An UHPLC/LC-MS illustrated the dynamic profiling of balanophorin B, gallic acid, and 4-hydroxycinnamic acid in rat as 3 molecular entities from Balanophora simaoensis.

An UHPLC/LC-MS was founded to detect balanophorin B (B), gallic acid (GA), 4-hydroxycinnamic acid (HC), and their in vivo profiling in rats, after oral administration of the ethanol extract of Balanophora simaoensis S. Y. Chang et Tam. The in vivo dynamic existence of 3 molecular entities in rats and the multistep biotransformation of GA were elucidated by their sensitive mass spectrometry response after efficient UHPLC and/or HPLC separation, through analyzing the bio-samples of rat plasma, bile, liver, kidneys, and excreta. The method was validated with satisfactory calibration curves having correlation coefficients r from 0.996 to 0.999 for concentration scaled from 0.100 nM to 0.100 µM, internal standard normalized matrix factors ranged from 0.923 to 0.993, sextuplicate recoveries valued from 95.0% to 103.6%, as well as accuracy and precision varied from 95.6% to 103.7%. The content of B, GA, and HC in the whole herb was of 4.66, 63.5, and 10.4 µmol/kg in dry weight, respectively. The Cmax for B, GA, and HC in rat systemic circulation was of 76.0 nM, 2.30 µM, and 51.0 µM, with tmax at 3, 2, and 2 h, respectively. B and GA stayed in rat liver over 4 hs to present a material base for the pharmacology and pharmacodynamics of the whole herb. The biotransformation of GA indicated a complicated scheme in rats. As a final metabolite from GA with total biotransformation conversion over 20%, 4-hydroxybenzaldehyde resourced from two steps of dehydroxylation and one step of reduction of GA, but not concerned with HC.

Leonurine hydrochloride-a new drug for the treatment of menopausal syndrome: Synthesis, estrogen-like effects and pharmacokinetics.

This research aimed to investigate the estrogen-like effects of Leonurine hydrochloride (Leo). First, we developed a total synthesis of Leo from 3,4,5-trimethoxy-benzoic acid and the structure was confirmed through 1H NMR and mass spectrometry (MS). Then the estrogenic activity of Leo in vitro and in vivo was studied. The proliferation and proliferation inhibitory effects of Leo on MCF-7 cells and MDA-MB-231 cells indicate that Leo exerts estrogen-like effects through estrogen receptor α (ERα) and estrogen receptor ß((ERß) in vitro. Uterotrophic assay in juvenile mice showed that Leo has an estrogen-like effect in vivo, as it can promote the development of the uterus of juvenile mice, increase its uterine coefficient and the size of the uterine cavity, as well as the increased number of uterine glands and the thickened uterine wall. For further research, cyclophosphamide (CTX) was used to establish a mouse model of ovarian function decline. Through this model, we found that Leo can restore the estrous cycle of mice, increase the number of primordial and primary follicles in the ovaries of mice, and regulate the disordered hypothalamic-pituitary-ovarian (HPOA) axis of mice. Finally, the pharmacokinetics of Leo was studied and oral bioavailability of Leo was calculated to be 2.21%. Leo was synthesized and the estrogen-like effect in vitro and in vivo was confirmed as well as its pharmacokinetics.

Study on mechanism of low bioavailability of black tea theaflavins by using Caco-2 cell monolayer.

This study aimed to clarify the bioavailability mechanism of theaflavins by using the Caco-2 monolayer in vitro model. Prior to the transport of theaflavin (TF), theaflavin-3-gallate (TF3G), theaflavin-3'-gallate (TF3'G), and theaflavin-3, 3'-digallate (TFDG), we found the cytotoxicity of theaflavins was in the order of TF3'G > TFDG > TF3G > TF, suggesting the galloyl moiety enhances the cytotoxicity of theaflavins. Meantime, the galloyl moiety made theaflavins unstable, with the stability in the order of TF > TFDG > TF3G/TF3'G. Four theaflavins showed poor bioavailability with the Papp values ranging from 0.44 × 10-7 to 3.64 × 10-7 cm/s in the absorptive transport. All the theaflavins showed an efflux ratio of over 1.24. And it is further confirmed that P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP) were all shown to contribute to the efflux transport of four theaflavins, with P-gp playing the most important role, followed by MRPs and BCRP. Moreover, theaflavins increased the expression of P-gp, MRP1, MPR3, and BCRP while decreased the expression of MRP2 at the transcription and translation levels. Additionally, the gallated theaflavins were degraded into simple theaflavins and gallic acids when transported through Caco-2 monolayers. Overall, the structural instability, efflux transporters, and cell metabolism were all responsible for the low bioavailability of four theaflavins in Caco-2 monolayers.

Pharmacokinetics of gallic acid and protocatechuic acid in humans after dosing with Relinqing (RLQ) and the potential for RLQ-perpetrated drug-drug interactions on organic anion transporter (OAT) 1/3.

CONTEXT: Relinqing granules (RLQ) are being used alone or in combination with antibacterial drugs to treat urological disorders. OBJECTIVE: This study investigates the pharmacokinetics of RLQ in humans and the potential for RLQ-perpetrated interactions on transporters. MATERIALS AND METHODS: Twelve healthy subjects (six women and six men) participated to compare single- and multiple-dose pharmacokinetics of RLQ. In the single-dose study, all 12 subjects received 8 g of RLQ orally. After a 7-d washout period, the subjects received 8 g of RLQ for seven consecutive days (t.i.d.) and then a single dose. Gallic acid (GA) and protocatechuic acid (PCA) in plasma and urine samples were analysed using LC-MS/MS. The transfected cells were used to study the inhibitory effect of GA (50-5000 µg/L) and PCA (10-1000 µg/L) on transporters OAT1, OAT3, OCT2, OATP1B1, P-gp and BCRP. RESULTS: GA and PCA were absorbed into the blood within 1 h after administration and rapidly eliminated with a half-life of less than 2 h. The mean peak concentrations of GA (102 and 176 µg/L) and PCA (4.54 and 7.58 µg/L) were lower in males than females, respectively. The 24 h urine recovery rates of GA and PCA were about 10% and 5%, respectively. The steady-state was reached in 7 d without accumulation. GA was a potent inhibitor of OAT1 (IC50 = 3.73 µM) and OAT3 (IC50 = 29.41 µM), but not OCT2, OATP1B1, P-gp or BCRP. DISCUSSION AND CONCLUSIONS: GA and PCA are recommended as PK-markers in RLQ-related pharmacokinetic and drug interaction studies. We should pay more attention to the potential for RLQ-perpetrated interactions on transporters.

Improving gallic acid and quercetin bioavailability by polymeric nanoparticle formulation.

The anticancer activity and pharmacokinetic properties of encapsulated polyherbal nanoparticles (gallic acid (GA) and quercetin nanocomposite) and polyherbal extract (amla and pomegranate fruit peels) in normal and DMH-induced colorectal cancer in rats were examined in this work. In normal and DMH-induced rats, a pharmacokinetic study demonstrated that polyherbal nanoparticles had a typical sustained release profile with a fourfold increase in bioavailability when compared to polyherbal extract. Based on serum-concentration profiles of polyherbal nanoparticles and polyherbal extract following oral administration, the pharmacokinetic parameters for polyherbal nanoparticles and polyherbal extract were established using a single compartmental approach. This research suggests that encapsulating GA and quercetin in polymeric nanoparticles improves their oral bioavailability and anti-colon cancer efficacy. Polymeric nanoparticles could be a novel therapeutic possibility for carcinogenesis prevention.

Gallic acid: Pharmacological activities and molecular mechanisms involved in inflammation-related diseases.

Gallic acid (GA), also known as 3,4,5-trihydroxybenzoic acid, is a natural secondary metabolite and widely isolated from various fruits, plants and nuts. In recent years, GA has received increasing attention for its powerful anti-inflammatory properties. The purpose of this review is to clearly illuminate the pharmacological activities and related molecular mechanisms of GA in inflammatory diseases. After consulting a large number of literatures, we made a comprehensive exposition on the chemical characteristics, plant origins, pharmacokinetics and toxicity of GA, especially its pharmacological activities and mechanisms of action. Although the plant source of GA is very rich, its lower extraction rate limits the application of GA in development. It is worth mentioning that GA can not only be separated from many plants, but also be produced in large quantities through biological and chemical synthesis. According to pharmacokinetic studies, the absorption and elimination of GA after oral administration are fast, while the structural optimization or dosage form adjustment of GA is beneficial to increase its bioavailability. Promisingly, toxicity studies have shown that GA scarcely has obvious toxicity or side effects in a variety of animal experiments and clinical trials. The results show that the anti-inflammatory mechanisms of GA mainly involved MAPK and NF-κB signaling pathways. It thus weakens the inflammatory response by reducing the release of inflammatory cytokines, chemokines, adhesion molecule and cell infiltration. Due to its excellent pharmacological activities, GA is expected to be a potential candidate for the treatment of various inflammation-related diseases. This paper will provide theoretical basis for the clinical application of GA and guide the future research and medicinal development of GA.

Tissue distribution and molecular docking research on the active components of Bidens bipinnata L. against hyperlipidemia.

Bidens bipinnata L. is a folk medicinal plant in China that shows significant antihyperlipidemia effectiveness. However, studies of the underlying mechanism study are lacking. In order to explore the potential action sites and the underlying mechanism of treating hyperlipidemic, this work undertook tissue distribution and molecular docking research on the markers of B. bipinnata L., which were obtained through serum pharmacochemistry and network database retrieval. The results showed that seven compounds (gallic acid, protocatechuic acid, rutin, hyperoside, bipinnate polyacetylenicloside, luteolin and quercetin) were screened out as markers. Owing to the diversity of chemical structures, they exhibited an inconsistent trend in tissue distribution. However, all of them had high levels in the liver and no specific distribution in other tissues. More interestingly, seven proteins-HMGCR (1HWK), NR3C1 (4P6W), CYP1A2 (2HI4), RXRA (4PP3), CES1 (1MX1), HSD11B1 (2RBE) and CYP1A1 (4I8V)-showed significant binding affinity with three or more markers, suggesting that they may be the target proteins of B. bipinnata L. This study preliminarily sheds light on the tissue distribution and targets of B. bipinnata L., providing some useful information on the underlying mechanisms of the antihyperlipidemia effect.

Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-ß-glucuronide.

BACKGROUND: Leonurine (Leo), a promising antilipemic agent that has been approved for clinical trials, is extensively metabolized into bioactive Leonurine-10-O-ß-glucuronide (L-10-G) vivo. OBJECTIVE: To explore the effects of breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2) on the disposition of L-10-G. METHODS: The pharmacokinetics, tissue distribution and intestinal perfusion of Leo were studied by using efflux transporter gene knockout mouse models. The enzyme kinetics via liver and intestinal microsomes were also examined. RESULTS: After intravenous injection with Leo, the AUC0-∞ values of L-10-G in Bcrp1-/- and Mrp2-/- mice were 1.55-fold and 16.80-fold higher, respectively, than those in wild-type FVB mice (P < 0.05). After oral administration, the AUC0-∞ value of L-10-G showed a 2.82-fold increase in Mrp2-/- mice compared with wild-type FVB mice (P < 0.05). After gavage with Leo for 10 and 25 min, the bile accumulation of L-10-G in Mrp2-/- mice was 3-fold and 22-fold lower, respectively, than that in wild-type FVB mice (P < 0.05). Besides, the intestinal excreted amount of L-10-G showed 2.22-fold and 2.68-fold decrease in Bcrp1-/- and Mrp2-/- mice, respectively, compared with that in wild-type FVB mice (P < 0.05). The clearance of L-10-G decreased in liver microsomes and increased in intestinal microsomes of Bcrp1-/- and Mrp2-/- mice compared to the wild-type FVB mice (P < 0.05). CONCLUSION: Both Bcrp and Mrp2 are involved in the disposition of L-10-G, and Mrp2 exhibits a superior influence.

Zein/Phospholipid Composite Nanoparticles for Successful Delivery of Gallic Acid into aHSCs: Influence of Size, Surface Charge, and Vitamin A Coupling.

PURPOSE: Zein/phospholipid composite nanoparticles (CNPs) were developed as a delivery platform for gallic acid (GA), a polyphenolic compound with reported preclinical antifibrotic activities. However, the therapeutic applicability of GA is hampered owing to its low bioavailability and rapid clearance. Accordingly, we developed GA-loaded CNPs. The effect of their size, surface charge and targeting strategies was investigated and optimized, with the aim of enhancing their ability to deliver GA to the activated hepatic stellate cells (aHSCs) in order to suppress hepatic fibrosis progression. METHODS: Different CNP systems were prepared and characterized with regard to their particle size, zeta potential, and GA entrapment efficiency (EE%). Also, they were statistically optimized via response surface methodology. The optimized systems were investigated with regard to their in vitro GA release, in vitro efficacy on aHSCs, and in vivo biodistribution in healthy rats. RESULTS: The GA-loaded cationic CNPs coupled with vitamin A (GA-CACNP/VA; 192 nm) showed high GA EE% (60% w/w), highest cellular internalization via active targeting, and more selective hepatic distribution, relative to free GA solution, GA-loaded anionic, and GA-loaded cationic systems. Furthermore, GA-CACNP/VA markedly triggered the apoptosis of aHSCs, repressed collagen deposition, and inhibited HSCs' activation to a lesser extent. CONCLUSION: The GA-CACNP/VA was shown to be a promising candidate for specific and controlled delivery of GA to aHSCs, which may provide an effective antifibrotic therapeutic approach.

Simultaneous determination of gallic acid, methyl gallate, and 1,3,6-tri-O-galloyl-ß-d-glucose from Turkish galls in rat plasma using liquid chromatography-tandem mass spectrometry and its application to pharmacokinetics study.

Turkish galls (TG) is a traditional Uygur medicine typically used in clinics for dental disease and chronic ulcerative colitis. In this study, a novel liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of gallic acid, methyl gallate, and 1,3,6-tri-O-galloyl-ß-d-glucose in rat plasma, which are the major bioactive compounds of TG. After a feasible protein precipitation using acetonitrile for sample preparation, chromatographic separation was performed with a BDS Hypersil C18 column (2.1 × 100 mm, 5 µm) at 30°C, and water containing 10 mmol of ammonium acetate and acetonitrile was used as the mobile phase with a flow rate of 0.3 mL/min. The MS detector was operated in the selective reaction monitoring with negative-ionization mode. The results of the method validation, including selectivity, linearity, accuracy, precision, extraction recovery, matrix effect, and stability of the compounds in the biosamples, were all within the current acceptance criteria. The established method was successfully applied to the pharmacokinetics study of three analytes in rats after an oral administration of TG extract and laid the foundation for studying the active components and mechanism of TG in vivo.

Evaluation of the pharmacokinetic-pharmacodynamic integration of marbofloxacin in combination with methyl gallate against Salmonella Typhimurium in rats.

Fluoroquinolone resistance in Salmonella Typhimurium is becoming a major concern. Hence, an intervention to limit the growth in resistance is inevitable. One way to combat this challenge is through combination therapy. The combination of antibiotics with phytochemicals has become an ideal means of preventing antimicrobial resistance. Recently, in an in vitro study, the combination of methyl gallate (MG) with marbofloxacin (MAR) has shown to prevent Salmonella Typhimurium invasion. It is also worth to study the effects of plant extracts on the pharmacokinetics of antibiotics. Hence, the objective of this study was to determine the effect of MG on the pharmacokinetics of MAR and pharmacokinetics/pharmacodynamics integration of MG and MAR. The micro-broth dilution method was used to obtain the minimum inhibitory concentration (MIC), and fractional inhibitory concentration (FIC) of MAR and MG. Whereas, the pharmacokinetic was conducted in rats by administering either MAR alone or combined with MG through oral and/or intravenous routes. The results indicated that the MIC of MAR and MG against standard strain Salmonella Typhimurium (ATCC 14028) was 0.031 and 500 µg/mL, respectively. The FICindex of the combination of MAR and MG was 0.5. For orally administered drugs, the Cmax and AUC24h of MAR were 1.04 and 0.78 µg/mL and 5.98 and 6.11 h.µg/mL when MAR was given alone and in combination with MG, respectively. The intravenous administration of MAR showed a half-life of 3.8 and 3.9 h; a clearance rate of 1.1 and 0.73 L/h/kg and a volume of distribution of 5.98 and 4.13 L/kg for MAR alone and in combination with MG, respectively. The AUC24/MIC for MAR alone and in combination with MG was 192.8 and 381.9 h, respectively. In conclusion, MG has shown to increase the antimicrobial activity of MAR in vitro and ex vivo experiments without affecting the pharmacokinetics of MAR in rats.

Antioxidant activity and bioaccessibility of phenolic compounds in white, red, blue, purple, yellow and orange edible flowers through a simulated intestinal barrier.

This study assessed the phenolics and their bioaccessibility through an in vitro digestion system coupled to a simulated intestinal barrier in eight edible flowers of distinct colors, namely mini rose, torenia, mini daisy, clitoria, cosmos, cravine, begonia and tagete. The antioxidant activity of the flowers before in vitro digestion, in their derived dialyzed and non-dialyzed fractions was evaluated using distinct approaches. All flowers presented in their composition phenolic acids, stilbenes, flavanol, anthocyanin, flavonol and flavanone, however distinct compounds and contents were found in each flower. The bioaccessibility varied among the phenolics and within the flower source (p < 0.05). Cosmos presented the highest (p < 0.05) content of phenolics and activity in ORAC assay before in vitro digestion and in dialyzed and non-dialyzed fraction; the observed activity was correlated (r = 0.9) to its major compounds, hesperidin and rutin, as well as to caftaric acid and procyanidin B2. Mini rose displayed the highest antioxidant activity in FRAP and DPPH assays before in vitro digestion; its dialyzed and non-dialyzed fraction showed the highest activity in FRAP, correlated to pelargonidin 3,5-diglucoside, catechin, epicatechin galate, epicagocatechin galate, procyanidin A2, quercitin 3-glucoside and trans-resveratrol (r = 0.9). In DPPH assay, mini rose showed the highest activity in the non-dialyzed fraction, while cravine showed the highest activity in the dialyzed fraction, which was mainly correlated to syringic acid (r = 1.0), pelargonidin 3,5-diglucoside and epicatechin (r = 0.9). Results show great variability in the phenolic composition and their bioaccessibility among the edible flowers studied. Our findings indicate cosmos and mini rose as sources of bioaccessible phenolics with great antioxidant activity.

Improved recovery of galloyl metabolites from mango (Mangifera indica L.) in human plasma using protein precipitation with sodium dodecyl sulfate and methanol.

Extraction of polyphenolic metabolites from blood fractions can be challenging since compound recovery can be limited by chemical structure, polarity, and protein-binding affinity of analytes. Gallic acid and its metabolites exhibit particularly low recoveries from plasma and can lead to an underestimation of their bioavailability from foods. A modified method to extract free gallic acid and its metabolites from human plasma aided by sodium dodecyl sulfate and acidified methanol (SDS-MeOH) was applied to extract free gallic acid and its metabolites from human plasma after a single consumption of 400 g of mango (cv. Ataulfo) pulp by 10 healthy male and female subjects. The use of SDS-MeOH facilitated extraction of significantly (p < 0.05) more pyrogallol, free gallic acid, 4-O-methylgallic acid, and ethyl gallate with recovery rates exceeding 80% in standard recovery from human blood plasma when compared to conventional methods that rely on solvent extraction or solid phase extraction. The method was reproducible and precise for standards from 50 to 500 µg/L. In pharmacokinetic plasma samples five predominant metabolites of gallic acid were tentatively characterized by HPLC-MS and absorption kinetics evaluated over 8 h for catechol-O-sulfate, 4-O-methylgallic acid-3-O-sulfate, and pyrogallol-O-sulfate, methylpyrogallol-O-sulfate, and 4-O-methylgallic acid with AUC0-8h of 9520 ± 3370, 6030 ± 1310, 5990 ± 1690, 4020 ± 1040, and 2790 ± 1190 µg/L h respectively. Plasma extraction was rapid and reproducible with superior recovery rates compared to conventional methods when evaluating polar phenolic metabolites.

Development of TPGS/F127/F68 mixed polymeric micelles: Enhanced oral bioavailability and hepatoprotection of syringic acid against carbon tetrachloride-induced hepatotoxicity.

Syringic acid (SA), a natural polyphenol found in fruits and vegetables, is claimed to show notable hepatoprotection. Nevertheless, low solubility and bioavailability hamper the application of SA. This study aimed to investigate the potential of TPGS/F127/F68 mixed polymeric micelles as a sustained and liver-targeting nanocarrier for SA. Herein, the prepared SA-loaded TPGS/F127/F68 mixed polymeric micelles (SA-TPGS-Ms) were spherically-shaped and homogeneously-distributed nanoparticles with high entrapment efficiency (94.67 ± 2.05%) and sustained release. Besides, in-vitro cell culture studies revealed that SA-TPGS-Ms substantially promoted cellular uptake with excellent biocompatibility. After oral administration, SA-TPGS-Ms demonstrated an increased bioavailability (2.3-fold) and delayed in-vivo elimination compared with the free SA. Furthermore, the alleviation of oxidative stress and amelioration of hepatic injury in CCl4-induced hepatotoxicity mice further demonstrated the excellent hepatoprotection of SA-TPGS-Ms. Collectively, SA-TPGS-Ms could be a promising nanocarrier for the utilization of SA in functional foods, with enhanced bioavailability and hepatoprotection.

Degradation of ZnGa2O4:Cr3+ luminescent nanoparticles in lysosomal-like medium.

The ultimate goal of in vivo imaging is to provide safe tools to probe the inside of a body in order to obtain pathological information, monitor activities, and examine disease progression or regression. In this context zinc gallate doped with chromium III (ZGO) nanoparticles with persistent luminescence properties have been previously developed, and their biodistribution as well as in vitro toxicity were evaluated. However, to date, nothing is known about their potential transformations in biological media, which may hinder their biomedical applications. In order to know if these nanoparticles could degrade, the present work consists of studying their fate over time depending on both their coating and the aqueous media in which they are dispersed. ZGO nanoparticles have been dispersed in three different aqueous solutions for up to 90 days and characterized by numerous techniques. Among the evaluated dispersion media, Artificial Lysosomal Fluid (ALF) mimicking the intracellular lysosome environment elicited significant degradation of ZGO nanoparticles. The chelating agents present in ALF have proved to play a major role in the degradation of the ZGO, by stabilizing the nanoparticles and increasing the contact. An important time decrease of the luminescence properties has also been observed, which correlated with the release of ions from ZGO nanoparticles as well as their decreasing size. This information is valuable since it indicates, for the first time, the long-term degradation of persistent luminescent nanoprobes in an in vivo like model medium. Therefore, possible elimination of the imaging probes after in vivo preclinical applications could be foreseen.

Biodegradable and biocompatible spherical dendrimer nanoparticles with a gallic acid shell and a double-acting strong antioxidant activity as potential device to fight diseases from "oxidative stress".

Gallic acid (GA) is a natural polyphenol with remarkable antioxidant power present in several vegetables and fruits. A normal feeding regime leads to a daily intake of GA which is reasonably regarded as "natural" and "safe" for humans. It owns strong potentials as alternative to traditional drugs to treat several diseases triggered by oxidative stress (OS), but poor gastrointestinal absorbability, pharmacokinetic drawbacks, and fast metabolism limit its clinical application. In this work, a fifth-generation polyester-based dendrimer was firstly prepared as a better absorbable carrier to protect and deliver GA. Then, by its peripheral esterification with GA units, a GA-enriched delivering system (GAD) with remarkable antioxidant power and high potential against diseases from OS was achieved. Scanning electron microscopy results and dynamic light scattering analysis revealed particles with an average size around 387 and 375 nm, respectively, and an extraordinarily spherical morphology. These properties, by determining a large particles surface area, typically favour higher systemic residence time and bio-efficiency. Z-potential of - 25 mV suggests satisfactory stability in solution with tendency to form megamers and low polydispersity index. GAD showed intrinsic antioxidant power, higher than GA by 4 times and like prodrugs, and it can carry contemporary several bioactive GA units versus cells. In physiological condition, the action of pig liver esterase (PLE), selected as a model of cells esterase, hydrolyses GAD to non-cytotoxic small molecules, thus setting free the bioactive GA units, for further antioxidant effects. Cytotoxicity studies performed on two cell lines demonstrated a high cell viability. Graphical Abstract Graphical Abstract.

Radiomodifying action, Pharmacokinetic and Biodistribution of Ethyl 3, 4, 5-trihydroxybenzoate-Implication in development of radiomitigator.

Ethyl 3, 4, 5-trihydroxybenzoate (GAE) is a major bioactive constituent of Hippophae Rhamnoides L. leaves and extract prepared from H. rhamnoides leaves exhibited radioprotective and pharmacological activity. Radiomodifying properties of polyphenol compounds through free radical neutralizing have been reported earlier. However, to date pharmacokinetic (PK) and biodistribution of polyphenol compounds post 60Co-γ-irradiation (5 Gy) exposure have not been studied yet. The study aims to investigate the radio modifying and inflammatory action, PK and biodistribution of GAE at a radioprotective dose and changes, if any, induced after irradiation. Male C 57 BL/6 mice (28-30 g) were administered GAE (200 mg/kg b.wt) orally 15 minutes post to irradiation. Mice were sacrificed at 15, 30 min, 1,2,4,8 and 24 h. PK and biodistribution of GAE in plasma and tissues were studied. The radiomodifying potential was assessed in terms of mitigating NF-kB activity and SGOT, SGPT, urea and creatinine levels in liver and kidney post irradiation. Our study suggested the potential use of GAE as radiomodifying agent inhibits NF-kB expression and maintains the SGOT 24.10 ± 2.4, SGPT 36.01 ± 6.1 U/l, urea18.16 ± 0.003, and creatinine 1.05 ± 0.04 mg/dL upto 8 h in comparison to irradiated mice. Moreover, in biodistribution studies, showed that GAE crosses the blood-brain barrier and is found in brain tissue. Plasma level of GAE peaked at about 15 min, with Cmax 4390.85 ± 285.20 in GAE and in 3391.78 ± 78.13 ng/mL in radiation + GAE-treated animals, Biodistribution resulted in the highest concentration to be found in liver and kidney. These radiomodifying and pharmacokinetic result may be useful for study of the bioactive mechanism associated with radiation injury and to develop a potent formulation of GAE for clinical application.

Comparative Pharmacokinetics of Gallic Acid, Protocatechuic Acid, and Quercitrin in Normal and Pyelonephritis Rats after Oral Administration of a Polygonum capitatum Extract.

Polygonum capitatum Buch.-Ham. ex D. Don is traditionally used by Hmong for the treatment of urinary tract infections and pyelonephritis. Information regarding the pharmacokinetic behavior of the extract in the condition of pyelonephritis is lacking. In the present study, we aimed to compare the pharmacokinetic properties of gallic acid (GA), protocatechuic acid (PCA), and quercitrin (QR)-the main bioactive constituents in the herb-in normal and pyelonephritis rats. The plasma samples were collected at various time points after administration of a single dose of Polygonum capitatum extract. The plasma level of GA, PCA, and QR at the designed time points was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and drug concentration versus time plots were constructed to estimate the pharmacokinetic parameters. The AUC(0-t), AUC(0-∞), MRT(0-t), and CL of GA, PCA, and QR in pyelonephritis rats was significantly different from those of the normal rats. The results indicated that the three constituents have higher rate of uptake and slower rate of elimination in the rats with pyelonephritis, suggesting altered rate and extent of drug metabolism.

Gallic and carnosic acids improve quality of frozen-thawed ram spermatozoa.

The objective was to determine effects of gallic acid (GA) and carnosic acid (CA), present in carob pods and rosemary extract respectively, on frozen-thawed ram spermatozoa. Thirty ejaculates were collected from five Merino rams, pooled, diluted in Tris-based extender and divided into five equal portions containing: 0.05 or 2 mM of GA; 0.05 or 0.2 mM of CA; or no additive (control). Extended semen was equilibrated at +4°C, loaded into straws, held 5 cm above liquid nitrogen for 12 min then plunged. Computer-aided sperm analysis was used to assess motility, whereas flow cytometry was used to assess high mitochondrial membrane potential (HMMP) and percentages of spermatozoa with plasma membrane and acrosome integrity (PMAI). Spermatozoa supplemented with 2 mM GA had greater total motility than control spermatozoa (39.9 ± 3.01 vs. 29.2 ± 1.31%, mean ± SEM, p < .05). The PMAI was greatest in 0.2 mM CA (13.3 ± 0.68%), whereas HMMP was highest in 0.05 mM CA but lowest in control (22.9 ± 4.95 and 11.4 ± 3.64% respectively; p < .05). In conclusion, for cryopreservation of ram semen in Tris-based extender, supplementation with 2 mM GA increased post-thaw motility, whereas supplementation with 0.05 mM CA enhanced mitochondrial function.

Dual-responsive (pH/temperature) Pluronic F-127 hydrogel drug delivery system for textile-based transdermal therapy.

A dual-responsive hydrogel (pH/temperature) was developed from a thermos-responsive polymer, pluronic F-127 (PF127), and pH-responsive polymers, N,N,N-trimethyl chitosan (TMC) and polyethylene glycolated hyaluronic acid (PEG-HA). Gallic acid, the principal component of the traditional Chinese drug Cortex Moutan was loaded into the hydrogel (PF127/TMC/PEG-HA) for possible application in textile-based transdermal therapy as Cortex Moutan has been proven to be an effective drug for the treatment of atopic dermatitis (AD). TMC and PEG-HA were synthesized, characterized (1H-NMR and FTIR), and added to the formulations to enhance drug release from the hydrogels, and increase the drug targeting of the carriers. The thermo-responsive properties of the hydrogel were assessed by dynamic viscosity analysis and the tube inversion method, and the pH-responsiveness of the formulation was determined by changing the pH of the external media. Rheology study of the hydrogels showed that complex viscosity and storage/loss moduli for PF127/TMC/PEG-HA hydrogel formulation are higher than PF127 hydrogel. The microstructure analysis by reflection SAXS indicated similar type of frozen inhomogeneity of hydrogel formulations. Various characterizations such as FTIR, SEM, TEM, zeta potential, and degradation of the hydrogel formulation indicated that the PF127/TMC/PEG-HA hydrogel showed better physico-chemical properties and morphology than did the PF127 hydrogel, and drug release was also higher for the PF127/TMC/PEG-HA hydrogel than for PF127. The drug release from hydrogels followed more closely first-order rate model than other rate models.