The ethnobotanical, phytochemical and pharmacological properties and medicinal applications of essential oils and extracts of different Ziziphora species

Acacetin, a flavone with diverse therapeutic potential in cancer, inflammation, infections and other metabolic disorders.

Scrophularia kakudensis is an important medicinal plant with pharmaceutically valuable secondary metabolites. To develop a sustainable source of naturaceuticals with vital therapeutic importance, a cell suspension culture was established in S. kakudensis for the first time. Friable calli were induced from the leaf explants cultured on a Murashige and Skoog (MS) medium containing 3.0 mg·L−1 6-benzyladenine (BA) in a combination with 2 mg·L−1 2,4-dichlorophenoxy acetic acid (2,4-D). From the callus cultures, a cell suspension culture was initiated and the cellular differentiation was investigated. In addition, the effect of biotic elicitors such as methyl jasmonate (MeJa), salicylic acid (SA), and sodium nitroprusside (SNP) on the accumulation of secondary metabolites and antioxidant properties was demonstrated. Among the elicitors, the MeJa elicited the accumulation of total phenols, flavonoids, and acacetin, a flavonoid compound with multiple pharmaceutical values. Similarly, the higher concentrations of the MeJa significantly modulated the activities of antioxidant enzymes and enhanced the scavenging potentials of free radicals of cell suspension extracts. Overall, the outcomes of this study can be utilized for the large scale production of pharmaceutically important secondary metabolites from S. kakudensis through cell suspension cultures.

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Chemical Elicitor-Induced Modulation of Antioxidant Metabolism and Enhancement of Secondary Metabolite Accumulation in Cell Suspension Cultures of Scrophularia kakudensis Franch

The evaluation of the antioxidant, anti-secretory and anti-inflammatory potentials of the ethyl acetate fraction (ELC) from the root bark of Lycium chinense against ethanol-induced gastric ulcer in mice and the possible mechanisms underlying this action was performed. The results indicated that oral administration of ELC (50, 100, 200 and 400 mg/kg) before ethanol-induced ulcer increased the gastric mucus content, restored the superoxide dismutase and glutathione levels, reduced malondialdehyde levels and inhibited the activity of myeloperoxidase. Furthermore, ELC displayed its anti-secretory activity by decreasing the gastric juice and increased the gastric pH and reduced pro-inflammatory markers and caspase-3 tissue levels. These results suggest that L. chinense displays gastroprotective properties as a result of its antioxidant, anti-inflammatory, anti-secretory and anti-apoptotic effects.

Anti-oxidative, anti-secretory and anti-inflammatory activities of the extract from the root bark of Lycium chinense (Cortex Lycii) against gastric ulcer in mice

Acacetin, a dietary component, is abundant in acacia honey and has superior anticancer activities. To date, no research on the metabolism of acacetin has been reported. In the current research, an online detection strategy of ultra-high-performance liquid chromatography connected to a quadrupole time-of-flight mass spectrometer (UHPLC-Q-TOF-MS/MS) was utilized for metabolite identification in vivo (rat plasma, bile, urine, and feces) and in vitro (rat liver microsomes). A total of 31 metabolites were structurally characterized in rats, and 25 metabolites were detected in rat liver microsomes, among which, 4 metabolites were compared with standards. Oxidation, the loss of CH2, reduction, hydrolysis, glucuronide conjugation, sulfate conjugation, methylation, and N-acetylation were the main metabolic pathways of acacetin. This study is the first to characterize acacetin metabolites in vivo and in vitro, and the results of this study offer novel and valuable evidence for a comprehensive understanding of the safety and efficacy of acacetin.

A Systematic Study of the Metabolites of Dietary Acacetin in Vivo and in Vitro Based on UHPLC-Q-TOF-MS/MS Analysis.

Background: The total flavonoids from ethanol extract of the aerial part of Ziziphora clinopodioides Lam. (Lamlaceae) (Xintahua) showed protective activities against rat acute myocardial ischemia in rats. This study aims to isolate acacetin, a flavonoid, from the aerial part of Z. clinopodioides, to develop an HPLC method for its detection, and to evaluate its protective effects on neonatal rat cardiomyocytes. Methods: Sephadex LH-20 silicagel and pillar layer chromatography silica gel were applied for the isolation and purification of acacetin and its structure was elucidated on the basis of 1 H and 13 C NMR spectroscopy. The content of acacetin in Z. clinopodioides collected from three different origins was determined by HPLC. The neonatal rat cardiomyocytes were isolated and cultured in vitro to establish a hypoxia/reoxygenation injury model. The viability of cardiomyocytes was measured by the MTT method. Changes of malondialdehyde (MDA) content in the medium were also determined. Results: The acacetin content in various batches of Z. clinopodioides ranged from 45.50 to 47.41 μg/g. Acacetin of 25, 10, 5 μg/mL significantly decreased the MDA content in a model of hypoxia/reoxygenation injury (P < 0.001, P< 0.001 and P = 0.033, respectively). Conclusions: Acacetin protects neonatal cardiomyocytes from the damage induced by hypoxia/reoxygenation stress through reduction of lipid peroxidation and enhancement of the antioxidant activity.

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Protective effects of acacetin isolated from Ziziphora clinopodioides Lam. (Xintahua) on neonatal rat cardiomyocytes

Ziziphora bungeana Juz. is a folk medicine from the Xinjiang Uygur Autonomous Region. The herb or the aerial parts of it have been used to medicinally treat cardiovascular diseases. Flavonoids are the main pharmacologically active ingredients in Z. bungeana. Identification of the tissue-specific distribution of flavonoids in Z. bungeana is crucial for effective and sustainable medicinal use of the plant. Furthermore, understanding of the biosynthesis pathways of these flavonoids in Z. bungeana is of great biological significance. The flavonoids from different tissues of Z. bungeana were identified using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The full-length transcriptome of Z. bungeana was determined using a strategy based on a combination of Illumina and PacBio sequencing techniques. The functions of differentially expressed unigenes were predicted using bioinformatics methods and further investigated by real-time quantitative PCR and phylogenetic relationship analysis. Among the 12 major flavonoid components identified from Z. bungeana extracts, linarin was the most abundant component. Nine flavonoids were identified as characteristic components of specific tissues. Transcriptome profiling and bioinformatic analysis revealed that 18 genes were putatively involved in flavonoid biosynthesis. The gene expression and phylogenetic analysis results indicated that ZbPALs, Zb4CL3, ZbCHS1, and ZbCHI1 may be involved in the biosynthesis of the main flavonoid intermediate. ZbFNSII, ZbANS, and ZbFLS may be involved in the biosynthesis of flavones, anthocyanins, and flavonols, respectively. A map of the biosynthesis pathways of the 12 major flavonoids in Z. bungeana is proposed. The chemical constituent analysis revealed the compositions of 9 characteristic flavonoids in different tissues of Z. bungeana. Linarin can be hydrolysed into acacetin to exert a pharmaceutical role. Apigenin-7-O-rutinoside is hypothesised to be the precursor of linarin in Z. bungeana. There was greater content of linarin in the aerial parts of the plant than in the whole herb, which provides a theoretical basis for using the aerial parts of Z. bungeana for medicine. These results provide a valuable reference for further research on the flavonoid biosynthesis pathways of Z. bungeana and will be significant for the effective utilisation and ecological protection of Z. bungeana.

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Integrated metabolomic and transcriptomic profiling reveals the tissue-specific flavonoid compositions and their biosynthesis pathways in Ziziphora bungeana

To investigate effects of Ziziphora clinopodioides Lam. flavonoids on ischemia-reperfusion injury of myocardial cells. After application of 6.25, 25, and 100 μg/mL Ziziphora clinopodioides Lam. flavonoids to H9C2 myocardial cells for 24H, they were treated for 4 hours with hydrogen peroxide to induce oxidative damage, whereas controls were cells without treatment and cells only incubated with hydrogen peroxide. Cell viability, lactate dehydrogenase release and mitochondrial membrane potential, intracellular Na+/K+-ATPase activity and ATP content, and reactive oxygen species formation were monitored. An ischemia-reperfusion injury rat model was established by left anterior descending coronary artery ligature in 48 Sprague-Dawley rats, which were divided into positive control with isosorbide mononitrate (10 mg/kg) injection (n=8), model (ischemia-reperfusion, n=8), sham-operated (n=8), and Ziziphora clinopodioides Lam. flavonoids low (75 mg/kg, n=8), medium (150 mg/kg, n=8), and high concentration (300 mg/kg, n=8) groups. Superoxide dismutase activity and malondialdehyde content in homogenized hearts were measured and ischemic and infarction areas were triphenyl tetrazolium chloride and H&E stained for pathological and morphological examinations. Ziziphora clinopodioides Lam. flavonoids preconditioning improved cell viability (P<0.01), intracellular Na/K ATPase activity (P<0.001), and intracellular ATP content (P<0.001) and maintained mitochondrial membrane potential (P<0.05) in hydrogen peroxide treated H9C2 cells as well as rescued superoxide dismutase activity (P<0.01), decreased the malondialdehyde content (P<0.001), and reduced myocardial damage in the ischemia-reperfusion rat model (P<0.001) compared to the controls. Ziziphora clinopodioides Lam. flavonoids may be an effective drug for protecting myocardial tissue from ischemia-reperfusion injury by reducing reactive oxygen species related damage.

https://downloads.hindawi.com/journals/ecam/2018/8495010.pdf

Ziziphora clinopodioides Flavonoids Protect Myocardial Cell Damage from Myocardial Ischemia-Reperfusion Injury.

Protection of Citrullus colocynthis Fruit Extracts on Carbon Tetrachloride-induced and Bacillus Calmette-Guerin plus Lipopolysaccharide-induced Hepatotoxicity in Mice

Ziziphora bungeana is a kind of medicinal plants belongs to Labiatae,and it also a kind of geoherbs in Xinjiang. The main active ingredient linarin has a higher content in inflorescence than in other parts. In this study,high-throughput sequencing technology was used to reveal the transcriptome of the inflorescence of Z. bungeana,77 366 unigenes were acquired,of which 56 375 unigenes were annotated based on search of the database and classification. Through the analysis of metabolic pathways,sixty unigenes were probably encoding some enzymes involved in the flavonoid biosynthesis pathways. The contents of linarin in different parts were determined and the key genes were verified by qRT-PCR. The discovery provides the research basis for further analysis of the enzyme genes involved in the biosynthesis of the major flavonoid components in Z. bungeana.

Wei-Jun Yang

Papers

Protective effects of acacetin isolated from Ziziphora clinopodioides Lam. (Xintahua) on neonatal rat cardiomyocytes

Integrated metabolomic and transcriptomic profiling reveals the tissue-specific flavonoid compositions and their biosynthesis pathways in Ziziphora bungeana

Ziziphora clinopodioides Flavonoids Protect Myocardial Cell Damage from Myocardial Ischemia-Reperfusion Injury.

Protection of Citrullus colocynthis Fruit Extracts on Carbon Tetrachloride-induced and Bacillus Calmette-Guerin plus Lipopolysaccharide-induced Hepatotoxicity in Mice

Transcriptome analysis reveals candidate genes involved in flavonoid biosynthesis in Ziziphora bungeana