Phytochemical studies on the whole herb of Sphaerophysa salsula has resulted in the discovery of one new 8-isopentenyl isoflavone derivative, named sphaerosin s2 (3-(8-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-furo[2,3-h]chromen-3-yl)-2,6-dimethoxyphenol) (1), along with four know 8-isopentenyl isoflavone derivatives (2-5). Compounds (2, 4 and 5) were isolated for the first time from this species. Their structures were elucidated on the basis of ESI-MS, UV, IR, 1D NMR and 2D NMR data.
OBJECTIVES: The hepatoprotective effect of Gentianae macrophyllae root extract (GME) on alcoholic liver disease (ALD) was evaluated through ethanol induced ALD animal model.METHODS: Mice were randomly divided into control normal group (10 mice), ethanol-induced ALD model group (10 mice) and GME plus ethanol group (30 mice). Mice in model group were given intragastric administration with 50% (v/v) ethanol aqueous solution (200 μl for each) once daily for 19 days. Mice in control normal group received equal volumes of water. Mice in GME plus ethanol group were given intragastric administration with 50% (v/v) ethanol aqueous solution (200 μl for each) once daily at 10:00 a.m., after 1 h, mice in GME group sequentially were treated with 20, 40 and 100 mg/kg of GME by gastric gavage for 19 days. the average food and water consumed by the mice in every group were recorded every 2 days and body weight of every mouse in every group was measured every 2 days.
KEY FINDINGS: Results showed that GME significantly improved alcohol induced liver injury in a dose-dependent manner. The impaired hepatic tissue structure was repaired and the collagen deposition declined after GME administration. Meanwhile, the level of malonaldehyde (MDA), Aspartate transaminase (AST) and alanine transaminase (ALT) (indicators of liver damage) in blood serum were significantly controlled by GME with a dose-dependent manner, moreover, body weight and liver index were also improved after administration of GME. Pro-inflammatory cytokines including MCP-1, TNF-α, IL-1 and IL-6 were detected through RT-PCR and ELISA in experiment and GME can significantly inhibit the expression of TNF-α, IL-1 and IL-6 but have no effect on MCP-1. In order to explore the mechanism of GME on ALD, MAPKs pathway was examined and results indicated that GME attenuated ALD through inhibiting the phosphorylation of JNK and P38 and further suppressing the initiation of inflammation.
CONCLUSIONS: GME attenuated ALD through inhibiting the phosphorylation of JNK and P38 and further suppressing the initiation of inflammation.
This study was to investigate the anti-diabetic effects and molecular mechanisms of Tang-Kang-Fu-San (TKFS), a traditional Tibetan medicine, in treating type 2 diabetes mellitus of spontaneous diabetic db/db mice. Firstly HPLC fingerprint analysis was performed to gain the features of the chemical compositions of TKFS. Next different doses of TKFS (0.5 g/kg, 1.0 g/kg, and 2.0 g/kg) were administrated via oral gavage to db/db mice and their controls for 4 weeks. TKFS significantly lowered hyperglycemia and ameliorated insulin resistance (IR) in db/db mice, indicated by results from multiple tests, including fasting blood glucose test, intraperitoneal insulin and glucose tolerance tests, fasting serum insulin levels and homeostasis model assessment of IR analysis as well as histology of pancreas islets. TKFS also decreased concentrations of serum triglyceride, total and low-density lipoprotein cholesterol, even though it did not change the mouse body weights. Results from western blot and immunohistochemistry analysis indicated that TKFS reversed the down-regulation of p-Akt and p-AMPK, and increased the translocation of Glucose transporter type 4 in skeletal muscles of db/db mice. In all, TKFS had promising benefits in maintaining the glucose homeostasis and reducing IR. The underlying molecular mechanisms are related to promote Akt and AMPK activation and Glucose transporter type 4 translocation in skeletal muscles. Our work showed that multicomponent Tibetan medicine TKFS acted synergistically on multiple molecular targets and signaling pathways to treat type 2 diabetes mellitus.
The aim of this study was to investigate the antidiabetic effects of a Tibetan medicine, Tang-Kang-Fu-San (TKFS), on experimental type 2 diabetes mellitus (T2DM) rats and to explore its underlying mechanisms. Firstly two major chemical compositions of TKFS, gallic acid and curcumin, were characterized by HPLC fingerprint analysis. Next T2DM in rats was induced by high-fat diet and a low-dose streptozotocin (STZ 35 mg/kg). Then oral gavage administration of three different doses of TKFS (0.3 g/kg, 0.6 g/kg, and 1.2 g/kg) was given to T2DM rats. Experimental results showed that TKFS dramatically reduced the levels of fasting blood glucose, fasting blood insulin, triglyceride, total cholesterol, LDL cholesterol, and HDL cholesterol, even though it did not alter the animal body weight. The downregulation of phosphorylation-AKT (p-AKT) and glucose transporter-4 (GLUT4) in skeletal muscle of T2DM rats was restored and abnormal pathological changes in pancreas tissues were also improved. Our work showed that TKFS could alleviate diabetic syndromes, maintain the glucose homeostasis, and protect against insulin resistance in T2DM rats, and the improvement of AKT phosphorylation and GLUT4 translocation in skeletal muscle would be one of its possible underlying mechanisms.
Background: Hypecoum leptocarpum Hook. f. et Thoms., which is used in traditional Tibetan medicine as an antipyretic, antitussive, analgesic, and anti-inflammatory agent, contains a variety of alkaloids that could be responsible for its analgesic and anti-inflammatory properties. Objective: The present study was designed to investigate the anti-inflammatory activity of the total alkaloids from H. leptocarpum (AHL) in vitro and to elucidate the chemical structure of the anti-inflammatory components in AHL. Materials and Methods: Chemical characterization was performed using liquid chromatography/quadrupole-time-of-flight mass and diode-array detector-high performance liquid chromatography. The anti-inflammatory effects of AHL were investigated by measuring the production of inflammatory cytokines using enzyme-linked immunosorbent assay and mRNA expression by real-time polymerase chain reaction in lipopolysaccharide-induced RAW 264.7 macrophages. Results: Chemical analysis of AHL revealed the presence of seven alkaloids, protopine (13.3%), cryptopine (1.5%), leptopidinine, leptocarpine, corydamine, dihydroleptopine, and oxohydrastinine. AHL significantly suppressed the production of nitric oxide (NO), interleukin-1 beta (IL-1 β), IL-6, and tumor necrosis factor-alpha (TNF-α) in LPS-induced RAW 264.7 cells. The maximum levels of suppression of NO, IL-1 β, IL-6, and TNF-α were 86.8% ± 2.2%, 70.1% ± 1.5%, 100.1% ± 2.5%, and 50.8% ± 3.6%, respectively. IC50values of suppression of cytokine production by AHL were 7.47 ± 2.81 μg/mL (NO), 0.12 ± 0.28 μg/mL (IL-1 β), 0.56 ± 0.37 μg/mL (IL-6), and 18.95 ± 5.23 μg/mL (TNF-α). AHL was also shown to downregulate mRNA expression of inducible NO synthase, IL-1 β, IL-6, and TNF-α in vitro. Conclusion: The study provides convincing evidence that AHL has strong anti-inflammatory activity. The potent activity is likely a result of synergy between the different alkaloids. Abbreviations used: The total alkaloids from H. leptocarpum: AHL; Nitric oxide: NO; Interleukin-1 beta IL-1β; Interleukin-6: IL-6; Tumor necrosis factor-alpha: TNF-α; Prostaglandin E2: PGE2; Inducible nitric oxide synthase: iNOS; Nonsteroidal anti-inflammatory drugs: NSAIDs; lipopolysaccharide: LPS; The total ion chromatograms: TIC; The liquid chromatography/quadrupole-time of flight: LC/Q-TOF; Nuclear factor-kappa B: NF-κB; Janus kinase-signal transducers and activators of transcription: JAK-STAT. [ABSTRACT FROM AUTHOR]
Bioactive equivalent combinatorial components play a critical role in herbal medicines. However, how to discover and enrich them efficiently is a question for herbal pharmaceuticals researchers. In our work, a novel two-dimensional reversed-phase/hydrophilic interaction high-performance liquid chromatography method was established to perform real-time components trapping and combining for preparation and isolation of coeluting components. Arenaria kansuensis was taken as an example, and solid-phase extraction coupled with liquid-liquid extraction as a simple and efficient method for enriching trace components, reversed phase column coupled with hydrophilic interaction liquid chromatography XAmide column as two-dimensional chromatography technology for isolation and preparation of coeluting constituents, enzyme-linked immune-sorbent assay as bio-guided assay, and anti-inflammatory bioactivity evaluation for bioactive constituents. A combination of 12 β-carboline alkaloids was identified as anti-inflammatory bioactive equivalent combinatorial components from A. kansuensis, which accounts for 1.9% w/w of original A. kansuensis. This work answers the key question of which are real anti-inflammatory components from A. kansuensis and provides a fast and efficient approach for discovering and enriching trace β-carboline alkaloids from herbal medicines for the first time. More importantly, the discovery of bioactive equivalent combinatorial components could improve the quality control of herbal products and inspire a herbal medicine based on combinatorial therapeutics.
Jerusalem artichoke (JA, Helianthus tuberosus L.) has been researched extensively due to its wide range of uses, but there are limited studies on its flowers. In this study, we report the first detailed phytochemical study on JA flowers, which yielded 21 compounds. Compound 4 was identified as a major water-soluble yellow pigment of JA flowers. In addition, the methanol extract of JA flowers and the isolates were evaluated for their antioxidant and α-glucosidase inhibitory activities. Among the tested compounds, compound 13 showed the strongest ABTS+ free radical scavenging activity with SC50 value of 2.30 ± 0.13 μg/mL, and compound 6 showed most potent α-glucosidase inhibitory activity with inhibition rate of 60.0% ± 10.3% at a concentration of 250 μg/mL. Results showed that methanol extract of JA flowers exhibited antioxidant and α-glucosidase inhibitory activities which could be attributed to its phenolic ingredients including chlorogenic acid derivatives, flavonoids and phenols.
<br>Display Omitted<br> Two new phenolic acids (<b>1</b>⿿<b>2</b>) were isolated from the aerial parts of <b>Asterothamnus centrali-asiaticus</b>. Five knownphenolic acids (<b>3</b>⿿<b>7</b>) were also obtained from the title plant. <b>1</b>⿿<b>7</b> were evaluated for their anti-oxidant activity. <b>1</b>⿿<b>7</b> showed anti-oxidant activity with IC50 values ranging from 7.65 to 22.44 μg/mL.<br>Two new phenolic acids 2-hydroxy-5-[(6⿲-<b>O</b>-(<b>E</b>)-caffeoyl)-β-d-glucopyranosyl]-oxybenzoic acid (<b>1</b>) and 2-hydroxy-5-[(3⿲-<b>O</b>-(<b>E</b>)-caffeoyl)-β-d-glucopyranosyl]-oxybenzoic acid (<b>2</b>) were isolated from the aerial parts of <b>Asterothamnus centrali-asiaticus</b>, together with five known ones (<b>3</b>-<b>7</b>). Their structures were elucidated by extensive 1D and 2D NMR studies and HRESIMS investigations. The anti-oxidant activity of the isolates was evaluated through ABTS radical cation decolorization assay. The results showed that all of them exhibited anti-oxidant activity, and compound <b>7</b> was the most active compound with an IC50 value of 7.65 μg/mL.
The young leaves and shoots of Sibiraea laevigata, known as "Liucha", are used as tea by Tibetans to improve digestion after meals. Long-term consumption of "Liucha" will cause weight loss. In present work, we reported on the isolation and NMR and chemical analysis-based elucidation of seven new sorbitol O-caffeic acid ester derivatives named sorbitol esters A-G (1-7) and eighteen known phenolic compounds from S. laevigata. All of the isolates were evaluated for their antioxidant and α-glucosidase inhibitory activities. Among them sorbitol ester A (1), sorbitol ester D (4), sorbitol ester F (6), sorbitol ester G (7), isoferulic acid (15), methyl caffeate (18), trans-p-hydroxycinnamic acid (19), and kaempferol 3-O-β-d-(6″-E-p-coumaroyl)-glucopyranoside (25) showed more potent α-glucosidase inhibitory activity than the clinical drug acarbose.
• <b>Saxifraga tangutica</b> Engl. is a promising source of antioxidants against DPPH and FRAP. • The 50% ethanol extract of S. <b>tangutica</b> showed strong antioxidative activity against DPPH and FRAP. • Eight phenols were isolated from S. <b>tangutica</b>; all of the compounds are reported for the first time from this plant. • The antioxidative S. <b>tangutica</b> extracts and isolated phenols supports the antioxidant of this plant.<br><b>Saxifraga tangutica</b> Engl., is a medicinal herb that grows on the Qinghai-Tibet Plateau. Extracts and phenols from the Qinghai population have been subjected to antioxidative assays against DPPH radical-scavenging and reducing power (FRAP). The 50% ethanol extract showed strong antioxidative activity against DPPH and FRAP, with IC50 ± SEM [μg/mL] values of 9.38 ± 0.46 and 15.46 ± 0.52, respectively. The antioxidative activity-guided fractionations were performed according to the DPPH and FRAP screening results. Fourteen fractions from the 50% ethanol extract showed dissimilar antioxidative activity against DPPH and FRAP of 8.16 ± 0.76 ∼ 38.42 ± 0.58 μg/mL and 13.22 ± 0.68 ∼ 61.47 ± 0.49 μg/mL. The chemical assay-guided separation of the active fractions (fractions 3, 6, 7 and 8) led to eight phenols: protocatechuic aldehyde (<b>1</b>), ethyl gallate (<b>2</b>), rhododendrin (<b>3</b>), <b>p</b>-hydroxyacetophenone (<b>4</b>), rhododendrol (<b>5</b>), protocatechuic acid ethyl ester (<b>6</b>), frambinone (<b>7</b>) and ethylparaben (<b>8</b>). All phenols are reported here for the first time from <b>S. tangutica</b> Engl. Protocatechuic aldehyde (<b>1</b>), ethyl gallate (<b>2</b>), rhododendrin (<b>3</b>) and protocatechuic acid ethyl ester (<b>6</b>) showed strong antioxidative activities (IC50 ± SEM [mM] between 8.79 ± 0.15 and 4.25 ± 0.47 and between 6.15 ± 0.48 and 2.83 ± 0.49) against DPPH and FRAP.
Purpose. To examine the effects of a Tai Chi Chung (TCC) program, an efficiency approach, on anxiety and cardiovascular risk factors. Cardiovascular diseases (CVDs) reDesign. A quasi-experimental study. main the leading cause of morbidity Setting. A community in Taipei City, Taixuan. and mortality worldwide and constitute Subjects. One hundred thirty-three adults aged 55 years and older. a major problem to medical science and Intervention. Sixty-four participants (experimental group) attended a 60-minute Tai Chi exercise three public health.' In Taiwan, heart disease times per lueekfor 12 weeks, whereas 69 participants (control group) maintained their usual daily activities. and CVD are the second and third Measures. Anxiety states, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass leading causes of death, respectively.^ index (BMI), and waist circumference (WC) were assessed at baseline, 6 weeks into the experiment, and 12 weeks into tlie experiment. Analysis. Generalized estimjiting equations were used to evaluate the changes.Results. Participants showed a greater drop in anxiety levels (ß = -2.57, p= .001) and DBP (ß = -7.02, p < .001) at the 12-week follow-up than did the controls. SBP significantly decreased in the 6-week follow-up and 12-week folloxo-up tests. The participants in the intervention achieved a greater drop in BMJ at the 6-week and 12-zueek follow-up visits than the controls. The interventions demonstrated decreased average WC at the 6-week and 12-week folhw-up visits as compared to tlie controls.
Conclusion. The results highlight the long-term benefits of a TCC program in facilitating health promotion by reducing anxiety and risk factors for cardiovascular diseases. (Am f Health Promot 201328[l]:16-22.)
Zuota is regarded as the king of Tibetan medicine. However, due to the confidentiality of this precious medicine, the scientific characterization of Zuota is very scarce, which limits the pharmacology and biosafety studies of Zuota. Herein, we collected four different Zuota samples from Tibet, Qinghai, Gansu, and Sichuan and characterized them by multiple techniques. Our results showed that Zuota was mainly an inorganic mixture of HgS, sulfur, and graphite. Morphologically, Zuota samples were composed of nanoparticles, which further aggregated into microsized particles. Chemically, the majorities of Zuota were S and Hg (in the forms of HgS and pure sulfur). All samples contained pure sulfur with orthorhombic crystalline. Zuota from Qinghai province had different HgS crystalline, namely, hexagonal crystalline. The others were all face-centered cubic crystalline. Carbon in Zuota NPs was in the form of graphite. The implication to future studies of Zuota was discussed.
Zuota is regarded as the king of Tibetan medicine. However, due to the confidentiality of this precious medicine, the scientific characterization of Zuota is very scarce, which limits the pharmacology and biosafety studies of Zuota. Herein, we collected four different Zuota samples from Tibet, Qinghai, Gansu, and Sichuan and characterized them by multiple techniques. Our results showed that Zuota was mainly an inorganic mixture of HgS, sulfur, and graphite. Morphologically, Zuota samples were composed of nanoparticles, which further aggregated into microsized particles. Chemically, the majorities of Zuota were S and Hg (in the forms of HgS and pure sulfur). All samples contained pure sulfur with orthorhombic crystalline. Zuota from Qinghai province had different HgS crystalline, namely, hexagonal crystalline. The others were all face-centered cubic crystalline. Carbon in Zuota NPs was in the form of graphite. The implication to future studies of Zuota was discussed.
The first phytochemical investigation on the roots of <b>Ligularia purdomii</b> led to the isolation and identification of 18 compounds, including two eremophilane sesquiterpenoids (<b>1</b> and <b>2</b>), three benzofuran derivatives (<b>3</b>-<b>5</b>), a triterpenoid (<b>6</b>), two steroids (<b>7</b> and <b>8</b>), nine phenolic components (<b>9</b>-<b>17</b>), and a monofatty glyceride (<b>18</b>). The structural elucidation of the isolated compounds was performed by spectroscopic data and comparison with the literature. Compounds (−)-syringaresinol (<b>11</b>), scopoletin (<b>13</b>), 3,5-dimethoxy-4-hydroxy-benzaldehyde (<b>14</b>), and glycerol monolinoleate (<b>18</b>) have not been recorded in <b>Ligularia</b> genus previously. The chemotaxonomic significance of these isolated compounds has been summarized.<br>• First phytochemical investigation on <b>L. purdomii.</b> • 18 compounds were identified from the acetone extract of <b>L. purdomii.</b> • Four compounds were reported from the genus <b>Ligularia</b> for the first time. • The results had important significance for chemotaxonomy of <b>L. purdomii.</b>
Objective: To investigate the chemical constituent from the roots of Gentiana straminea.; Methods: The constituents were separated by microporous resin,silica gel,Sephadex LH-20 and preparative column chromatography and their structures were elucidated by NMR and MS spectral methods.; Results: Twelve chemical constituents were isolated from the roots of Gentiana straminea and their structures were identified as daucosterol( 1),β-sitosterol( 2),ursolic acid( 3),sweroside( 4),swertiamarin( 5),gentiopicroside( 6),6’-O-acetyl-gentiopicroside( 7),6’-O-β-D-glucopyranosyl-sweroside( 8),protocatech uic aldehyde( 9),protocatechuic acid( 10),methyl gallate( 11) and dibutyl phthalate( 12).; Conclusion: The compounds 8,9,10,11 and 12 are obtained from this plant for the first time.;
Three compounds were isolated from alcoholic extracts of Gentiana tizuensis Franch.. On the basis of spectroscopic methods. Their structures were identified as ursolic acid (1), isooreintin (2), swertiajaponin (3). Among them,compound 2 was isolated from the plant for the first time,compound 3 was isolated from Gentiana for the first time.
A phytochemical investigation of <b>Saxifraga tangutica</b> led to the isolation of 11 compounds, including eight diarylheptanoids (<b>1</b>-<b>6</b>, <b>10</b> and <b>11</b>) and three phenylpropanoids (<b>7</b>-<b>9</b>). The chemical structures were established by extensive analysis of their MS and NMR spectroscopic data or comparison with literature data. In the present research, we report the isolated compounds <b>1</b>-<b>11</b>, for the first time, in the species <b>S. tangutica</b>. Moreover, compounds <b>1</b>, <b>2</b> and <b>4</b>-<b>11</b> have not been reported from any species in Saxifragaceae family. Furthermore, we discuss the chemotaxonomic significance of the isolated compounds.<br>• Eight diarylheptanoids and three phenylpropanoids have been isolated from <b>Saxifraga tangutica.</b> • Compounds <b>1</b>-<b>11</b> are firstly reported in the species <b>Saxifraga tangutica.</b> • Compounds <b>1</b>, <b>2</b> and <b>4</b>-<b>11</b> are firstly isolated from genus <b>Saxifraga</b> or family Saxifragaceae.
[Objectives] To explore the mechanism for the attenuate-synergistic effect of Zuota to Renqing Mangue, a contrasted study on the tissue distribution of Tibetan medicines Renqing Mangue compatible with Zuota was carried out. [Methods] The SD rats gastric ulcer model were made successfully, and then respectively were given Renqing Mangue compatible with Zuota or not according to the dose of 0.144 g/kg and normal saline by gavage administration, once a day. After 14 d of administration, various organs and tissue were isolated, including brain, heat, liver, spleen, lung, kidney, jejunum, skeletal muscle, fat, skin, submandibular gland, uterus and ovary (or testicle and epididymis). The LC-MS/MS methods were used for determining the contents of brucine and strychnine in various organs and tissue, and significant difference analysis, main target site analysis and clustering analysis were implemented. [Results] Between the Zuota group and non-Zuota group, there was extremely significat diference in the content of brucine in the liver, kidney, muscle, lung, ovary, and heart (P < 0.01), significant difference in the jeeunum (P <0.05), and no significant diference in the epididymis, testis, brain, skin and uterus (P > 0.05); the content of brucine in the submadibular gland, spleen, liver and ovary increased significantly, but significanty reduced in the kidney, muscle, jeeunum, lung and heart. And there was extremely significant diference in the content of strychnine in the liver, kidney, ovary, brain and heat (P <0.01), and no significat difference in the uterus (P > 0.05); the strychnine content increased significantly in the liver, spleen and ovary, and significanty decreased in the kidney, muscle, testis, lung, brain and heart. [Conclusions] Compatibility of Zuota can afect the distribution of brucine and strychnine in some tissue and organs, so a to achieve attenuate-synergistic effect of Zuota to Renqing Mague. [ABSTRACT FROM AUTHOR]
To provide insights into the mechanism for the attenuate-synergistic effect of Zuota to Tibetan medicine Renqing Mangjue, a contrasted study was carried out on the pharmacokinetics of brucine and strychnine in mice plasm, which are active and toxicant ingredient in the Tibetan medicine Renqing Mangjue. LC-MS/MS was used to detect simultaneously the concentrations of brucine and strychnine in mice plasm at-different time intervals after administration parallelly and randomly, and the pharmacokinetic software Kinetica 5. 0 was selected to non-compartmental analysis (NCA) for data, and statistical analysis software SPSS 19. 0 was used for significance test on the pharmacokinetic parameters. A reliable LC-MS/MS method was established for the determination of brucine and strychnine in blood plasma, which are consistent with the requirements of the preclinical pharmacokinetic study confirmed by the methodology. The linear concentration ranges of brucine and strychnine were 0.301-104.4 µg · L(-1) (r = 0.999 5) and 0.305-106 µg · L(-1) (r = 0.999 7), respectively; The intra-day and inter-day variable coefficients were both less than 10.0% with good precision; The average extraction recoveries of brucine and strychnine were 116.23% and 112.82%, and RSD were 3.2% and 2.3% separately;The average matrix effects of brucine and strychnine were 122.48% and 116.36%, and RSD were 7.7% and 4.4%, respectively. The pharmacokinetic results showed that AUCtot of brucine and strychnine in Zuota group were both increased remarkably (P < 0.05), and the Cmax of brucine in Zuota group was about 5.25-fold higher than that of brucine in non-Zuota group (P < 0.05). The Tmax of brucine and strychnine reduced to one-eighth and one-quarter respectively compared with those in Non-Zuota group. In addition, the eliminations of brucine and strychnine in vivo were accelerated after the compatibility of Zuota. A significant difference (P < 0.05) occurred at the MRT0-t, of brucine, while the MRT0-∞ and Lz of strychnine were statistically significant upon the inspection level α = 0.1. It was found that the absorption degree of brucine and strychnine in Zuota group increased in the range of the safe dose (or concentration), while their elimination rates were accelerated, which may be one of the mechanisms for attenuate-synergistic effect of Zuota to Tibetan medicine Renqing Mangjue.
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