International comparisons of intraocular pressures, as measured by Tono-Pen and Goldmann applanation tonometry, in healthy adults: A meta-analysis.

BACKGROUND: Investigate intraocular pressure (IOP), as measured by Tono-Pen (TP) and Goldmann applanation tonometry (GAT), in healthy adults. Provide an updated synthesis of multinational, primary studies, reported during the 10-year period 2011 to 2021 and offer an evidence-based benchmark, against which IOP can be evaluated across subject variables and pathologies. Three primary research questions are investigated: Is there a statistically significant difference between IOP measured by TP and GAT? If yes, is the difference clinically significant? Is measurement of IOP affected by the country or setting location, in which the measurements are made? METHODS: An aggregate meta-analysis was conducted on 22 primary studies, from 15 different countries. IOP measurements were made from each healthy adult subject, with both the TP and GAT. Primary studies were identified and data extracted according to recommended preferred reporting items for systematic reviews and meta-analysis protocol guidelines. Meta-analysis summary results are reported as the point estimate of the raw mean difference of IOP. RESULTS: Meta-analysis reveals a statistically significant difference in raw mean differences in IOP, when measured by TP and GAT, in the healthy adult population. Tono-Pen IOP measurements are higher than GAT IOP measurements. The point estimate for the summary effect size = -0.73 mm Hg, P = .03. The prediction interval for the true effect size, in 95% of all comparable populations, is -4.03 to 2.58 mm Hg. There is no clinically significance difference in IOP when measured by TP and GAT. Meta-regression analysis reveals statistically significant differences in measurement of IOP by countries, R2 analog = 0.75, P = .001. There is no statistically significant difference in measurement of IOP as a function of measurement location setting, R2 analog = -0.17, P = .65. CONCLUSIONS: IOP measured by TP are marginally higher compared to GAT, in the healthy adult population. However, from a clinical practice perspective, TP and GAT produce similar IOP measurements. There is evidence of significant variabilities in IOP measurements as a function of country. IOP measurements collected in a research laboratory setting are similar to IOP collected in a clinical setting. Results have implications for the primary care physician requiring a portable, inexpensive, reliable, and easily administered instrument to assess IOP.

Antidiuretic hormone release associated with increased intracranial pressure independent of plasma osmolality.

OBJECTIVE: Introduce and evaluate a new model which explains the release of brain antidiuretic hormone (ADH) independent of plasma osmolality. METHODS: Systematic review and critical analysis of the professional literature. RESULTS: Primary electronic database searches using key terms revealed 57,432 hits. Secondary searches with application of specific inclusion and exclusion criteria and manual inspection for completeness reduced the total number of studies to fourteen (N = 14). Twelve (N = 12) studies investigated human subjects in the hospital settings, and two (N = 2) studies investigated animals (rhesus monkeys and dog) under invasive experimental conditions. All fourteen studies included direct or indirect indicators of intracranial pressure (ICP), measurements of plasma ADH, and plasma osmolality or urine osmolality. Findings, in brief, reveal a stable and positive association between increased intracranial pressure (ICP) and increased ADH release, in patients with low or normal blood osmolality. Findings are reliable and reproducible across human and animal populations. CONCLUSIONS: Findings support the proposed model, which explains increase secretion of brain ADH when plasma osmolality is low or within normal limits. Mechanical pressures exerted on hypothalamic nuclei, especially paraventricular and supra-optic nuclei, as a consequence of increased intracranial pressure, produce release of ADH, independent of plasma osmolality. The mechanical pressure model explains release of ADH previously unexplained by traditional plasma osmolality models. Findings have important clinical implications for the medical and surgical management of patients.

Bioassay-Guided Isolation of Antioxidant and Cytoprotective Constituents from a Maqui Berry (Aristotelia chilensis) Dietary Supplement Ingredient As Markers for Qualitative and Quantitative Analysis.

Bioassay-guided phytochemical investigation of a commercially available maqui berry (Aristotelia chilensis) extract used in botanical dietary supplement products led to the isolation of 16 compounds, including one phenolic molecule, 1, discovered for the first time from a natural source, along with several known compounds, 2-16, including three substances not reported previously in A. chilensis, 2, 14, and 15. Each isolate was characterized by detailed analysis of NMR spectroscopic and HRESIMS data and tested for their in vitro hydroxyl radical scavenging and quinone-reductase inducing biological activities. A sensitive and accurate LC-DAD-MS method for the quantitative determination of the occurrence of six bioactive compounds, 6, 7, 10-12, and 14, was developed and validated using maqui berry isolates purified in the course of this study as authentic standards. The method presented can be utilized for dereplication efforts in future natural product research projects or to evaluate chemical markers for quality assurance and batch-to-batch standardization of this botanical dietary supplement component.

Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation including Citrus bergamia, in subjects with moderate cardiometabolic risk factors.

We examined the clinical safety and efficacy of F105 in 11 subjects with moderate dyslipidemia. F105 is a combination of bergamot fruit extract (Citrus bergamia, BFE) and 9 phytoextracts selected for their ability to improve the antioxidant and anti-inflammatory activity of BFE. In vitro F105 exhibited a synergistic inhibition of oxygen radical absorbing capacity, peroxynitrite formation, and myeloperoxidase activity. Following 12 weeks of F105 daily, no treatment-related adverse events or changes in body mass were seen. Statistically significant changes were noted in total cholesterol (-7.3%), LDL-cholesterol (-10%), non-HDL cholesterol (-7.1%), cholesterol/HDL (-26%), and apolipoprotein B (-2.8%). A post hoc analysis of 8 subjects with HbA1c > 5.4 and HOMA-IR score > 2 or elevated triglycerides revealed additional statistically significant changes in addition to those previously observed in all subjects including triglycerides (-27%), oxLDL (-19%), LDL/HDL (-25%), triglycerides/HDL (-27%), oxLDL/HDL (-25%), and PAI-1 (-37%). A follow-up case report of a 70-year-old female patient, nonresponsive to statin therapy and placed on F105 daily, demonstrated improved cardiometabolic variables over 12 weeks similar to the subgroup. In summary, F105 was clinically well-tolerated and effective for ameliorating dyslipidemia in subjects with moderate cardiometabolic risk factors, particularly in the individuals with HbA1c > 5.4%.

LC-MS-Based Quality Assessment of a Traditional Chinese Medicine YANG XIN Formulation.

YANG XIN is a traditional Chinese medicine formulation used for nervous fatigue and consists of a proprietary blend of concentrated extracts from 18 plant ingredients. The 18 constituent plant ingredients, YANG XIN capsules, and formulations 2014-005_1 A and 1B were extracted by consecutive 24-hour macerations with dichloromethane followed by methanol. Metabolite separation was carried out through LC-MS in 40 minutes. Data acquisitions for qualitative and quantitative analyses of the samples were collected under (±) ESI modes and (+) APCI mode using full spectrum scan analysis.A total of 18 analytical markers were identified by LC-MS for YANG XIN formulations based on accurate mass measurements, molecular formula, double bond equivalent, MFG score, and error (ppm) of the measurement. Aditionally, a comparison of the data with previously reported results for the compounds, followed by identity confirmation with standard compounds, was performed. Seventeen analytical markers representing 17 plant ingredients in the different YANG XIN formulations were quantified for the first time. The YANG XIN capsules and the 2014-005_1B formulation were similar to each other and different from the 2014-005_1 A formulation based on the fact that both YANG XIN capsules and the 2014-005_1B formulation contain the same analytical markers. This method provides good linearity (r(2) > 0.9945), intraday precision (R. S. D. < 3.9 %), interday precision (R. S. D. < 5.6 %), accuracy (99.2-101 %), recovery (145.7 %), limit of detection (0.0011-0.0732 µg/mL), and limit of quantitation (0.0038-0.2441 µg/mL).

Computer-Assisted Structure Elucidation of Black Chokeberry (Aronia melanocarpa) Fruit Juice Isolates with a New Fused Pentacyclic Flavonoid Skeleton.

Melanodiol 4″-O-protocatechuate (1) and melanodiol (2) represent novel flavonoid derivatives isolated from a botanical dietary supplement ingredient, dried black chokeberry (Aronia melanocarpa) fruit juice. These noncrystalline compounds possess an unprecedented fused pentacyclic core with two contiguous hemiketals. Due to having significant hydrogen deficiency indices, their structures were determined using computer-assisted structure elucidation software. The in vitro hydroxyl radical-scavenging and quinone reductase-inducing activity of each compound are reported, and a plausible biogenetic scheme is proposed.

Pyrrole alkaloids with potential cancer chemopreventive activity isolated from a goji berry-contaminated commercial sample of African mango.

Bioassay-guided fractionation of a commercial sample of African mango (Irvingia gabonensis) that was later shown to be contaminated with goji berry (Lycium sp.) led to the isolation of a new pyrrole alkaloid, methyl 2-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl]propanoate, 1, along with seven known compounds, 2-8. The structures of the isolated compounds were established by analysis of their spectroscopic data. The new compound 1g showed hydroxyl radical-scavenging activity with an ED50 value of 16.7 µM, whereas 4-[formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]butanoic acid (2) was active in both the hydroxyl radical-scavenging (ED50 11.9 µM) and quinone reductase-induction [CD (concentration required to double QR activity) 2.4 µM)] assays used. The isolated compounds were shown to be absent in a taxonomically authenticated African mango sample but present in three separate authentic samples of goji berry (Lycium barbarum) using LC-MS and (1)H NMR fingerprinting analysis, including one sample that previously showed inhibitory activity in vivo in a rat esophageal cancer model induced with N-nitrosomethylbenzylamine. Additionally, microscopic features characteristic of goji berry were observed in the commercial African mango sample.

Antioxidant and quinone reductase-inducing constituents of black chokeberry (Aronia melanocarpa) fruits.

Using in vitro hydroxyl radical-scavenging and quinone reductase-inducing assays, bioactivity-guided fractionation of an ethyl acetate-soluble extract of the fruits of the botanical dietary supplement, black chokeberry (Aronia melanocarpa), led to the isolation of 27 compounds, including a new depside, ethyl 2-[(3,4-dihydroxybenzoyloxy)-4,6-dihydroxyphenyl] acetate (1), along with 26 known compounds (2-27). The structures of the isolated compounds were identified by analysis of their physical and spectroscopic data ([α](D), NMR, IR, UV, and MS). Altogether, 17 compounds (1-4, 9, 15-17, and 19-27) showed significant antioxidant activity in the hydroxyl radical-scavenging assay, with hyperin (24, ED(50) = 0.17 µM) being the most potent. The new compound (1, ED(50) = 0.44 µM) also exhibited potent antioxidant activity in this assay. Three constituents of black chokeberry fruits doubled quinone reductase activity at concentrations <20 µM, namely, protocatechuic acid [9, concentration required to double quinone reductase activity (CD) = 4.3 µM], neochlorogenic acid methyl ester (22, CD = 6.7 µM), and quercetin (23, CD = 3.1 µM).

Quantitative analysis of anthocyanins in Euterpe oleracea (açaí) dietary supplement raw materials and capsules by Q-TOF liquid chromatography/mass spectrometry.

CONTEXT: Euterpe oleracea Mart. (Arecaceae) fruits and their dietary supplements are gaining much popularity internationally. Anthocyanins and their aglycons are responsible for the dense color of açaí fruit and are associated with a wide spectrum of health promoting effects. OBJECTIVE: Quantitative analysis of anthocyanins in açaí dietary supplement raw materials; processed açaí powder (ADSR-1), organic açaí powder (ADSR-2), and nonorganic açaí powder (ADSR-3) by quadrupole-time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS) have been reported in this study. MATERIALS AND METHODS: The chromatographic separation for anthocyanins was achieved using a C-18 column with a gradient of 0.1% formic acid in water and 0.1% formic acid in methanol and acetonitrile (50:50, v/v). MS and MS/MS experiments were carried out on an electrospray ionization-Q-TOF LC/MS. RESULTS: Except for ASDR-2, all the açaí samples were found to have cyanidin 3-glucoside (1), cyanidin 3-sambubioside (2), cyanidin 3-rutinoside (3), and peonidin 3-rutinoside (4). ASDR-2 contained anthocyanins 1 and 3. Among the açaí samples quantified, ADSR-3 showed higher concentration of anthocyanins compared to other raw materials and capsules tested in this study. DISCUSSION AND CONCLUSION: The anthocyanins 1-4 present in ADSR-3 were 27.13 ± 0.37, 1.76 ± 0.04, 31.07 ± 0.49, and 3.46 ± 0.08 mg/100 g dry wt, respectively. The LOQ values for anthocyanins 1-4 were in the range of 2.44-9.76 ng/mL. Accuracy of the method was assessed by performing a recovery experiments. The intraday and interday variations (RSDs) were <10%. This is the first report on quantitation of anthocyanins in açaí dietary supplement raw materials and capsules.

The classical drug discovery approach to defining bioactive constituents of botanicals.

In this review, several recently identified biologically active principles of selected botanical dietary supplement ingredients are described, and were isolated using classical phytochemical chromatographic methods, with various spectroscopic procedures used for their isolation and structure elucidation. A central component of such an approach is "activity-guided fractionation" to monitor the compound purification process. In vitro assays germane to cancer chemoprevention were used to facilitate the work performed. Bioactive compounds, including several new substances, were characterized from açai (Euterpe oleracea), baobab (Adansonia digitata), licorice (Glycyrrhiza glabra), mangosteen (Garcinia mangostana), and noni (Morinda citrifolia). Many of these compounds exhibited quite potent biological activity, but tended to be present in their plant of origin only at low concentration levels.

Lignans and other constituents of the fruits of Euterpe oleracea (Acai) with antioxidant and cytoprotective activities.

Using a hydroxyl radical scavenging assay, bioactivity-guided fractionation of a methanol-soluble extract of the fruits of Euterpe oleracea (acai) led to the isolation of 22 compounds of previously known structure. Altogether, 14 of these isolates were found to be active in an in vitro hydroxyl radical scavenging assay and seven of these isolates in a 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Dihydroconiferyl alcohol, (+)-lariciresinol, (+)-pinoresinol, (+)-syringaresinol, and protocatechuic acid methyl ester exhibited cytoprotective activity in cultured MCF-7 cells stressed by H2O2. Lignans have not been previously reported as constituents of this species and were found to be representative of the aryltetrahydronaphthalene, dihydrobenzofuran, furofuran, 8-O-4'-neolignan, and tetrahydrofuran structural types.

Antioxidant and cytoprotective compounds from Berberis vulgaris (barberry).

Activity-guided fractionation of an EtOAc-soluble partition of the MeOH extract from the root bark of Berberis vulgaris L. (barberry), using a hydroxyl radical-scavenging assay, led to the isolation and identification of three phenolic compounds of a previously known structure, N-(p-trans-coumaroyl)tyramine, cannabisin G and (+/-)-lyoniresinol. Of these, cannabisin G and (+/-)-lyoniresinol exhibited antioxidant activity in this bioassay. Furthermore, it was found that cannabisin G showed cytoprotective activity in cultured MCF-7 cells modulated by hydrogen peroxide.

Xanthones with quinone reductase-inducing activity from the fruits of Garcinia mangostana (Mangosteen).

Bioactivity-guided fractionation of a dichloromethane-soluble extract of Garcinia mangostana fruits has led to the isolation and identification of five compounds, including two xanthones, 1,2-dihydro-1,8,10-trihydroxy-2-(2-hydroxypropan-2-yl)-9-(3-methylbut-2-enyl)furo[3,2-a]xanthen-11-one (1) and 6-deoxy-7-demethylmangostanin (2), along with three known compounds, 1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl)xanthone (3), mangostanin (4), and alpha-mangostin (5). The structures of compounds 1 and 2 were determined from analysis of their spectroscopic data. All isolated compounds in the present study together with eleven other compounds previously isolated from the pericarp of mangosteen, were tested in an in vitro quinone reductase-induction assay using murine hepatoma cells (Hepa 1c1c7) and an in vitro hydroxyl radical antioxidant assay. Of these, compounds 1-4 induced quinone reductase (concentration to double enzyme induction, 0.68-2.2microg/mL) in Hepa 1c1c7 cells and gamma-mangostin (6) exhibited hydroxyl radical-scavenging activity (IC50, 0.20microg/mL).

Anthraquinones with quinone reductase-inducing activity and benzophenones from Morinda citrifolia (noni) roots.

Two new benzophenones, morintrifolins A ( 1) and B ( 2), together with 14 known anthraquinones and four other known compounds, were isolated from a chloroform-soluble extract of Morinda citrifolia roots. Of the isolated compounds, four known anthraquinones, namely, 1,2-dihydroxyanthraquinone ( 3), 1,3-dihydroxy-2-methylanthraquinone ( 4), 2-hydroxy-3-(hydroxymethyl)anthraquinone ( 5), and 1,3,6-trihydroxy-2-methylanthraquinone ( 6), exhibited quinone reductase (QR)- inducing activity in Hepa lclc7 cells, with concentrations required to double QR activity of 12.0, 8.1, 0.94, and 0.56 microM, respectively.

Anti-oxidant constituents of the roots and stolons of licorice (Glycyrrhiza glabra).

As part of a search for new cancer chemopreventive agents, a new chalcone derivative (1), a novel group of neolignan lipid esters (2), and seven known phenolic compounds (formononetin, glabridin, hemileiocarpin, hispaglabridin B, isoliquiritigenin, 4'-O-methylglabridin, and paratocarpin B) (3-9) were isolated from the roots and stolons of licorice (Glycyrrhiza glabra). The structures of compound 1 and the individual components of isolate 2 were elucidated using various spectroscopic and chemical methods. All isolates were tested in an authentic peroxynitrite anti-oxidant assay. Of these compounds, hispaglabridin B (6), isoliquiritigenin (7), and paratocarpin B (9) were found to be the most potent anti-oxidant agents. Furthermore, isoliquiritigenin (7) was demonstrated to prevent the incidence of 1,2-dimethylhydrazine-induced colon and lung tumors in mice when administered at a dose of 300 mg/kg.

Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen).

As part of ongoing research on cancer chemopreventive agents from botanical dietary supplements, Garcinia mangostana L. (commonly known as mangosteen) was selected for detailed study. Repeated chromatography of a CH2Cl2-soluble extract of the pericarp led to the isolation of two new highly oxygenated prenylated xanthones, 8-hydroxycudraxanthone G (1) and mangostingone [7-methoxy-2-(3-methyl-2-butenyl)-8-(3-methyl-2-oxo-3-butenyl)-1,3,6-trihydroxyxanthone, 2], together with 12 known xanthones, cudraxanthone G (3), 8-deoxygartanin (4), garcimangosone B (5), garcinone D (6), garcinone E (7), gartanin (8), 1-isomangostin (9), alpha-mangostin (10), gamma-mangostin (11), mangostinone (12), smeathxanthone A (13), and tovophyllin A (14). The structures of compounds 1 and 2 were elucidated by spectroscopic data analysis. Except for compound 2, which was isolated as a minor component, the antioxidant activities of all isolates were determined using authentic and morpholinosydnonimine-derived peroxynitrite methods, and compounds 1, 8, 10, 11, and 13 were the most active. Alpha-mangostin (10) inhibited 7,12-dimethylbenz[alpha]anthracene-induced preneoplastic lesions in a mouse mammary organ culture assay with an IC50 of 1.0 microg/mL (2.44 microM).

An anthraquinone with potent quinone reductase-inducing activity and other constituents of the fruits of Morinda citrifolia (noni).

Morinda citrifolia, commonly known as noni, has a long history of utilization throughout much of tropical Polynesia and is considered to be the second most important medicinal plant in the Hawaiian Islands. Recently, the use of noni as a dietary supplement in the United States has greatly increased. Bioassay-guided fractionation of a dichloromethane-soluble partition of a MeOH extract of noni fruits has led to the isolation of an extremely potent quinone reductase inducer, 2-methoxy-1,3,6-trihydroxyanthraquinone (1). This new anthraquinone (1) was nearly 40 times more potent than a positive control, l-sulforaphane. Furthermore, compound 1 demonstrated no discernible cytotoxicity at the highest dose tested. In addition to compound 1, 11 known compounds were also isolated and identified in the present investigation. This is the first report of the isolation of anthraquinones from noni fruits.

Chemical constituents of the fruits of Morinda citrifolia (Noni) and their antioxidant activity.

Purification of a n-BuOH-soluble partition of the MeOH extract of Morinda citrifolia (Noni) fruits led to the isolation of two new iridoid glucosides, 6alpha-hydroxyadoxoside (1) and 6beta,7beta-epoxy-8-epi-splendoside (2), as well as 17 known compounds, americanin A (3), narcissoside (4), asperuloside, asperulosidic acid, borreriagenin, citrifolinin B epimer a, citrifolinin B epimer b, cytidine, deacetylasperuloside, dehydromethoxygaertneroside, epi-dihydrocornin, d-glucose, d-mannitol, methyl alpha-d-fructofuranoside, methyl beta-d-fructofuranoside, nicotifloroside, and beta-sitosterol 3-O-beta-d-glucopyranoside. The structures of the new compounds were determined by spectroscopic data interpretation. Compound 4, borreriagenin, cytidine, deacetylasperuloside, dehydromethoxygaertneroside, epi-dihydrocornin, methyl alpha-d-fructofuranoside, and methyl beta-d-fructofuranoside were isolated for the first time from M. citrifolia. The antioxidant activity was evaluated for all isolates in terms of both DPPH and ONOO(-) bioassays. The neolignan, americanin A (3), was found to be a potent antioxidant in these assays.