Showing papers in "Archives of Pharmacal Research in 2014"

Therapeutic applications of electrospun nanofibers for drug delivery systems.

Abstract: Electrospun nanofiber drug delivery systems have been studied using various techniques. Herein, we describe the fabrication of a drug-incorporating nanofiber. Drugs, such as proteins, peptide, antibodies, and small molecule drugs, can be loaded within or on the surface of nanofibers according to their properties. Hydrophobic drugs are directly dissolved with a polymer in an organic solvent before electrospinning. However, it is preferred to surface-immobilize bioactive molecules on nanofibers by physical absorption or chemical conjugation. Especially, chemically surface-immobilized proteins on a nanofiber mesh stimulate cell differentiation and proliferation. Using a dual electrospinning nozzle to create nanofiber sheet layers, which are stacked on top of one another, the initial burst release is reduced compared with solid nanofibers because of the layers. Furthermore, hybridization of electrospun nanofibers with nanoparticles, microspheres, and hydrogels is indirect drug loading method into the nanofibers. It is also possible to produce multi-drug delivery systems with timed programmed release.

Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system

Abstract: Multidrug resistance (MDR), the principal mechanism by which many cancers develop resistance to chemotherapy, is one of the major obstacles to the successful clinical treatment of various types of cancer. Several key regulators are responsible for mediating MDR, a process that renders chemotherapeutic drugs ineffective in the internal organelles of target cells. A nanoparticulate drug delivery system (DDS) is a potentially promising tool for circumventing such MDR, which can be achieved by targeting tumor cells themselves or tumor endothelial cells that support the survival of MDR cancer cells. The present article discusses key factors that are responsible for MDR in cancer cells, with a specific focus on the application of DDS to overcome MDR via the use of chemotherapy or macromolecules.

Natural and synthetic biomaterials for controlled drug delivery

Abstract: A wide variety of delivery systems have been developed and many products based on the drug delivery technology are commercially available. The development of controlled-release technologies accelerated new dosage form design by altering pharmacokinetic and pharmacodynamics profiles of given drugs, resulting in improved efficacy and safety. Various natural or synthetic polymers have been applied to make matrix, reservoir or implant forms due to the characteristics of polymers, especially ease of control for modifications of biocompatibility, biodegradation, porosity, charge, mechanical strength and hydrophobicity/hydrophilicity. Hydrogel is a hydrophilic, polymeric network capable of imbibing large amount of water and biological fluids. This review article introduces various applications of natural and synthetic polymer-based hydrogels from pharmaceutical, biomedical and bioengineering points of view.

The effects of C-glycosylation of luteolin on its antioxidant, anti-Alzheimer’s disease, anti-diabetic, and anti-inflammatory activities

Abstract: To investigate the effect of C-glycosylation at different positions of luteolin, the structure-activity relationships of luteolin and a pair of isomeric C-glycosylated derivatives orientin and isoorientin, were evaluated. We investigated the effects of C-glycosylation on the antioxidant, anti-Alzheimer's disease (AD), anti-diabetic and anti-inflammatory effects of luteolin and its two C-glycosides via in vitro assays of peroxynitrite (ONOO(-)), total reactive oxygen species (ROS), nitric oxide (NO), 1,1-diphenyl-2-picrylhydraxyl (DPPH), aldose reductase, protein tyrosine phosphatase 1B (PTP1B), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor cleaving enzyme 1 (BACE1), and cellular assays of NO production and inducible nitric oxide synthase (iNOS)/cyclooxygenase-2 expression in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Of the three compounds, isoorientin showed the highest scavenging activity against DPPH, NO, and ONOO(-), while luteolin was the most potent inhibitor of ROS generation. In addition, luteolin showed the most potent anti-AD activity as determined by its inhibition of AChE, BChE, and BACE1. With respect to anti-diabetic effects, luteolin exerted the strongest inhibitory activity against PTP1B and rat lens aldose reductase. Luteolin also inhibited NO production and iNOS protein expression in LPS-stimulated macrophages, while orientin and isoorientin were inactive at the same concentrations. The effects of C-glycosylation at different positions of luteolin may be closely linked to the intensity and modulation of antioxidant, anti-AD, anti-diabetic, and anti-inflammatory effects of luteolin and its C-glycosylated derivatives.

Age-related inflammation and insulin resistance: a review of their intricate interdependency

Abstract: Chronic inflammation is a major risk factor underlying aging and the associated diseases of aging; of particular interest is insulin resistance during aging. Chronic inflammation impairs normal lipid accumulation, adipose tissue function, mitochondrial function, and causes endoplasmic reticulum (ER) stress, which lead to insulin resistance. However, some studies show that insulin resistance itself amplifies chronic inflammation. The activity of the insulin-dependent Akt signaling pathway is highlighted because of its decrease in insulin-sensitive organs, like liver and muscle, which may underlie insulin resistance and hyperinsulinemia, and its increased levels in non-metabolic organs, such as kidney and aorta. In that the prevalence of obesity has increased substantially for all age groups in recent years, our review summarizes the data showing the involvement of chronic inflammation in obesity-induced insulin resistance, which perpetuates reciprocal interactions between the chronic inflammatory process and increased adiposity, thereby accelerating the aging process.

Carbon-based drug delivery carriers for cancer therapy

Abstract: In the search to improve anticancer therapies, several drug carriers, including carbon-based nanomaterials have been studied. Both liposomes and polymeric microspheres have been used in anticancer drugs. However, there remains an on-going need for better therapeutic materials that have good drug solubility, an ability to reduce systemic toxicity through specific-tumor targeting, and rapid clearance. In this regard, carbon allotropes such as graphene oxide (GOs), carbon nanotubes (CNTs), and nanodiamonds (NDs), have been investigated, as they possess sufficient surface-to-volume ratio, thermal conductivity, rigid structural properties capable of post-chemical modification, and excellent biocompatibility. This review is aimed at exploring these carbon-based nanomaterials for use as multifaceted cancer drug carriers and is intended to demonstrate that GOs, CNTs, and NDs are likely to improve chemotherapeutical strategy for cancers in either a sole or combinational manner.

Potentiation of paclitaxel activity by curcumin in human breast cancer cell by modulating apoptosis and inhibiting EGFR signaling

Abstract: It has been suggested that combined effect of natural products may improve the treatment effectiveness in combating proliferation of cancer cells. Here, we examined the combined anticancer activities of compounds of three natural origin including baicalein, curcumin, and resveratrol with chemotherapy drug paclitaxel respectively, which showed that combination of paclitaxel with curcumin exhibited synergistic growth inhibition and induced significant apoptosis in MCF-7 cell lines. Treatment of MCF-7 cell lines with paclitaxel and curcumin induced the apoptosis of regulatory protein Bcl-2 but decreased Bax expression. In addition, simultaneous treatment with paclitaxel and curcumin strongly inhibited paclitaxel-induced activities of EGFR signaling. Furthermore, the combination of paclitaxel and curcumin exerted increased anti-tumor efficacy on mouse models. Overall, our data described the promising therapeutic potential and underlying mechanisms of combining paclitaxel with curcumin in treating breast cancer.

Flavonoids from Astragalus membranaceus and their inhibitory effects on LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells

Abstract: Radix Astragali (Astragalus membranaceus) is an important traditional Chinese medicine that is widely used as a tonic to enhance the body’s natural defense mechanisms. In this phytochemical study, 12 flavonoids, isoliquiritigenin (1), liquiritigenin (2), calycosin (3), calycosin 7-O-β-d-glucoside (4), formononetin (5), formononetin 7-O-β-d-glucoside (6), daidzein (7), daidzein 7-O-β-d-glucoside (8), methylnissolin (9), methylnissolin 3-O-β-d-glucoside (10), isomucronulatol (11), and isomucronulatol 7-O-β-d-glucoside (12), were isolated from the roots of A. membranaceus. Their structures were elucidated by comparing spectroscopic data with reported values. The effects of the isolated compounds on lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells were investigated. Compounds 1 and 2 exhibited significant inhibitory effects on LPS-induced IL-6 and IL-12 p40 production, with IC50 values ranging from 2.7 to 6.1 μM. Compound 1 also showed a moderate inhibitory effect on LPS-stimulated production of TNF-α with an IC50 value of 20.1 μM. Further studies of the potential anti-inflammatory effects and benefits of flavonoids from A. membranaceus are warranted.

Gold nanoparticle (AuNP)-based drug delivery and molecular imaging for biomedical applications

Abstract: Gold nanoparticles (AuNPs) can be readily synthesized and modified with chemical and biological molecules, making them attractive inorganic biomaterials for drug delivery and molecular diagnostics. The surface of AuNPs supports the efficient attachment of various biomacromolecules via chemisorption, chemical conjugation and electrostatic interaction. Based on advantages of facile surface modification and unique optical properties, AuNPs have been extensively used as drug carriers for the intracellular delivery of therapeutics as well as molecular nanoprobes for detection and monitoring of the target molecules of interest. In this review, we highlight advanced approaches in the biomedical applications of AuNPs such as gene and drug therapy, molecular diagnostics and imaging.

Accelerated wound healing and anti-inflammatory effects of physically cross linked polyvinyl alcohol-chitosan hydrogel containing honey bee venom in diabetic rats.

Abstract: Diabetes is one of the leading causes of impaired wound healing. The objective of this study was to develop a bee venom-loaded wound dressing with an enhanced healing and anti-inflammatory effects to be examined in diabetic rats. Different preparations of polyvinyl alcohol (PVA), chitosan (Chit) hydrogel matrix-based wound dressing containing bee venom (BV) were developed using freeze-thawing method. The mechanical properties such as gel fraction, swelling ratio, tensile strength, percentage of elongation and surface pH were determined. The pharmacological activities including wound healing and anti-inflammatory effects in addition to primary skin irritation and microbial penetration tests were evaluated. Moreover, hydroxyproline, glutathione and IL-6 levels were measured in the wound tissues of diabetic rats. The bee venom-loaded wound dressing composed of 10 % PVA, 0.6 % Chit and 4 % BV was more swellable, flexible and elastic than other formulations. Pharmacologically, the bee venom-loaded wound dressing that has the same previous composition showed accelerated healing of wounds made in diabetic rats compared to the control. Moreover, this bee venom-loaded wound dressing exhibited anti-inflammatory effect that is comparable to that of diclofenac gel, the standard anti-inflammatory drug. Simultaneously, wound tissues covered with this preparation displayed higher hydroxyproline and glutathione levels and lower IL-6 levels compared to control. Thus, the bee venom-loaded hydrogel composed of 10 % PVA, 0.6 % Chit and 4 % BV is a promising wound dressing with excellent forming and enhanced wound healing as well as anti-inflammatory activities.

Resiquimod, a TLR7/8 agonist, promotes differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells

Abstract: Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice, subsequently suppressing the host immune system. MDSCs represent a group of immature myeloid cells expressing CD11b and Gr-1. Here, we show that a Toll-like receptor (TLR) agonist, resiquimod, which binds to TLR7 and TLR8, induces the differentiation of MDSCs into mature myeloid cells. MDSCs were isolated from mice bearing mammary carcinoma 4T1 cells, and the purified MDSCs were cultured in the presence of resiquimod for 5 days. Phenotypic analysis showed that the resiquimod-treated MDSCs differentiated into F4/80⁺ macrophages and CD11c⁺/I-A(d⁺) dendritic cells. Functional analysis showed that the MDSCs also lost their suppressive activity on T cells. Resiquimod-treated MDSCs significantly enhanced the proliferation of T cells that were treated with anti-CD3 and anti-CD28 monoclonal antibodies. These results show that resiquimod induces the differentiation of MDSCs into macrophages and dendritic cells, and also suggest that resiquimod may improve cancer immunotherapy by reducing immunosuppressive MDSCs.

Role of metabolism by intestinal microbiota in pharmacokinetics of oral baicalin.

Abstract: Baicalin (baicalein-7-glucuronide) is a flavonoid purified from Scutellaria baicalensis Georgi that has traditionally been used for treatment of hypertension, cardiovascular diseases, and viral hepatitis. In this study, the effects of intestinal microbiota on the pharmacokinetics of baicalin were investigated in normal and antibiotic-pretreated rats following p.o. administration of 100 mg/kg baicalin by using liquid chromatography/ion trap mass spectrometry. When rats were pretreated orally with cefadroxil, oxytetracycline and erythromycin for 3 days to control the number of intestinal bacteria, the pharmacokinetic parameters of oral baicalin were significantly affected by antibiotics: Cmax, T1/2(β), Kel and AUC values were significantly changed compared to those in normal rats. These results indicate that intestinal microbiota might play a key role in the oral pharmacokinetics of baicalin.

Application of magnetic nanoparticle for controlled tissue assembly and tissue engineering.

Abstract: Magnetic nanoparticles have been subjected to extensive studies in the past few decades owing to their promising potentials in biomedical applications. The versatile intrinsic properties of magnetic nanoparticles enable their use in many biomedical applications. Recently, magnetic nanoparticles were utilized to control the cell's function. In addition, intracellular delivery of magnetic nanoparticles allowed cell's positioning by appropriate use of magnetic field and created cellular cluster. Furthermore, magnetic nanoparticles have been utilized to assemble more complex tissue structures than those that are achieved by conventional scaffold-based tissue engineering strategies. This review addresses recent work in the use magnetic nanoparticle for controlled tissue assembly and complex tissue formation.

Nano-enabled delivery systems across the blood-brain barrier

Abstract: The development of drugs to treat disorders of the central nervous system (CNS) faces difficulties in achieving penetration of a drug through the blood–brain barrier (BBB) and allowing the drug to reach its intended target in the brain There have been strategies to improve drug delivery to the brain through endogenous transport pathways such as passive diffusion, endocytosis, and active transport Among various strategies, nano-enabled delivery systems offer a promising solution to improve the uptake and targeted delivery of drugs into the brain Various nanocarriers including liposomes, bolaamphiphiles and nanoparticles can be used as a means to encapsulate drugs, either alone or in combination with targeting ligands Moreover, most of materials used in nanocarrier fabrication are both biodegradable and biocompatible, thereby increasing the clinical utility of them Here, we review the possibility to employ nano-enabled materials for delivery of drug across the BBB and the recent advances in nanotechnologies for therapy of the CNS diseases

Antiviral activity of Rheum palmatum methanol extract and chrysophanol against Japanese encephalitis virus.

Abstract: Rheum palmatum, Chinese traditional herb, exhibits a great variety of anti-cancer and anti-viruses properties. This study rates antiviral activity of R. palmatum extracts and its components against Japanese encephalitis virus (JEV) in vitro. Methanol extract of R. palmatum contained higher levels of aloe emodin, chrysophanol, rhein, emodin and physcion than water extract. Methanol extract (IC50 = 15.04 μg/ml) exhibited more potent inhibitory effects on JEV plaque reduction than water extract (IC50 = 51.41 μg/ml). Meanwhile, IC50 values determined by plaque reduction assay were 15.82 μg/ml for chrysophanol and 17.39 μg/ml for aloe-emodin, respectively. Virucidal activity of agents correlated with anti-JEV activity, while virucidal IC50 values were 7.58 μg/ml for methanol extract, 17.36 μg/ml for water extract, 0.75 μg/ml for chrysophanol and 0.46 μg/ml for aloe-emodin, respectively. In addition, 10 μg/ml of extract, chrysophanol or aloe emodin caused 90 % inhibition of JEV yields in cells and significantly activated gamma activated sequence-driven promoters. Hence, methanol extract of R. palmatum and chrysophanol with high therapeutic index might be useful for development of antiviral agents against JEV.

Anti-adipogenic activity of the edible brown alga Ecklonia stolonifera and its constituent fucosterol in 3T3-L1 adipocytes.

Abstract: Fucosterol is a sterol metabolite of brown algae and regulates genes involved with cholesterol homeostasis. As a part of our continuous search for anti-obesity agents from natural marine sources, the anti-adipogenic activities of Ecklonia stolonifera and its sterol, fucosterol, were evaluated for the inhibition of adipocyte differentiation and lipid formation. Oil Red O staining was used to evaluate triglyceride contents in 3T3-L1 pre-adipocytes primed by differentiation medium (DM) I and DM II. The methanolic extract of E. stolonifera showed strong anti-adipogenic activity, and was thus fractionated with several solvents. Among the tested fractions, the dichloromethane (CH2Cl2) fraction was found to be the most active fraction, with significant inhibition (40.5 %) of intracellular lipid accumulation at a non-toxic concentration, followed by the ethyl acetate fraction (30.2 %) at the same concentration, while the n-butanol and water fractions did not show inhibitory activity within the tested concentrations. The strong anti-adipogenic CH2Cl2-soluble fraction was further purified by a repeated chromatography to yield fucosterol. Fucosterol reduced lipid contents in a concentration-dependent manner without showing any cytotoxicity. Fucosterol treatment also yielded a decrease in the expression of the adipocyte marker proteins peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) in a concentration-dependent manner. Taken together, these results suggest that fucosterol inhibits expression of PPARγ and C/EBPα, resulting in a decrease of lipid accumulation in 3T3-L1 pre-adipocytes, indicating that the potential use of E. stolonifera and its bioactive fucosterol as an anti-obesity agent.

The effective mechanism of the polysaccharides from Panax ginseng on chronic fatigue syndrome.

Abstract: Ginseng acidic polysaccharide WGPA isolated from the root of Panax ginseng C. A. Meyer was fractionated into WGPA-A and WGPA-N by anion-exchange chromatography. The antifatigue activity of ginseng acidic polysaccharide WGPA has been reported in our previous research. This present study was designed to identify its active component and elucidate the mechanism for preventing chronic fatigue syndrome (CFS). WGPA, WGPA-A and WGPA-N were orally administered to mice once daily for 15 days. The effects of these compounds on physiological biomarkers of oxidative stress and on the morphology of the mitochondria in striated skeletal muscle were assessed. The results of forced swimming test-induced indicated that WGPA and WGPA-A could lengthen the swimming time, while WGPA-N could not. In addition, malondialdehyde and lactate dehydrogenase levels in serum were enhanced; while those of superoxide dismutase and glutathione peroxidase were lowered. Interestingly, the structural degeneration of mitochondria were all ameliorated. These findings suggested that WGPA-A is the active component of WGPA, it might have potential therapeutic effects for CFS and the oxidative stress might be involved in the pathogenesis. Our results also provided essential data for a better understanding of the antifatigue effects of P. ginseng extracts.

Anti-hyperuricemic and nephroprotective effects of Rhizoma Dioscoreae septemlobae extracts and its main component dioscin via regulation of mOAT1, mURAT1 and mOCT2 in hypertensive mice

Abstract: Rhizoma Dioscoreae septemlobae (RDSE) has been widely used for the treatment of hyperuricemia in China. However, the therapeutic mechanism has been unknown. This study investigated the antihyperuricemic mechanisms of the extracts obtained from RDSE and its main component dioscin (DIS) in hyperuricemic mice. Hyperuricemic mice were induced by potassium oxonate (250 mg/kg). RDSE or DIS was orally administered to hyperuricemic mice at dosages of 319.22, 638.43, 1276.86 mg/kg/day for 10 days, respectively. Uric acid or creatinine in serum and urine was determined by HPLC or HPLC-MS/MS, respectively. The xanthine oxidase (XO) activities in mice liver were examined in vitro. Protein levels of organic anion transporter 1 (mOAT1), urate transporter 1 (mURAT1) and organic cation transporter 2 (mOCT2) in the kidney were analyzed by western blotting. The results indicated that uric acid and creatinine in serum were significantly increased by potassium oxonate, as compared to that of control mice. Compared saline-treated group, after RDSE treatment in the high and middle dose, the expression of mOAT1 increased 47.98 and 54.48 %, respectively, which accompanied with the decreased expression of mURAT1 (47.63 %) in high dose. After DIS treatment in high, middle and low dose, the expression of mOAT1 increased 23.93, 32.80 and 25.28 % compared to saline-treated group, respectively, which accompanied with the decreased expression of mURAT1 (51.07, 51.42 and 51.35 %). However, RDSE and DIS displayed a weak XO inhibition activity compared with allopurinol. Therefore, RDSE and DIS processed uricosuric and nephroprotective actions by regulation of mOAT1, mURAT1 and mOCT2.

Antithrombotic activities of sulforaphane via inhibiting platelet aggregation and FIIa/FXa

Abstract: Sulforaphane (SFN), a natural isothiocyanate that is present in cruciferous vegetables such as broccoli and cabbage, is effective in preventing carcinogenesis, diabetes and inflammatory responses. Here, the anticoagulant activities of SFN were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time, and the activities of thrombin (Factor IIa, FIIa) and activated factor X (FXa). And, the effects of SFN on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor-α activated human umbilical vein endothelial cells (HUVECs). Treatment with SFN resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, SFN inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. SFN also elicited anticoagulant effects in mice. In addition, treatment with SFN resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, SFN possesses antithrombotic activities and offers a basis for development of a novel anticoagulant.

Phenolic compounds with IL-6 inhibitory activity from Aster yomena.

Abstract: A new biflavonoid, named asteryomenin (1), as well as six known phenolic compounds, esculetin (2), 4-O-β-D-glucopyranoside-3-hydroxy methyl benzoate (3), caffeic acid (4), isoquercitrin (5), isorhamnetin-3-O-glucoside (6), and apigenin (7) were isolated from the aerial parts of Aster yomena. The structures of compounds (1-7) were identified based on 1D and 2D NMR, including (1)H-(1)H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Compounds 2-7 were isolated from this plant for the first time. For these isolates, the inhibitory activity of IL-6 production in the TNF-α stimulated MG-63 cell was examined. Among these isolates, compounds 4 and 7 appeared to have potent inhibitory activity of IL-6 production in the TNF-α stimulated MG-63 cell, while compounds 1-3 and 5-6 showed moderate activity.

Ginsenoside Rc modulates Akt/FoxO1 pathways and suppresses oxidative stress.

Abstract: Ginsenoside Rc (Rc), a protopanaxadiol type ginsenoside, is the active component mainly responsible for the therapeutic and pharmacologic properties of ginseng, which are derived from its suppression of superoxide-induced free radicals. Forkhead box O (FoxO1) regulates various genes involved in cellular metabolism related to cell death and response to oxidative stress, and Rc is known to prevent FoxO1 phosphorylation by activation of PI3K/Akt and subsequent inhibition of AMP-activated protein kinase (AMPK) in cells exposed to tert-butylhydroperoxide (t-BHP). In the current study, we attempted the mechanism of increased catalase expression by Rc through inhibition of FoxO1 activation resulting from t-BHP-induced production of reactive species (RS). We found that overexpression of catalase induced by Rc resulted in suppression of RS production in kidney human embryo kidney 293T cells (HEK293T) cells, and that oxidative stress induced activation of PI3K/Akt and inhibition of the AMPK pathway and FoxO1 phosphorylation, leading to down-regulation of catalase, a FoxO1-targeting gene. In addition, treatment of HEK293T cells with Rc resulted in cAMP-response element-binding protein (CREB)-binding protein (CBP) regulated FoxO1 acetylation. Our results suggest that Rc modulates FoxO1 phosphorylation through activation of PI3K/Akt and inhibition of AMPK and FoxO1 acetylation through interaction with CBP and SIRT1, and that this leads to upregulation of catalase under conditions of oxidative stress.

New eremophilane-type sesquiterpenes from an Antarctic deepsea derived fungus, Penicillium sp. PR19 N-1.

Abstract: Chemical investigation of an Antarctic deep-sea derived fungus Penicillium sp. PR19 N-1 yielded five new eremophilane-type sesquiterpenes 1–5 and a new rare lactam-type eremophilane 6, together with three known compounds 7–9. The structures of these diverse sesquiterpenes were determined by extensive NMR and mass spectroscopic analyses. Compounds 1, 2, 4–6, 8 and 9 were evaluated for their cytotoxities against HL-60 and A-549 human cancer cell lines, and 5 was the most active one with IC50 value of 5.2 μM against the A-549 cells.

Layer-by-layer assembly of multilayer films for controlled drug release

Abstract: Drug efficacy has been improved using various methods that enhance targeting, decrease toxicity, and facilitate timely and sustained drug release. To achieve these properties, various drug loading and release platforms have been developed. Layer-by-layer (LbL) self-assembly is widely used to generate controlled and sustained drug release LbL multilayer films because it allows desired functions and structures to be obtained through a simple procedure. In this review article, we highlight controlled drug release from LbL self-assembling films with diverse release kinetics, particularly with regard to mechanisms of drug release.

Luteolin mediates the antidepressant-like effects of Cirsium japonicum in mice, possibly through modulation of the GABAA receptor

Abstract: Cirsium japonicum (CJ) has been shown to possess antidepressant-like properties. In the present study, we sought to identify which constituent of CJ might be responsible for its antidepressant effects and determine probable mechanism of action. The ethanol extract of CJ was administered to mice then behavioral changes were evaluated in the forced-swimming test (FST) and open-field test (OFT). In addition, its effects on norepinephrine (NE) reuptake and intracellular chloride (Cl(-)) flux were determined, in vitro. The effects of CJ's major constituents (linarin, pectolinarin, chlorogenic acid, luteolin) were also evaluated. CJ showed antidepressant-like effect by significantly reducing immobile behavior of mice in the FST, without increasing locomotor activity in the OFT. CJ had no effect on monoamine (NE) uptake, but it significantly promoted Cl(-) ion influx in human neuroblastoma cells. This CJ-induced Cl(-) influx was significantly blocked by co-administration of the competitive GABAA receptor antagonist, bicuculline. Among the major constituents of the CJ extract, only luteolin produced similar antidepressant-like effect, in vivo, and Cl(-) ion influx, in vitro. Altogether, the present results suggest that the antidepressant-like effect of CJ was most probably induced by its constituent luteolin, mediated through potentiation of the GABAA receptor-Cl(-) ion channel complex.

Astragaloside IV possesses antiarthritic effect by preventing interleukin 1β-induced joint inflammation and cartilage damage.

Abstract: The saponin astragaloside IV (AST) is one of major active components purified from Astragalus membranaceus (Fisch) Bge, which has been used in traditional Chinese medicine to treat immune disorders including rheumatoid arthritis (RA). The effects of AST on the suppression of experimental arthritis and its possible mechanisms are unknown. We measured the paw swelling of ankle joints, splenocyte proliferation, interleukin 1β (IL-1β), tumor necrosis factor α (TNFα) and nitric oxide (NO) formation by macrophages in rat adjuvant-induced arthritis (AIA). Intraarticular injection of IL-1β to rat knee joint for inducing the edema and in vitro IL-1β-stimulated cartilage impairment were examined. The results showed that oral treatment of AST (100 mg/kg/day) suppressed the joint inflammation and inhibited IL-1β, TNFα and NO production in macrophages from AIA rats. Macrophages were one of AST targeted cells, and mediated the reduced splenocyte proliferation in AIA rats. In addition, AST reduced the swelling induced by intraarticular injection of IL-1β, and protected against IL-1β-induced damage of cartilage proteoglycan synthesis and chondrocyte proliferation. We conclude that AST possesses antiarthritic effect and prevents IL-1β-induced joint inflammation and cartilage destruction. These findings suggest that AST may be used for the treatment of RA and other inflammatory joint diseases.

Ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells via bile acid receptor activation

Abstract: Compound K (CK) is a major metabolite of ginsenosides that is absorbed. CK has antidiabetic effects, although the mechanisms underlying the effects of CK have not fully been known. To elucidate the mechanisms underlying the antidiabetic effects of CK, we studied the effects of CK on GLP-1 secretion from NCI-H716 cells, and explored the mechanisms underlying CK-induced GLP-1 secretion. Treatment of NCI-H716 cells with 10, 50, and 100 μM CK significantly increased GLP-1 secretion, and intracellular Ca2+ and cAMP levels in a dose-dependent manner. Transfection of NCI-H716 cells with siRNA specific to α-gustducin and siRNA specific to TAS1R3 had no effect on CK-induced GLP-1 secretion and Ca2+ increase. However, transfection of NCI-H716 cells with TGR5-specific siRNA significantly inhibited CK-induced GLP-1 secretion and the increase in Ca2+ and cAMP levels. Moreover, CK showed human TGR5 agonist activity in CHO-K1 cells transiently transfected with human TGR5. Our data provide a novel mechanism of CK for antidiabetic effects. Moreover, the findings might suggest that CK is a potential agent that has multiple biological functions in the body via GLP-1 secretion and TGR5 activation.

Latest status of the clinical and industrial applications of cell sheet engineering and regenerative medicine

Abstract: Cell sheet engineering, which allows tissue engineering to be realized without the use of biodegradable scaffolds as an original approach, using a temperature-responsive intelligent surface, has been applied in regenerative medicine for various tissues, and a number of clinical studies have been already performed for life-threatening diseases. By using the results and findings obtained from the initial clinical studies, additional investigative clinical studies in several tissues with cell sheet engineering are currently in preparation stage. For treating many patients effectively by cell sheet engineering, an automated system integrating cell culture, cell-sheet fabrication, and layering is essential, and the system should include an advanced three-dimensional suspension cell culture system and an in vitro bioreactor system to scale up the production of cultured cells and fabricate thicker vascularized tissues. In this paper, cell sheet engineering, its clinical application, and further the authors’ challenge to develop innovative cell culture systems under newly legislated regulatory platform in Japan are summarized and discussed.

Caffeic acid regulates LPS-induced NF-κB activation through NIK/IKK and c-Src/ERK signaling pathways in endothelial cells.

Abstract: The redox sensitive, proinflammatory nuclear transcription factor NF-κB plays a key role in inflammation. In a redox state disrupted by oxidative stress, pro-inflammatory genes are upregulated by the activation of NF-κB via diverse kinases. Thus, the search and characterization of new substances that modulate NF-κB are topics of considerable research interest. Caffeic acid is a component of garlic, some fruits, and coffee, and is widely used as a phenolic agent in beverages. In the present study, caffeic acid was examined with respect to the modulation of inflammatory NF-κB activation via the redox-related c-Src/ERK and NIK/IKK pathways via the reduction of oxidative stress. YPEN-1 cells (an endothelial cell line) were used to explore the molecular mechanism underlying the anti-inflammatory effect of caffeic acid by examining its modulation of NF-κB signaling pathway by LPS. Our results show that LPS-induced oxidative stress-related NF-κB activation upregulated pro-inflammatory COX-2, NF-κB targeting gene which were all inhibited effectively by caffeic acid. Our study shows that caffeic acid inhibits the activation of NF-κB via the c-Src/ERK and NIK/IKK signal transduction pathways. Our results indicate that antioxidative effect of caffeic acid and its restoration of redox balance are responsible for its anti-inflammatory action. Thus, the study provides new information regarding the anti-inflammatory properties of caffeic acid and the roles in the regulation of LPS-induced oxidative stress induces alterations in signal transduction pathways.

Aloin protects against chronic alcoholic liver injury via attenuating lipid accumulation, oxidative stress and inflammation in mice

Abstract: The present study was designed to investigate the protective effect of aloin against alcoholic liver disease in a chronic alcohol feeding mouse model. Mice were given alcohol twice a day by intragastric administration for 11 weeks (4.0, 4.7, 5.5 g/kg bw/day for the first 3 weeks respectively, 6.3 g/kg bw/day for the following 8 weeks). Aloin (10, 30 mg/kg bw) or vehicle was given by gavage to mice after each alcohol administration. Alcohol elevated the serum transaminases alanine aminotransferase, aspartate aminotransferase, total cholesterol and triglyceride levels which were significantly attenuated by the co-administration of aloin (p < 0.05). Histopathological observations were consistent with these indices. Co-administration of aloin significantly suppressed the alcohol-dependent induction of sterol regulatory element-binding protein-1c expression (p < 0.01) and remarkably up-regulated the mRNA levels of AMP-activated protein kinase-α2 (p < 0.001). Furthermore, aloin supplementation significantly inhibited the alcohol-dependent elevation of malondialdehyde and cytochrome P4502E1 expression (p < 0.05), and significantly elevated superoxide dismutase activity (p < 0.01). The up-regulation of serum lipopolysaccharide (LPS), hepatic nitric oxide, tumor necrosis factor α, toll-like receptor-4, and myeloid differentiation primary response gene 88 were also markedly suppressed by the co-administration of aloin (p < 0.05) in alcohol-treated mice. These results suggest that aloin may represent a novel, protective strategy against chronic alcoholic liver injury by attenuating lipid accumulation, oxidative stress and LPS-induced inflammatory response.

Protocatechuic acid extends lifespan and increases stress resistance in Caenorhabditis elegans

Abstract: Veronica peregrina has a wide range of types of constituents with various pharmacological properties. Here in this study, we isolated protocatechuic acid (PCA) from V. peregrina and examined PCAs effects on the lifespan and stress tolerance using Caenorhabditis elegans model system. We found that lifespan of wild-type worms was significantly lengthened in the presence of PCA in a dose dependent manner. PCA also elevated tolerance of worms against osmotic, heat shock, and oxidative stress. We also demonstrated antioxidant capacity of PCA by checking intracellular reactive oxygen species level and antioxidant enzyme activities such as catalase and superoxide dismutase. We further investigated several factors including pharyngeal pumping rate and progeny production that might influence prolonged lifespan and enhanced stress tolerance by PCA. Interestingly, both factors were significantly reduced after PCA exposure, indicating PCA exerts longevity activity by shifting food intake and reproduction at least in part. In addition, PCA-treated aged worms showed increased body movement compared to untreated controls suggesting PCA could enhance healthspan as well as lifespan.