Anti-angiogenic effect of α-mangostin

Eleven known prenyl xanthones, isolated from the pericarp of Garcinia mangostana, were tested for their ability to inhibit the phosphorylation of kinase domain receptor (KDR) tyrosine kinase. α-Mangostin was found to inhibit phosphorylation of KDR. α-Mangostin also showed to inhibit phosphorylation of the Y1175 residue of KDR (10 μM). This is the first report that α-mangostin inhibited the phosphorylation of KDR tyrosine kinase and also the Y1175 residue of KDR. α-Mangostin also showed inhibitory effects on proliferation of human umbilical vein endothelial cells (HUVECs) (IC₅₀ 1.2 μM) and human umbilical artery endothelial cells (IC₅₀ 2.4 μM), as well as the migration (IC₅₀ 0.034 μM) and tubule formation (at the concentrations of 0.6 and 1.2 μM) of HUVECs. These results suggest that the inhibition of the phosphorylation of KDR tyrosine kinase is concerned in the anti-angiogenic activity of α-mangostin.     

Probing simple structural modification of α-mangostin on its cholinesterase inhibition and cytotoxicity

α-Mangostin has been reported to possess a broad range of pharmacological effects including potent cholinesterase inhibition, but the development of α-mangostin as a potential lead compound is impeded by its toxicity. The present study investigated the impact of simple structural modification of α-mangostin on its cholinesterase inhibitory activities and toxicity toward neuroblastoma and liver cancer cells. The dialkylated derivatives retained good acetylcholinesterase (AChE) inhibitory activities with IC₅₀ values between 4.15 and 6.73 µM, but not butyrylcholinesterase (BChE) inhibitory activities, compared with α-mangostin, a dual inhibitor (IC₅₀: AChE, 2.48 µM; BChE, 5.87 µM). Dialkylation of α-mangostin produced AChE selective inhibitors that formed hydrophobic interactions at the active site of AChE. Interestingly, all four dialkylated derivatives of α-mangostin showed much lower cytotoxicity, being 6.4- to 9.0-fold and 3.8- to 5.5-fold less toxic than their parent compound on neuroblastoma and liver cancer cells, respectively. Likewise, their selectivity index was higher by 1.9- to 4.4-fold; in particular, A2 and A4 showed improved selectivity index compared with α-mangostin. Taken together, modification of the hydroxyl groups of α-mangostin at positions C-3 and C-6 greatly influenced its BChE inhibitory and cytotoxic but not its AChE inhibitory activities. These dialkylated derivatives are viable candidates for further structural modification and refinement, worthy in the search of new AChE inhibitors with higher safety margins.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Bioactivity and pharmacological properties of α-mangostin from the mangosteen fruit: a review

Introduction: α-Mangostin (α-MG) is the most representative xanthone isolated from the pericarp of mangosteen, possessing extensive biological activities and pharmacological properties, considered as an antineoplastic agent, antioxidant, anti-proliferation and induces apoptosis.

Areas covered: The bioactivity and pharmacological properties of α-MG are being actively investigated by various industrial and academic institutions. The bioactivities of α-MG have been summarized in several previous reviews, which were worthy of high compliment. However, recently, many new literatures about the bioactivities of α-MG have been further reported from 2016 to 2017. Herein, the activities of α-MG are supplemented and summarized in this text.

Expert opinion: As previously said, α-MG possesses good bioactivities pharmacological properties. More recently, it found that α-MG has the effect of maintaining cardiovascular system and gastrointestinal health and controlling free radical oxidation. Furthermore, α-MG has more applications in cosmetics, with the effects of anti-aging, anti-wrinkle, acne treatment, maintenance of skin lubrication. The application of α-MG in treating rheumatoid arthritis has been disclosed and the MG-loaded self-micro emulsion (MG-SME) was designed to improve its pharmacokinetic deficiencies. As mentioned above, α-MG can be a promising drug, also worthy of developing, and further research is crucial for the future application of α-MG.     

Molecular mechanisms of α-crystallinopathy and its therapeutic strategy

α-B-Crystallin (CryAB, gene map locus: 11q22.3-q23.1) is a member of the small heat shock protein (HSP) family, a group of proteins that prevent protein aggregation upon exposure of a cell to heat and/or restore the biological activity of cell substrates. The missense mutation and the deletion mutation of CryAB can cause various forms of muscular disorder, including restrictive, hypertrophic, and dilated cardiomyopathies, heart failure, and skeletal muscle weakness. Collectively, these diseases constitute a rare autosomal-dominant inherited disorder called α-crystallinopathy (crystallinopathy), also known as desmin-related cardiomyopathy. The disease is a misfolded protein-related disease characterized by the formation of insoluble protein aggregates consisting of the CryAB protein in the patient's cardiomyocytes and skeletal myocytes. The details of crystallinopathy are unclear at the present time; what has been discovered concerning the disease mechanisms underlying crystallinopathy has been through experiments with genetically modified mice such as the CryAB knockout mouse and various mutant CryAB transgenic (TG) mice. Crystallinopathy can be recapitulated in TG mice by expressing the mutant CryAB Arg120Gly (R120G) protein, a causal mutation of crystallinopathy, specifically in the cardiomyocytes. CryAB R120G causes perinuclear formation of aggresomes containing preamyloid oligomer intermediates, which are wellknown as a primary toxic species in neurodegenerative disease. This suggests that crystallinopathy caused by the CryAB mutation could be considered one of the aggresomal and amyloid-related diseases. Moreover, recent findings have indicated that enhancement of HSP induction and inhibition of apoptotic cell death by mitochondrial protection may be a new therapeutic strategy for patients with crystallinopathy.     

Effect of cations on the microstructure and in-vitro drug release of κ- and ι-carrageenan liquid and semi-solid aqueous dispersions

Objectives The main objective of this study was to determine the effect of potassium and calcium ions on the microstructure and release dynamics of kappa (κ) and iota (ι) carrageenan. Methods The microstructure of the dispersions was imaged using a cryogenic scanning electron microscope. Franz‐cell diffusion apparatus was used to determine the release kinetics of a model hydrophilic drug, sodium fluorescein, incorporated in selected polymer dispersions. Release profiles were analysed using Higuchi, Korsmeyer‐Peppas and dual first‐order models. Key Findings Cryogenic scanning electron microscope images showed that κ‐carrageenan forms hexagonal structures, whereas ι‐carrageenan forms rectangular pores at low cation concentrations. In‐vitro release studies showed sustained release profiles for all carrageenan systems; however the model drug, fluorescein, diffusion from ι‐carrageenan with 0.06% w/v calcium was significantly higher than other ι‐carrageenan systems. This may be attributed to improved tortuosity of this system. However further increase in cation concentration led to a reduction in fluorescein release from the matrices. The dual first‐order release model illustrated two distinct release rates, an initial rapid release followed by a slow diffusion of fluorescein from the carrageenan matrices. Conclusions The observed microstructural differences may account for the well known variation in mechanical properties of κ‐ and ι‐carrageenan gels. The dual first order release model adds a new tool in the elucidation of release mechanisms from polymer matrices, where parallel processes contribute to drug release.     

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.     

Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of α- 1 -antitrypsin

α - 1 - antitrypsin （AAT） is the most abundant circulating serine proteinase inhibitor of the serpin superfamily. Deficiency of circulating AAT is the most widely recognized abnormality of a proteinase inhibitor that causes lung disease. AAT deficiency is caused by mutations of the AAT gene that lead to AAT protein retention in the endoplasmic reticulum （ER）. Moreover, the mutant AAT accumulated in the ER predisposes the homozygote to severe liver injuries, such as neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Despite the fact that mutant AAT protein is subject to Erassociated degradation we report that gp78, a ubiquitin ligase （E3） pairing with mammalian Ubc7 for ERAD, ubiquitinates and facilitates degradation of ATZ. the classic deficiency variant of AAT having a Z mutation （Glu342Lys）.     

Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin

The objectives of the study were to investigate the effects of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility and dissolution rate of norfloxacin prepared using three different methods, at drug to cyclodextrin weight ratios of 1:1, 1:2, 1:4 and 1:8. All the methods increased the solubility and dissolution rate of norfloxacin via inclusion complexation with βCD and HPβCD. Norfloxacin was converted from crystalline to amorphous form through inclusion complexation. Solvent evaporation method was the most effective method in terms of norfloxacin solubilisation, while inclusion complex of HPβCD has higher solubility than βCD complex when prepared using the same procedure.     

Antidiabetic components of Cassia alata leaves: Identification through α-glucosidase inhibition studies

Context: Cassia alata Linn. [syn. Senna alata (L.) Roxb.] (Caesalpiniaceae) is used for treating various disease conditions including diabetes but its mechanism(s) of action and active principles remain to be elucidated.

Objective: The antidiabetic principles were identified using an in vitro α-glucosidase inhibition study.

Materials and methods: The methanol extract of leaves of C. alata, which showed potent α-glucosidase inhibitory activity (IC₅₀, 63.75?±?12.81 µg/ml), was fractionated. Active fractions were taken for further analysis by a variety of techniques including HPLC and Combiflash chromatography. The identity of the isolated compounds was established by spectroscopic analysis while their potential antidiabetic activity was assessed by in vitro enzyme inhibition studies.

Results: The α-glucosidase inhibitory effect of the crude extract was far better than the standard clinically used drug, acarbose (IC₅₀, 107.31?±?12.31 µg/ml). A subsequent fractionation of the crude extract was made using solvents of ascending polarity (petroleum ether, chloroform, ethyl acetate, n-butanol and water). The ethyl acetate (IC₅₀, 2.95?±?0.47 µg/ml) and n-butanol (IC₅₀, 25.80?±?2.01 µg/ml) fractions which contained predominantly kaempferol (56.7?±?7.7 µM) and kaempferol 3-O-gentiobioside (50.0?±?8.5 µM), respectively, displayed the highest carbohydrate enzyme inhibitory effect.

Discussion: One of the possible antidiabetic mechanisms of action of C. alata is by inhibiting carbohydrate digestion. This is the first report on α-glucosidase activity of kaempferol 3-O-gentiobioside.

Conclusion: Considering the activity profile of the crude extract and isolated bioactive compounds, further in vivo and clinical studies on C. alata extracts and compounds are well merited.     

Synthesis of γ Phase and Amorphous Solid Dispersion of Glycine from α-Glycine During the Solvent-Free Ball Milling Process

Nano α-glycine crystals, γ-glycine crystals, and amorphous solid dispersion (ASD) of glycine were prepared through solvent-free ball milling of commercial α-glycine. The solid-state polymorph conversion of glycine from α to γ was completely realized by ball milling with 0.2 wt.% NaCl for 1 h or by ball milling with 0.02 wt.% NaCl for 1 h with subsequent storage for one week. The ASD of glycine was prepared by ball milling α-glycine with an equal amount of CaCl₂ for 1 h. We studied the effect of inorganic salt types and their concentrations on the extent of polymorph conversion and amorphization of glycine in our experiments. This solvent-free ball milling method could be used for the synthesis of polymorphs and amorphous phase of drugs and other organic materials.     

A fluorimetric,potentiometric and conductimetric study of the aqueous solutions of naproxen and its association with hydroxypropyl-β-cyclodextrin

The dissociation constant, K_a, of naproxen, a nonsteroidal antiinflammatory drug of the family of arylpropionic acids, has been determined in aqueous solutions at 25°C by using a potentiometric and a conductimetric techniques. The solubility limit of the drug in water, a controversial point in the literature, has been found to be less than 3×10⁻⁵ M. The interaction of naproxen with hydroxypropyl-β-cyclodextrin (HPBCD), in terms of the binding constants of the complexes formed by the CD and the nonionic (HNAP) and ionic (NAP⁻) species of the drug, has been evaluated at 25°C as well by means of steady-state fluorescence enhancement studies. A discussion of the results, K_HPBCD:HNAP=6500±400 M⁻¹ and K_HPBCD:NAP−=1400±80 M⁻¹, emphasizing the crucial importance of the choice of the pH at a value that pH≥pK_a +2 or pH≤pK_a −2, is also included.     

Methoxamine inhibits noradrenaline release through activation of α1- and α2-adrenoceptors in rat isolated kidney: involvement of purines and prostaglandins

Summary The effects of the at-adrenoceptor agonist methoxamine and the ₂-adrenoceptor agonist bromoxidine (UK 14034) on the stimulation induced (S-1) outflow of radioactivity at 100 Hz/6 pulses from rat isolated kidney preincubated with ³H-noradrenaline were investigated. Methoxamine (0.3 – 30 mol/l) inhibited S-1 outflow of radioactivity to a maximum of 83% with a pEC₅₀ of 5.85 (5.71–5.94). UK 14304 (0.0003-0.3 mol/l) inhibited S-I outflow of radioactivity to a maximum of 99% with a pEC₅₀ of 8.35 (8.26–8.47). a Adrenoceptor antagonist affinities (pK_D) against methoxamine and UK 14304 at prejunctional -adrenoceptors were determined. The concentration response curve of methoxamine was shifted to the right by the 1/_2B-adrenoceptor antagonist prazosin (0.1 mol/l) with a pK_D of 7.41 and that of UK 14304 by prazosin (0.3 mol/l) with a pK_D of 6.24. The ₂-adrenoceptor antagonist rauwolscine (0.1 mol/l) shifted the concentration response curve of UK 14304 potently to the right with a p_KD of 8.34. The concentration response curve of methoxamine was shifted also to the right by rauwolscine (0.1 mol/l) and the ₂-adrenoceptor antagonist idazoxan (0.1 mol/l), however, both antagonists suppressed the maximum response of methoxamine to 466% and 56%, respectively. A ten times lower concentration of rauwolscine (0.01 mol/l) did not shift the concentration response curve of methoxamine but the inhibitory effect of methoxamine still reached only a maximum of 59%. The concentration response curve of methoxamine obtained in the presence of rauwolscine (0.01 mol/l) was shifted to the right by further addition of prazosin (0.1 mol/l) with a pK_D of 8.80 but was also shifted to the right by either the purinoceptor antagonist 8-(p-sulfophenyl) theophylline (8-SPT; 100 mol/l) or the prostaglandin synthesis inhibitor indomethacin (20 mol/l). These results suggest that methoxamine inhibits S-1 outflow of radioactivity in rat isolated kidney probably through three different mechanisms. 1. Activation of postjunctional 1-adrenoceptors and prostaglandin mediated transjunctional inhibition. 2. Activation of postjunctional ₂-adrenoceptors and purine mediated transjunctional inhibition. 3. Activation of prejunctional inhibitory ₂-adrenoceptors at which methoxamine seems to be a partial agonist. Correspondence to L. C. Rump at the above address     

Discovery of Novel α4β2 Neuronal Nicotinic Receptor Modulators through Structure-Based Virtual Screening

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Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin and Mammary Papilla (Nipple)

Purpose

Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast.

Methods

Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies.

Results

Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment.

Conclusions

The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

     

Long-term dietary isoflavone exposure enhances estrogen sensitivity of rat uterine responsiveness mediated through estrogen receptor α

The outcome of long-term exposure to dietary isoflavones on estrogen sensitive tissues is discussed controversially. We performed a study on tissue specific effects of lifelong isoflavone exposure on the rat uterus with exposure being initiated prenatally. We compare the effects of the dietary isoflavones, genistein (GEN) and daidzein, or GEN alone to those of isoflavone free diet. Therefore, one group received a phytoestrogen-free diet (PE-free), one an isoflavone-high diet (ISO-high) and one the PE-free diet supplemented with GEN (GEN-rich) throughout their whole lifetime. In ovariectomized adult females a uterotrophic assay was performed, comparing 17β-estradiol, GEN and two estrogen receptor subtype-specific agonists.