellular reactive oxygen species (ROS), causing a marked reduce in cell viability and apoptosis. However, BCN treatment restored the PAO-induced suppression of SIRT3 and AKT expression, reduced intracellular ROS generation, and markedly suppressed both caspase-3 activation and apoptosis induction. However, the protective effect of BCN was significantly attenuated after pretreatment with nicotinamide, an inhibitor of SIRT3. These findings indicate that BCN protects against cell death induced by PAO via inhibiting excessive intracellular ROS generation via restoring SIRT3 activity and reactivating downstream AKT pathway. In this study, we firstly shown that BCN is an efficient drug to prevent PAO-induced skin cytotoxicity, and these findings need to be confirmed by in vivo and clinical investigations., 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. Published by Elsevier Inc.)

Morin (MRN), an intriguing bioflavonol, has received increasing interest for its antioxidant properties, as have its metal complexes (M z+ -MRN). Understanding their antioxidant behavior is critical to assess their pharmaceutical, nutraceutical potential, and therapeutic impact in the design of advanced antioxidant drugs. To this end, knowing the speciation of different H + -MRN and M z+ -MRN is pivotal to understand and compare their antioxidant ability. In this work, the protonation constant values of MRN under physiological ionic strength and temperature conditions (I = 0.15 mol L -1 and t = 37 °C), determined by UV-vis spectrophotometric titrations, are introduced. Thus, a reliable speciation model on H + -MRN species in aqueous solution is presented, which exhibits five stable forms depending on pH, supplemented by quantum-mechanical calculations useful to determine the proton affinities of each functional group and corresponding deprotonation order. Furthermore, potentiometry and UV-vis spectrophotometry have been exploited to determine the thermodynamic interaction parameters of MRN with different metal cations (Mg 2+ , Mn 2+ , Zn 2+ , Al 3+ ). The antioxidant ability of H + -MRN and M z+ -MRN has been evaluated by the 2,2'-diphenyl-1-benzopyran-4-one (DPPH) method, and the Zn 2+ -MRN system has proven to afford the most potent antioxidant effect. Ab initio molecular dynamics simulations of M z+ -MRN species at all possible chelation sites and under explicit water solvation allowed for the fine characterization not only of the metal chelation modalities of MRN in explicit water, but also of the role played by the local water environment around the metal cations. Those microscopic patterns reveal to be informative on the different antioxidant capabilities recorded experimentally., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Ten C-geranylated flavonoids, along with three known analogues, were isolated from the leaves of Artocarpus communis. The chemical structures of these compounds were unambiguously determined via comprehensive spectroscopic analysis, single-crystal X-ray diffraction experiments, and quantum chemical electronic circular dichroism calculations. Structurally, artocarones A-I (1-9) represent a group of unusual, highly modified C-geranylated flavonoids, in which the geranyl chain is cyclised with the ortho-hydroxy group of flavonoids to form various heterocyclic scaffolds. Notably, artocarones E and G-I (5 and 7-9) feature a 6H-benzo[c]chromene core that is hitherto undescribed in C-geranylated flavonoids. Artocarone J (10) is the first example of C-9-C-16 connected C-geranylated aurone. Meanwhile, the plausible biosynthetic pathways for these rare C-geranylated flavonoids were also proposed. Notably, compounds 1, 2, 4, 8, 11, and 12 exhibited promising in vitro inhibitory activities against respiratory syncytial virus and herpes simplex virus type 1., 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.)

The screening of based target compounds supported by LC/MS, MS/MS and Global Natural Products Social (GNPS) used to identify the compounds 1-10 of Butea monsperma. They were evaluated in human malignant embryonic rhabdomyoma cells (RD cells) infected with Human coronavirus OC43 (HCoV-OC43) and showed significant inhibitory activity. Target inhibition tests showed that compounds 6 and 8 inhibited the proteolytic enzyme 3CLpro, which is widely present in coronavirus and plays an important role in the replication process, with an effective IC 50 value. The study confirmed that dioxymethylene of compound 8 may be a key active fragment in inhibiting coronavirus (EC 50 7.2 μM, SI > 139.1). The results have led to identifying natural bioactive compounds for possible inhibiting HCoV-OC43 and developing drug for Traditional Chinese Medicine (TCM)., 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. Published by Elsevier B.V.)

Background: Obesity is recognized as a lifestyle-related disease and the main risk factor for a series of pathological conditions, including cardiovascular diseases, hypertension and type 2 diabetes. Citrus limon is an important medicinal plant, and its fruits are rich in flavonoids investigated for their potential in managing obesity. In the present work, a green extraction applied to lemon squeezing waste (LSW) was optimized to recover pancreatic lipase (PL) inhibitors., Results: The microwave-assisted procedure yielded an extract with higher lipase inhibitory activity than those obtained by maceration and ultrasound. The main compounds present in the extract were identified by high-performance liquid chromatographic-mass spectrometric analysis, and hesperidin, eriocitrin and 4'-methyllucenin II were isolated. The three compounds were evaluated for in vitro PL inhibitory activity, and 4'-methyllucenin II resulted in the most promising inhibitor (IC 50  = 12.1 μmol L -1 ; K i  = 62.2 μmol L -1 ). Multispectroscopic approaches suggested the three flavonoids act as competitive inhibitors and the binding studies indicated a greater interaction between PL and 4'-methyllucenin II. Docking analysis indicated the significant interactions of the three flavonoids with the PL catalytic site., Conclusion: The present work highlights flavonoid glycosides as promising PL inhibitors and proposes LSW as a safe ingredient for the preparation of food supplements for managing obesity. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Scuellaria Root (SR, root of Scutellaria baicalensis), which has potent anti-inflammatory effects, is a component of useful Kampo formulae. Albeit a low frequency, SR induces serious interstitial pneumonia and liver dysfunction. In this study, to control the adverse effects of SR, we investigated the causal constituent responsible for its hepatocytotoxicity and aimed to develop a method to control it. As a result, we revealed that the hepatocytotoxicity of SR was correlated with its baicalin content, a major constituent in SR. It was confirmed by preparing a baicalin-free SR extract, which exhibited reduced hepatocytotoxicity. The addition of baicalin to the baicalin-free SR extract restored the hepatocytotoxicity, indicating that the hepatocytotoxicity of SR is dependent on its baicalin content. Thus, SR extract-induced hepatocytotoxicity can be controlled by regulating its baicalin content., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Flavonoids and their methylated derivatives have immense market potential in the food and biomedical industries due to their multiple beneficial effects, such as antimicrobial, anti-inflammatory, and anticancer activities. The biological synthesis of flavonoids and their derivatives is often accomplished via the use of genetically modified microorganisms to ensure large-scale production. Therefore, it is pivotal to understand the properties of O -methyltransferases (OMTs) that mediate the methylation of flavonoids. However, the properties of these OMTs are governed by their: sources, substrate specificity, amino acid residues in the active sites, and the intricate mechanism. In order to obtain a clue for the selection of suitable OMTs for the biosynthesis of a target methylated flavonoid, we made a comprehensive review of the currently reported results, with a particular focus on their comparative regioselectivity for different flavonoid substrates. Additionally, the possible mechanisms for the diversity of this class of enzymes were explored using molecular simulation technology. Finally, major gaps in our understanding and areas for future studies were discussed. The findings of this study may be useful in selecting genes that encode OMTs and designing enzyme-based processes for synthesizing O -methylated flavonoids.

Icariin has been shown the promising therapeutic potential to treat inflammatory airway diseases, yet its poor lung distribution and retention restrict the clinical applications. To this end, this work aimed to prepare an icariin-phospholipid complex (IPC) formulation for sustained nebulization delivery that enabled excellent inhalability, improved lung exposure and prolonged duration of action. Icariin was found to react with soybean phospholipid to form supramolecular IPC, which was able to self-assemble into nanoparticle suspension. The suspension was stable during steam sterilization and nebulization processes, and its aerosols generated by a commercial nebulizer exhibited excellent aerodynamic properties and delivery efficiency. In vitro studies showed that the formation of complex sustained drug release, enhanced lung affinity and slowed lung clearance. The drug distribution in lung epithelial lining fluid (ELF) also demonstrated in vivo sustained release after intratracheal administration to mice. In addition, compared to free icariin, IPC improved the drug exposure to lung tissues and immune cells in the ELF by 4.61-fold and 39.5-fold, respectively. This resulted in improved and prolonged local anti-inflammatory effects up to 24 h in mice with lipopolysaccharide (LPS)-induced acute lung injury. Moreover, IPC improved survival rate of mice with acute respiratory distress syndrome (ARDS). Overall, the present phospholipid complex represented a promising formulation of icariin for the treatment of acute lung injury/ARDS by nebulization delivery., 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 B.V. All rights reserved.)

Three undescribed seco-iridoid glycosides, one undescribed flavonoid glycoside, and three known glycosides were isolated and identified from Gentiana olivieri Griseb. The structures of these compounds were determined through spectroscopic analysis and ECD calculations. Olivierisecosides NP (1-3) were identified as aromatic conjugated seco-iridoid glucosides, among them olivierisecoside N was representing a particularly rare subtype known as the morroniside seco-iridoids. The compounds 2, 3, 5, and 6 exhibited significant inhibition of COX-2 expression, particularly compound 5 which demonstrated the most pronounced inhibitory activity with IC 50 value of 23.33 ± 0.51 μM. This study provides evidence for the potential development and utilization of G. olivieri as a source of anti-inflammatory components., 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 B.V. All rights reserved.)

Background: Flavonoids are one of the most important metabolites with vast structural diversity and a plethora of potential pharmacological applications, which have drawn considerable attention in the laboratory. Nevertheless, it remains uncertain how many candidates were progressed to clinical application., Aim of Review: We carried out a critical review of natural and semi-synthetic flavonoid drugs and candidates undergoing different clinical phases worldwide by applying an adequate search method and conducted a brief cheminformatic and bioinformatic analysis. It was expected that the obtained results might narrow the screening scope and reduce the cost of drug research and development., Key Scientific Concepts of Review: To our knowledge, this is the most systematic summarization of flavonoid-based drugs and clinical candidates to date. It was found that a total of 19 flavonoid-based drugs have been approved for the market, and of these, natural flavonoids accounted for 52.6%. Besides, a total of 36 flavonoid-based clinical candidates are undergoing or suspended in different phases, and of these, natural flavonoids account for 44.4%. Thus, natural flavonoids remain the best option for finding novel agents/active templates, and when investigated in conjunction with synthetic chemicals and biologicals, they offer the potential to discover novel structures that can lead to effective agents against a variety of human diseases. Additionally, flavonoid-based marketed drugs have been successful in cardiovascular treatment, and the related drugs account for more than 30% of marketed drugs. However, the use of flavonoids as antineoplastic and immunomodulating agents is not likely for approximately 50% of the candidates suspended in the clinical stage. Interestingly, the marketed drugs covered a broader range of chemical spaces based on size, polarity, and three-dimensional structure compared to the clinical candidates. In addition, flavonoid glycosides with poor oral bioavailability account for 36.8% of the marketed drugs, and thus, they could be thoroughly investigated., 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. Production and hosting by Elsevier B.V.)

Leishmaniases comprise a group of infectious parasitic diseases caused by various species of Leishmania and are considered a significant public health problem worldwide. Only a few medications, including miltefosine, amphotericin B, and meglumine antimonate, are used in current therapy. These medications are associated with severe side effects, low efficacy, high cost, and the need for hospital support. Additionally, there have been occurrences of drug resistance. Additionally, only a limited number of drugs, such as meglumine antimonate, amphotericin B, and miltefosine, are available, all of which are associated with severe side effects. In this context, the need for new effective drugs with fewer adverse effects is evident. Therefore, this study investigated the anti-Leishmania activity of a dichloromethane fraction (DCMF) extracted from Arrabidaea brachypoda roots. This fraction inhibited the viability of L. infantum, L. braziliensis, and L. Mexicana promastigotes, with IC 50 values of 10.13, 11.44, and 11.16 µg/mL, respectively, and against L. infantum amastigotes (IC 50 = 4.81 µg/mL). Moreover, the DCMF exhibited moderate cytotoxicity (CC 50 = 25.15) towards RAW264.7 macrophages, with a selectivity index (SI) of 5.2. Notably, the DCMF caused damage to the macrophage genome only at 40 µg/mL, which is greater than the IC 50 found for all Leishmania species. The results suggest that DCMF demonstrates similar antileishmanial effectiveness to isolated brachydin B, without causing genotoxic effects on mammalian cells. This finding is crucial because the isolation of the compounds relies on several steps and is very costly while obtaining the DCMF fraction is a simple and cost-effective process. Furthermore, In addition, the potential mechanisms of action of brachydins were also investigated. The computational analysis indicates that brachydin compounds bind to the Triosephosphate isomerase (TIM) enzyme via two main mechanisms: destabilizing the interface between the homodimers and interacting with catalytic residues situated at the site of binding. Based on all the results, DCMF exhibits promise as a therapeutic agent for leishmaniasis due to its significantly reduced toxicity in comparison to the adverse effects associated with current reference treatments., 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 B.V. All rights reserved.)

Twenty flavonoids (1-20) were isolated from the leaves and stems of Sedum japonicum var. senanense endemic to Japan. Among them, nine compounds were reported in nature for the first time, and identified as herbacetin 3-O-neohesperidoside-8-O-(2‴-acetylxyloside) (2), gossypetin 8-O-(2″-acetylxyloside) (4), gossypetin 8-O-(3″-acetylxyloside) (5), gossypetin 3-O-glucoside-8-O-(3‴-acetylxyloside) (9), gossypetin 3-O-glucoside-8-O-(2‴,3‴-diacetylxyloside) (10), gossypetin 3-O-neohesperidoside-8-O-xyloside (11), gossypetin 3-O-neohesperidoside-8-O-(2⁗-acetylxyloside) (12), gossypetin 3-O-neohesperidoside-8-O-(3⁗-acetylxyloside) (13) and gossypetin 3-O-glucoside-8-O-xylofuranoside (14) by UV spectral survey, HR-MS, LC-MS, acid hydrolysis, NMR including 1 H and 13 C NMR, COSY, NOESY, HSQC and HMBC. Moreover, nine major flavonoids were surveyed for antioxidant activity by H-ORAC method. As the results, gossypetin 3-O-glucoside-8-O-(2‴-acetylxyoside) (8) showed the highest antioxidant activity. Conversely, gossypetin 3-O-neohesperidoside-8-O-xyloside (11) and gossypetin 3-O-neohesperidoside-8-O-(2⁗-acetylxyloside) (12) which attach neohesperidose showed the lowest values., Competing Interests: Declaration of competing interest The authors declare that they no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Rationale: This study developed a method for the rapid classification and identification of the chemical composition of Qingyan dropping pills (QDP) to provide the theoretical basis and data foundation for further in-depth research on the pharmacological substance basis of the formula and the selection of quality control indexes., Methods: Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and data postprocessing technology were used to analyze the chemical composition of QDP. The fragmentation information on possible characteristic fragments and related neutral losses was summarized based on the literature and was compared with the MS data obtained from the assay, and thus a rapid classification and identification of chemical components in QDP could be achieved., Results: A total of 73 compounds were identified, namely 24 flavonoids, 14 terpenoids, 30 organic acids and their esters, 3 alkaloids, and 2 phenylpropanoids., Conclusions: In this study, UHPLC-Q-TOF-MS and data postprocessing technology were used to realize the rapid classification and identification of the chemical constituents of QDP, which provided a comprehensive, efficient, and fast qualitative analysis method, a basis for further quality control and safe medication of QDP., (© 2024 John Wiley & Sons Ltd.)

N-Ethyl-2-pyrrolidinone-substituted flavan-3-ols (EPSFs) are a newly discovered compound class in tea with various bioactivities. This study aimed to develop a novel processing technique to enhance EPSF contents in white tea efficiently. Using optimal processing parameters of 125 °C and 30 min in a high-temperature sterilizing oven, total EPSF content significantly increased by 1.42-18.80-fold to 1.57-6.22 mg/g without impacting sensory characteristics. Metabolomics analysis revealed elevated levels of nucleosides, nucleotides, bases, theaflavins, flavonol aglycones, EPSFs, and most flavone-C-glycosides, as well as decreased levels of amino acids, procyanidins, theasinensins, several flavanols, and flavonol-O-glycosides after EPSF-enrichment treatment. Furthermore, the EPSF-enriched white tea exhibited notable anti-inflammatory effects, mitigating xylene-induced ear edema in mice and carrageenan-induced paw edema and cotton ball-induced granulomas in rats. This study developed a new processing technique for highly efficient enhancement of EPSFs in white tea and demonstrated that EPSF-enriched white tea has a potential to serve as effective anti-inflammatory dietary supplement., 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.)

The characterization of structure of organic salts in complex mixtures has been a difficult problem in analytical chemistry. In the analysis of Scutellariae Radix (SR), the pharmacopoeia of many countries stipulates that the quality control component is baicalin (≥9% by high performance liquid chromatography (HPLC)). The component with highest response in SR was also baicalin detected by liquid chromatography-mass spectrometry (LC-MS). However, in the attenuated total reflection Fourier transform infrared spectroscopy, the carbonyl peak of glucuronic acid of baicalin did not appear in SR. The results of element analysis, time of flight secondary ion mass spectrometry, matrix assisted laser desorption ionization mass spectrometry and solid-state nuclear magnetic resonance all supported the existence of baicalin magnesium salt. Based on this, this study proposes an analysis strategy guided by infrared spectroscopy and combined with multi-spectroscopy techniques to analyze the structure of organic salt components in medicinal plant. It is meaningful for the research of mechanisms, development of new drugs, and quality control., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Saponins are considered the main source of the bitter taste of quinoa, however, it has not been confirmed by Song et al. (2024). These authors suggested that saponin extracts contribute to the umami taste, however, the stronger source of the bitter taste may be the flavonoids contained in the extracts. It is an interesting finding in view of the flavonoids role in the field of food sciences. The UPLC-MS results showed that besides saponins, also polyphenols were present in the analyzed samples. However, the presented results of UPLC-MS analysis should be substantially improved, mainly with respect to the reported accurate masses and retention times, as described in details in this comment., 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.)

Cereal grains play an important role in human health as a source of macro- and micronutrients, besides phytochemicals. The metabolite diversity was investigated in cereal crops and their milling fractions by untargeted metabolomics ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) of 69 samples: 7 species (barley, oat, pearl millet, rye, sorghum, triticale, and wheat), 23 genotypes, and 4 milling fractions (husk, bran, flour, and wholegrain). Samples were also analyzed by in vitro antioxidant activity. UHPLC-MS/MS signals were processed using XCMS, and metabolite annotation was based on SIRIUS and GNPS libraries. Bran and husk showed the highest antioxidant capacity and phenolic content/diversity. The major metabolite classes were phenolic acids, flavonoids, fatty acyls, and organic acids. Sorghum, millet, barley, and oats showed distinct metabolite profiles, especially related to the bran fraction. Molecular networking and chemometrics provided a comprehensive insight into the metabolic profiling of cereal crops, unveiling the potential of coproducts and super cereals such as sorghum and millet as sources of polyphenols.

This study evaluated and compared the phytochemical and antioxidant properties of the solvent extracts of Azadirachta indica A. Juss and Vernonia amygdalina Del leaves. Methanolic and aqueous extracts showed high (P ≤ 0.05) extract yields (in %), compared to chloroform and ethyl acetate extracts from both V. amygdalina and A. indica leaves. The study exhibited high phytochemical content in methanol and aqueous extracts compared to chloroform and ethyl acetate extracts, confirming the potential for medicinal use. V. amygdalina methanol and aqueous extracts had higher (P ≤ 0.05) total phenolic content (TPC), in mg GAE/gDW, (158.810±0.846 and 217.883±0.265, respectively) than chloroform (37.574±0.118) and ethyl acetate (104.758±0.236) but higher ethyl acetate content in A. indica extracts. Low polar solvents extracted high (P ≤ 0.05) total flavonoids, in mgQE/gDW, (367.051±0.858 and 149.808±0.009) compared to high polar solvents (14.863±0.071 and 54.226±0.014 ) in V. amygdalina while as in A. indica leaf extracts, low polar solvents showed high TFC ( 658.469±3.451 and 275.288±10.490) compared to high polar solvents (26.312±0.063 and 48.858±0.063) respectively. In vitro total antioxidant capacity, in mg/g, was higher in polar solvents than in low-polar solvents, ranging from 34.300±1.784 to 121.015±6.839 for A. indica ethyl acetate and methanolic extracts. A strong correlation between TPC and tannic acid content was observed, except in A. indica methanolic extracts of A. indica. Ferric reducing power was high, except for V. amygdalina chloroform and methanol leaf extracts, which were lower (P≤ 0.05) than that of the standard ascorbic acid. The study revealed that high polar solvents, such as methanol and water, are more efficient in the extraction of antioxidants from A. indica but lower in V. amygdalina extracts. High phytochemical content and antioxidative capacity could be significant in treating various diseases in humans., (© 2024. The Author(s).)

The flavonoid compounds in C. caudatus K., known for their various benefits, are prone to quick degradation, leading to reduced biological activity. This research aimed to evaluate the types of coatings: gum Arabic (GA), maltodextrin (MD), and a combination of both (MDGA) in C. caudatus K. extract microcapsules. The extract of C. caudatus K. was encapsulated by different coating materials, GA, MD, and MDGA, and then dried using a freeze-drying technique. The evaluation was carried out by comparing the encapsulation efficiency values, biological activity, and release tests of each type of microcapsule coating. The research results indicate that coating agents have impacts significantly at p < 0.05 on efficiency encapsulation. Flavonoids were retained up to 79.67% by the MDGA coating, compared with 72.8% and 47.66% a retained by single GA and MD coatings, respectively. The results of the encapsulation efficiency are supported by the results of characterization using a scanning electron microscope (SEM), where MDGA has rounder shapes with smoother surfaces compared with a single coating alone, like GA or MD. In addition, by particle size analysis using a particle size analyzer (PSA), the average sizes of MDGA, GA, and MD microcapsules were shown at 154.13  µ m, 152  µ m, and 166.81  µ m, respectively. The three microcapsules showed an order of activities as MDGA > GA > MD coatings in alpha-amylase inhibition assay. Similar results were also shown in the antioxidant assay, which demonstrated that the three microcapsules had moderate antioxidant activities, again in the order of MDGA > GA > MD. The three different coating types showed greater release at pH 7.4 compared to those at pH 2.2 in the controlled release test, which ran from 30 to 120 min. In summary, freeze-drying microencapsulation using biodegradable polymers was identified as a viable method for harnessing the health benefits of C. caudatus K. extracts. This process produced a convenient powder form that could be used in drug delivery systems. The use of MDGA mixed coating resulted in better impact based on %EE value and biological activity, as well as improved characteristics of microcapsules compared with single coating., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 Izaz Aqeiluz Zahara et al.)

Bitter taste receptors, also known as taste 2 receptors (T2R), are expressed throughout the body and are involved in regulating different physiological processes. T2R expression in the intestinal tract regulates orexigenic and anorexigenic peptide secretion, thus becoming potential a potential target for controlling food intake and the prevalence of obesity and overweight. The present study aims to investigate the implication of hop bitter compounds such as α-acids, β-acids, and xanthohumol in the secretion of anorexigenic hormones and T2R expression in intestinal STC-1 cells. The tested bitter compounds induced the secretion of the anorexigenic hormones glucagon-like peptide 1 and cholecystokinin concurrently with a selective increase of murine Tas2r expression. Xanthohumol and α-acids selectively increase Tas2r 138 and Tas2r 130- Tas2r 138 expression, respectively, in STC-1 cells, while β-acids increased the expression of all bitter receptors studied, including Tas2r 119, Tas2r 105, Tas2r 138, Tas2r 120, and Tas2r 130. Increased intracellular calcium levels confirmed this activity. As all investigated bitter molecules increased Tas2r 138 expression, computational studies were performed on Tas2r 138 and its human orthologue T2R38 for the first time. Molecular docking experiments showed that all molecules might be able to bind both bitter receptors, providing an excellent basis for applying hop bitter molecules as lead compounds to further design gastrointestinal-permeable T2R agonists.

Artichokes ( Cynara scolymus L.) are valuable foods, thanks to their health benefits, but they generate significant waste during their production, harvesting, and processing, which poses sustainability issues. This study applied an agroprospecting approach to convert Tema artichoke biowaste (TB) into valuable resources, starting from a global perspective of the production chain to the targeted applications based on chemical and biological analysis. The major TB was identified in the outer bracts of the immature flower heads, which were collected throughout the harvesting season, extracted, and analyzed. The most abundant compounds were phenolic acids including chlorogenic acid and caffeoylquinic derivatives. Among flavonoids, cynaroside was the most abundant compound. Multivariate analysis distinguished batches by collection period, explaining 77.7% of the variance, with most compounds increasing in concentration later in the harvest season. Subsequently, TB extracts were analyzed for their potential in wound healing and anti-aging properties. Fibroblasts were used to assess the effect of selected extracts on cell migration through a scratch wound assay and on cellular senescence induced by etoposide. The results show a significant decrease in senescence-associated β-galactosidase activity, γH2AX nuclear accumulation, and both p53 and p21 protein levels. Overall, this study ascribes relevant anti-skin aging effects to TB, thus increasing its industrial value in cosmeceutical and nutraceutical applications.

Porous poly (lactic-co-glycolic acid)/ β -tricalcium phosphate/Icaritin (PLGA/ β -TCP/ICT, PTI) scaffold is a tissue engineering scaffold based on PLGA/ β -TCP (PT) containing Icaritin, the main active ingredient of the Chinese medicine Epimedium. Due to its excellent mechanical properties and osteogenic effect, PTI scaffold has the potential to promote bone defect repair. However, the release of ICT from the scaffolds is difficult to control. In this study, we constructed Ti 3 C 2 T x @PLGA/ICT microspheres (TIM) and evaluated their characterization as well as ICT release under near-infrared (NIR) irradiation. We utilized TIM to modify the PT scaffold and performed biological experiments. First, we cultured rat bone marrow mesenchymal stem cells on the scaffold to assess biocompatibility and osteogenic potential under on-demand NIR irradiation. Subsequently, to evaluate the osteogenic properties of TIM-modified scaffold in vivo , the scaffold was implanted into a femoral condyle defect model. TIM have excellent drug-loading capacity and encapsulation efficiency for ICT, and the incorporation of Ti 3 C 2 T x endows TIM with photothermal conversion capability. Under 0.90 W cm -2 NIR irradiation, the temperature of TIM maintained at 42.0 ± 0.5 °C and the release of ICT was accelerated. Furthermore, while retaining its original properties, the TIM-modified scaffold was biocompatible and could promote cell proliferation, osteogenic differentiation, and biomineralization in vitro , as well as the osteogenesis and osseointegration in vivo , and its effect was further enhanced through the modulation of ICT release under NIR irradiation. In summary, TIM-modified scaffold has the potential to be applied in bone defects repairing., (Creative Commons Attribution license.)

Orthosiphon stamineus Benth. (OSB) is a popular plant used for making "Shen tea" or "Java tea". It has been demonstrated with antioxidant, anti-inflammatory, and hepatoprotective activities. However, its potential beneficial effects and bioactive material basis for nonalcoholic fatty liver disease (NAFLD) has not been convincingly studied. In the present work, we conducted dual phytochemical/activity-guided extraction optimization and component fractionation of OSB, and evaluated its beneficial effects on NAFLD. Flavonoids and polyphenols (caffeic acid/protocatechuic acid derivatives) were determined as the dominant phytochemicals in OSB. The extraction process for these phytochemicals was optimized by using response surface methodology. Noticeably, flavonoids showed a stronger correlation with the antioxidant activities of OSB than polyphenols. Likewise, the flavonoid-rich fraction of OSB exerted antioxidant activities stronger than those of other fractions. As expected, in vitro and in vivo studies demonstrated that the flavonoid-rich fraction effectively attenuated weight increase, improved lipid metabolism, alleviated hepatic steatosis, and reversed hepatic inflammation. Importantly, this fraction showed equivalent beneficial effects to the total extract of OSB, suggesting that flavonoids were the main bioactive constituents of OSB. The action mechanism was indicated as direct antioxidant effect through chemical interaction with free radicals and indirect mitochondria-mediated antioxidant defense. Our research offers bioactive substances for further exploitation and expands the potential application of OSB.

Danggui-Jianzhong decoction (DGJZ) is a famous classical traditional Chinese medicine formula, which ingredients are complex and the quality is difficult to control. Our study aimed to identify the overall chemical profile of DGJZ qualitatively by ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and UPLC. A total of 77 components, including terpenoids, flavonoids, phenolic acids, gingerols and other components, were firstly detected and characterized by UPLC-Q-TOF-MS and 18 peaks marked after analyzing the UPLC fingerprint. Finally, paeoniflorin, liquiritin, ferulic acid, cinnamic acid, glycyrrhizic acid and 6-gingerol were quantified, which was validated in terms of linearity, precision, accuracy, repeatability and recovery. Taken together, the chemical constitutes of DGJZ were systematically identified and a reliable quantitative method coupled with fingerprint analysis was successfully employed for evaluating the holistic quality, which will provide a robust foundation for the quality control of DGJZ., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Alpinae oxyphyllae fructus (AOF), the dried mature fruit of Alpinia oxyphylla Miquel of the Zingiberaceae family, shows many special pharmacological effects. In recent years, there has been an abundance of research results on AOF. In this paper, the new compounds isolated from AOF since 2018 are reviewed, including terpenes, flavonoids, diarylheptanoids, phenolic acid, sterols, alkanes, fats, etc. The isolation methods that were applied include the microwave-assisted method, response surface method, chiral high-performance liquid chromatography-multiple reaction monitoring-mass spectrometry (HPLC-MRM-MS) analytical method, ultra-high-performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry (UPLC-Orbitrap-HRMS) method, ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method, hot water leaching method, ethanol leaching method, and so on. Additionally, the pharmacological effects of AOF found from 2018 to 2024 are also summarized, including neuroprotection, regulation of metabolic disorders, antioxidant activity, antiapoptosis, antiinflammatory activity, antidiabetic activity, antihyperuricemia, antiaging, antidiuresis, immune regulation, anti-tumor activity, renal protection, hepatoprotection, and anti-asthma. This paper provides a reference for further research on AOF.

Quantitative Structure-Retention Relationship models were developed to identify phenolic compounds using a typical LC- system, with both UV and MS detection. A new chromatographic method was developed for the separation of fifty-two standard phenolic compounds. Over 5000 descriptors for each standard were calculated using AlvaDesc software and then selected through Genetic Algorithm. The selected descriptors were used as variables for models construction and to obtain a better understanding of the retention behaviour of phenols during reverse-phase separation. Three distinct molecule sets, including fifty-two phenolic compounds (Set 1), 32 flavonoids (Set 2) and 15 mono-substituted flavonoids were divided into training and validation sets to build Partial Least Square, Multiple Linear Regression and Partial Least Square-Artificial Neural Network models. To assess the predictivity of the models, these were tested on a bergamot juice sample. Partial Least Square and Partial Least Square-Artificial Neural Network exhibit the lowest prediction error, and the latter showed the best predictive power in real sample recognition. The building and implementation of such predictive models showed to be a powerful tool to identify phenolic compounds based on retention data and avoiding the use of expensive and sophisticated detectors such as tandem MS., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

A green and recyclable switchable supramolecular deep eutectic solvent (SS-DES) was designed and prepared for effective extraction of flavonoids from Scutellariae Radix. The novel SS-DES has both excellent extraction performance of DES and the host guest inclusion of cyclodextrin, thereby showing superior extraction efficiency and selectivity. The characteristic of polarity switching can endow the SS-DES with achieving homogeneous extraction and rapid two-phase separation, shorting per-treatment time largely. Parameters affecting the extraction performance were investigated by the response surface methodology. The results indicated that the SS-DES showed better extraction yield of total flavonoids (157.95 mg/g) compared with pure DES (135 mg/g) and traditional organic solvent (60 % ethanol, 104.87 mg/g). Moreover, the switching mechanism of SS-DES was characterized by FT-IR and 1 H NMR, and the extraction mechanism was studied by density functional theory and molecular docking analysis. After evaluating the ecological impact of the method, the cytotoxicity of SS-DES was investigated and the result displayed that its toxicity was very low or even negligible with the EC 50 >2000 mg/L. After being adsorbed by macroporous AB-8 resin, the regenerated SS-DES was recycled 5 times and the extraction efficiency still remained above 90 %, indicating the desirable reusability. Therefore, the proposed method was efficient and sustainable, and revealed favorable application prospect for the extraction of bio-active compounds from plant materials., 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 B.V. All rights reserved.)

The objectives of this study were to optimize the ultrasonic-assisted flavonoid extraction process from PR and to establish fingerprints in order to analyze the spectrum-effect relationship of antioxidant activity. The ultrasonic-assisted flavonoid extraction process from PR was optimized using RSM, and the fingerprints of twenty-eight batches of flavonoids from PR were established using UHPLC. Meanwhile, the in vitro antioxidant activity of PR was evaluated in DPPH and ABTS free radical-scavenging experiments. Then, the peaks of the effective antioxidant components were screened using the spectrum-effect relationships. The results show that the optimal extraction yield of flavonoids from PR was 3.24 ± 0.01 mg/g when using 53% ethanol, a 1:26 (g/mL) solid-liquid ratio, and 60 min of ultrasonic extraction. Additionally, the clearance of two antioxidant indices by the flavonoids extracted from PR had different degrees of correlation and showed concentration dependence. Simultaneously, the similarity of the UHPLC fingerprints of twenty-eight batches of PR samples ranged from 0.801 to 0.949, and four characteristic peaks, namely peaks 4, 12, 21, and 24, were screened as the peaks of the components responsible for the antioxidant effect of PR using a GRA, a Pearson correlation analysis, and a PLS-DA. In this study, characteristic peaks of the antioxidant effects of PR were screened in an investigation of the spectrum-effect relationship to provide a scientific basis for the study of pharmacodynamic substances and the elucidation of the mechanism of action of the antioxidant effect of PR.

Ainsliaea fragrans Champ, a strong heat-clearing and detoxifying traditional Chinese medicine, has been effectively used for treating chronic cervicitis, endometritis, pelvic inflammatory diseases, and other conditions caused by damp heat. It shows a good effect in the treatment of cervicitis and has broad clinical application prospects. Nevertheless, there is no comprehensive study on its in vivo and in vitro chemical analysis. UHPLC-QTOF-MS/MS combined with the non-targeted characteristic filter analysis were used to conjecture and characterize the chemical components and in vivo metabolites of rats following oral administration of Ainsliaea fragrans Champ. In this study, A total of 85 compounds were identified in Ainsliaea fragrans Champ, including 29 flavonoids, 14 sesquiterpenoids, 25 chlorogenic acids, and 17 other compounds. In the plasma of rats after administration of Ainsliaea fragrans Champ, 160 compounds were deduced (19 prototype compounds and 141 metabolites). The 141 metabolites consist of 50 flavonoids, 80 phenolic acids and 11 Chlorogenic acids. The related metabolic pathways mainly involved demethylation, reduction, sulfonation, decarboxylation, hydroxylation, methylation, and glucuronide conjunction. In summary, the chemical components and metabolites of Ainsliaea fragrans Champ were comprehensively identified by using a rapid and accurate analysis method, which laid a foundation for dissecting its bioactive substances. In addition, it provides a scientific basis for the in-depth study of the material basis of Ainsliaea fragrans Champ efficacy and theoretical support for illustrating the mechanism of medical action and its clinical application., 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 B.V. All rights reserved.)

Leukemia, particularly acute myeloid leukemia (AML) is considered a serious health condition with high prevalence among adults. Accordingly, finding new therapeutic modalities for AML is urgently needed. This study aimed to develop a biocompatible nanoformulation for effective oral delivery of the phytomedicine; baicalin (BAC) for AML treatment. Lipid nanocapsules (LNCs) based on bioactive natural components; rhamnolipids (RL) as a biosurfactant and the essential oil linalool (LIN), were prepared using a simple phase-inversion method. The elaborated BAC-LNCs displayed 61.1 nm diameter and 0.2 PDI. Entrapment efficiency exceeded 98 % with slow drug release and high storage-stability over 3 months. Moreover, BAC-LNCs enhanced BAC oral bioavailability by 2.3-fold compared to BAC suspension in rats with higher half-life and mean residence-time. In vitro anticancer studies confirmed the prominent cytotoxicity of BAC-LNCs on the human leukemia monocytes (THP-1). BAC-LNCs exerted higher cellular association, apoptotic capability and antiproliferative activity with DNA synthesis-phase arrest. Finally, a mechanistic study performed through evaluation of various tumor biomarkers revealed that BAC-LNCs downregulated the angiogenic marker, vascular endothelial growth-factor (VEGF) and the anti-apoptotic marker (BCl-2) and upregulated the apoptotic markers (Caspase-3 and BAX). The improved efficacy of BAC bioactive-LNCs substantially recommends their pharmacotherapeutic potential as a promising nanoplatform for AML treatment., 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 B.V. All rights reserved.)

Osteoporosis, a prevalent systemic bone metabolic disorder, primarily affects postmenopausal women and is characterized by increased bone fragility and a heightened risk of fractures. The efficacy of current osteoporosis treatments is often limited by non-specific drug targeting and undesirable off-target skeletal side effects. To address this challenge, we have developed a novel hydroxyapatite-responsive drug delivery system. This system utilizes a self-assembled p-phosphonatocalix[4]arene tetradodecyl ether (PC4A12C), engineered to specifically target and sustain the release of osteoporosis medication at sites of bone remodeling. Our focus centers on icariin (ICA), a drug known for its potent osteogenic properties and minimal adverse effects. In vitro, ICA-loaded PC4A12C (ICA@PC4A12C) demonstrated enhanced proliferation, differentiation, and mineralization in bone marrow mesenchymal stem cells (BMSCs). In vivo, ICA@PC4A12C exhibited superior efficacy in specifically targeting bone tissue, ensuring a controlled and slow release of icariin directly within the bone environment. In an osteoporosis mouse model, treatment with ICA@PC4A12C showed notable enhancement in osteogenic activity and a significant increase in bone density compared to ICA alone. These results demonstrate the potential of PC4A12C as an effective drug carrier in the development of advanced antiosteoporotic drug delivery systems., 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 B.V. All rights reserved.)