Efficacy, Stability, and Safety Evaluation of New Polyphenolic Xanthones Towards Identification of Bioactive Compounds to Fight Skin Photoaging.

Antioxidants have long been used in the cosmetic industry to prevent skin photoaging, which is mediated by oxidative stress, making the search for new antioxidant compounds highly desirable in this field. Naturally occurring xanthones are polyphenolic compounds that can be found in microorganisms, fungi, lichens, and some higher plants. This class of polyphenols has a privileged scaffold that grants them several biological activities. We have previously identified simple oxygenated xanthones as promising antioxidants and disclosed as hit, 1,2-dihydroxyxanthone (1). Herein, we synthesized and studied the potential of xanthones with different polyoxygenated patterns as skin antiphotoaging ingredients. In the DPPH antioxidant assay, two newly synthesized derivatives showed IC50 values in the same range as ascorbic acid. The synthesized xanthones were discovered to be excellent tyrosinase inhibitors and weak to moderate collagenase and elastase inhibitors but no activity was revealed against hyaluronidase. Their metal-chelating effect (FeCl3 and CuCl2) as well as their stability at different pH values were characterized to understand their potential to be used as future cosmetic active agents. Among the synthesized polyoxygenated xanthones, 1,2-dihydroxyxanthone (1) was reinforced as the most promising, exhibiting a dual ability to protect the skin against UV damage by combining antioxidant/metal-chelating properties with UV-filter capacity and revealed to be more stable in the pH range that is close to the pH of the skin. Lastly, the phototoxicity of 1,2-dihydroxyxanthone (1) was evaluated in a human keratinocyte cell line and no phototoxicity was observed in the concentration range tested.

Virtual screening, Docking, ADMET and System Pharmacology studies on Garcinia caged Xanthone derivatives for Anticancer activity.

Caged xanthones are bioactive compounds mainly derived from the Garcinia genus. In this study, a structure-activity relationship (SAR) of caged xanthones and their derivatives for anticancer activity against different cancer cell lines such as A549, HepG2 and U251 were developed through quantitative (Q)-SAR modeling approach. The regression coefficient (r2), internal cross-validation regression coefficient (q2) and external cross-validation regression coefficient (pred_r2) of derived QSAR models were 0.87, 0.81 and 0.82, for A549, whereas, 0.87, 0.84 and 0.90, for HepG2, and 0.86, 0.83 and 0.83, for U251 respectively. These models were used to design and screened the potential caged xanthone derivatives. Further, the compounds were filtered through the rule of five, ADMET-risk and synthetic accessibility. Filtered compounds were then docked to identify the possible target binding pocket, to obtain a set of aligned ligand poses and to prioritize the predicted active compounds. The scrutinized compounds, as well as their metabolites, were evaluated for different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Finally, the top hit compound 1G was analyzed by system pharmacology approaches such as gene ontology, metabolic networks, process networks, drug target network, signaling pathway maps as well as identification of off-target proteins that may cause adverse reactions.

Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies.

ETHNOPHARMACOLOGICAL RELEVANCE: The poly-herbal formulation DB14201 is a new combination of ayurvedic ingredients for treatment of diabetes. The aim of present study was to investigate safety and in vivo efficacy of DB14201 extract. Further this work was aimed to develop, characterize and standardize DB14201 extract and develop it as a botanical drug. MATERIALS AND METHODS: The polyherbal extract was standardized using four chemical markers. The LC-MS/MS method was developed for identification and quantification of mangiferin, berberine, kaempferol and curcumin. The extract was standardized for heavy metal content, aflotoxins, and microbial tests. The mechanism of action of DB14201 extract was explored through glucose uptake by adipocytes, TNF-α production and free fatty acid release, in vitro, was studied using murine adipocytes (3T3-L1). The effect of extract on insulin release was evaluated using murine pancreatic beta cell (ß TC-6). The safety and in vivo efficacy of extract was studied using suitable animal model. Hematology and blood biochemistry parameters were also assessed. RESULTS: In vitro studies of DB14201 in murine adipocytes and murine pancreatic beta cells demonstrated the plausible mechanism of action of DB14201 could be through increase in glucose uptake and by stimulation of insulin release by RIN-5f cells. The microbial load, heavy metals were found to be within the AYUSH permissible limits and aflotoxins were absent. Preclinical efficacy studies in animal models proved the anti-diabetic potential of the extract. The preclinical acute dose toxicity study and 90-days repeated dose toxicity study of DB14201 extract in wistar rats by oral route indicated that the extract is safe up to 1000mg/kg dose. Hematology and blood biochemistry parameters were within the normal range. CONCLUSIONS: The data presented herein demonstrated anti-diabetic potential of developed DB14201 extract and this study will serve as the benchmark for the further research on this polyherbal formulation.

Anticarcinogenic Effects of α-Mangostin: A Review.

Cancer chemoprevention is a promising strategy taken to block, reverse, or retard carcinogenesis. α-Mangostin, a natural xanthone isolated from the pericarps of mangosteen, represents one of the most studied chemopreventive agents. This compound has been reported to interfere with all the major stages of carcinogenesis: initiation, promotion, and progression. A number of mechanisms have been proposed for its anticarcinogenic activities. This review summarizes the current knowledge on the mechanisms that contribute to the observed activity of α-mangostin related to (i) modulation of carcinogenic biotransformation and mitigation of oxidative damage, (ii) induction of growth arrest and apoptosis, (iii) suppression of angiogenesis and metastasis, and (iv) combination with clinical chemotherapy drugs enhancing their efficacy and decreasing the toxic side effects. In addition, pharmacokinetic and toxicological studies of α-mangostin have also been highlighted in this review. Despite an overwhelming amount of knowledge in preclinical studies, there was almost no translation of α-mangostin into the clinic. It is hoped that continuous extensive and profound research will lead to the application of α-mangostin from experimental studies to evidence-based, clinically applicable pharmacotherapy.

A review of the efficacy of dietary polyphenols in experimental models of inflammatory bowel diseases.

Crohn's disease and ulcerative colitis presently have no cure and are treated with anti-inflammatory drugs or monoclonal antibodies targeting pro-inflammatory cytokines. A variety of rodent models have been used to model chronic and acute colitis. Dietary polyphenols in foods and botanicals are of considerable interest for prevention and treatment of colitis. Many dietary polyphenols have been utilized for prevention of colitis in rodent models. Berries, green tea polyphenols, curcumin, and stilbenes have been the most extensively tested polyphenols in rodent models of colitis. The majority of polyphenols tested have inhibited colitis in rodents, but increasing doses of EGCG and green tea, isoflavones, flaxseed, and α-mangostin have exacerbated colitis. Few studies have examined combination of polyphenols or other bioactives for inhibition of colitis. Translating polyphenol doses used in rodent models of colitis to human equivalent doses reveals that supplemental doses are most likely required to inhibit colitis from a single polyphenol treatment. The ability to translate polyphenol treatments in rodent models is likely to be limited by species differences in xenobiotic metabolism and microbiota. Given these limitations, data from polyphenols in rodent models suggests merit for pursuing additional clinical studies for prevention of colitis.

Dietary α-mangostin, a xanthone from mangosteen fruit, exacerbates experimental colitis and promotes dysbiosis in mice.

SCOPE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. α-Mangostin (α-MG), the most abundant xanthone in mangosteen fruit, exerts anti-inflammatory and antibacterial activities in vitro. We evaluated the impact of dietary α-MG on murine experimental colitis and on the gut microbiota of healthy mice. METHODS AND RESULTS: Colitis was induced in C57BL/6J mice by administration of dextran sulfate sodium (DSS). Mice were fed control diet or diet with α-MG (0.1%). α-MG exacerbated the pathology of DSS-induced colitis. Mice fed diet with α-MG had greater colonic inflammation and injury, as well as greater infiltration of CD3(+) and F4/80(+) cells, and colonic myeloperoxidase, than controls. Serum levels of granulocyte colony-stimulating factor, IL-6, and serum amyloid A were also greater in α-MG-fed animals than in controls. The colonic and cecal microbiota of healthy mice fed α-MG but no DSS shifted to an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes, a profile similar to that found in human UC. CONCLUSION: α-MG exacerbated colonic pathology during DSS-induced colitis. These effects may be associated with an induction of intestinal dysbiosis by α-MG. Our results suggest that the use of α-MG-containing supplements by patients with UC may have unintentional risk.

Absorption, tissue distribution, tissue metabolism and safety of α-mangostin in mangosteen extract using mouse models.

The commercially available herbal products as the form of extract were usually mixtures containing various compounds. In spite of the purported efficacy in each active constituent, the coexisting constituents in the herbal extract might interfere with the efficacy and safety and affect the pharmacokinetic properties of active constituents. To compare for the pharmacokinetic properties of α-mangostin, a major bioactive compound, in mangosteen extract and pure α-mangostin, the pharmacokinetics as well as tissue distribution, in vitro metabolism, plasma protein binding and safety evaluation were conducted in mice because a mouse model is required a small amount of compounds and useful to develop disease models. The absorption of α-mangostin was increased and hepatic metabolism of α-mangostin was decreased in mice treated with mangosteen extract. However, the intestinal metabolism α-mangostin is comparable and still extensive in mice treated with α-mangostin and mangosteen extract. Intraperitorial LC50 of α-mangostin and mangosteen extract was 150 and 231 mg/kg, respectively. These findings may be valuable to explain the different pharmacokinetics and safety of α-mangostin and mangosteen extract. Furthermore, these findings are useful to design the efficacy and safety investigation of α-mangostin or mangosteen extract in mice with disease models or combination therapies to extrapolate into the clinical levels.

An open-labeled, randomized, multicenter phase IIa study of gambogic acid injection for advanced malignant tumors.

BACKGROUND: Gambogic acid is a pure active compound isolated from the traditional Chinese medicinal plant gamboge (Garcinia morella Desv.). Based on the preliminary results of a phase I study, this phase IIa study compared the efficacy and safety of different dosage schedules of gambogic acid in patients with advanced malignant tumors. METHODS: Patients with advanced or metastases cancer who had not received any effective routine conventional treatment or who had failed to respond to the existing conventional treatment were randomly assigned to receive either 45 mg/m(2) gambogic acid intravenously from Days 1 to 5 of a 2-week cycle (Group A), or 45 mg/m(2) every other day for a total of five times during a 2-week cycle (Group B). The primary endpoint was objective response rate (ORR). RESULTS: Twenty-one patients assigned to Group A and 26 to Group B were included in the final analysis. The ORRs were 14.3% in Group A and 0% in Group B. It was not possible to analyze the significant difference because one of the values was zero. The disease control rates (DCRs) were 76.2% in Group A and 61.5% in Group B (P = 0.0456). The observed adverse reactions were mostly Grades I and II, and occurred in most patients after administration of the trial drug. There was no significant difference in the incidence of adverse reactions between the two arms. CONCLUSIONS: The preliminary results of this phase IIa exploratory study suggest that gambogic acid has a favorable safety profile when administered at 45 mg/m(2). The DCR was greater in patients receiving gambogic acid on Days 1 - 5 of a 2-week cycle, but the incidence of adverse reactions was similar irrespective of the administration schedule.

Reducing effect of mangiferin on serum uric acid levels in mice.

CONTEXT: Mangiferin, a natural bioactive xanthone C-glycoside, is widely present in medicinal plants like the leaf of Mangifera indica L. (Anacardiaceae). It has been reported that mangiferin possesses a variety of biological activities, including antidiabetic, hepatoprotective, anti-inflammatory, antioxidant, and anticarcinogenic. OBJECTIVE: The hypouricemic effect and xanthine oxidoreductase (XOR) inhibitory activity of mangiferin were investigated here for the first time. MATERIALS AND METHODS: The hypouricemic effect of mangiferin was investigated in normal and hyperuricemic mice induced by potassium oxonate. Mangiferin at a dose of 0.75-100.0 mg/kg was given intragastrically to mice. The serum urate levels were determined using the phosphotungstic acid method. The hepatic activities of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) in hyperuricemic mice were assayed using commercially available kits. RESULTS: The results showed that mangiferin at a dose of 1.5, 3.0, and 6.0 mg/kg significantly reduced the serum urate levels (148.7 ± 37.8, 142.2 ± 44.5, 121.7 ± 21.7 µmmol/L) in hyperuricemic mice, compared with untreated hyperuricemic mice (201.8 ± 71.2 µmmol/L). However, mangiferin did not decrease the serum urate levels in normal mice until mangiferin was up to 100 mg/kg. In addition, the hepatic activities of XDH in hyperuricemic mice were significantly decreased by mangiferin, while no changes of XOD were observed. Acute toxicity study in mice showed that mangiferin was very safe at a dose of up to 25 g/kg. DISCUSSION AND CONCLUSION: These findings demonstrate that mangiferin has the potential to be developed as a new therapeutic agent for the treatment of hyperuricemia and gout.