Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, head... more Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, headache, diarrhea, and stroke. Magnolol is a phenolic compound extracted from M. officinalis, with proven antibacterial, antioxidant, anti-inflammatory, and anticancer activities. In this study, we modified magnolol to synthesize a methoxylated derivative, 2-O-methylmagnolol (MM1), and investigated the use of MM1, and magnolol in the treatment of liver cancer. We found that both magnolol and MM1 exhibited inhibitory effects on the growth, migration, and invasion of hepatocellular carcinoma (HCC) cell lines and halted the cell cycle at the G1 phase. MM1 also demonstrated a substantially better tumor-suppressive effect than magnolol. Further analysis suggested that by inhibiting class I histone deacetylase expression in HCC cell lines, magnolol and MM1 induced p21 expression and p53 activation, thereby causing cell cycle arrest and inhibiting HCC cell growth, migration, and invasion. Subsequently, we verified the significant tumor-suppressive effects of magnolol and MM1 in an animal model. Collectively, these findings demonstrate the anti-HCC activities of magnolol and MM1 and their potential for clinical use.
Journal of Biomaterials Science-polymer Edition, 2009
The aim of this work was to evaluate the use of Pluronic F127 (PF) hydrogels incorporating liposo... more The aim of this work was to evaluate the use of Pluronic F127 (PF) hydrogels incorporating liposomes and/or grafted with alginate (AP) for the parenteral delivery of cisplatin. The physicochemical properties such as scanning electron microscopy (SEM), polarity and sol-gel transition temperature, as well as in vitro drug release of developed hydrogels were examined. The sol-gel temperature of PF, PF with liposomes and AP was 26.4, 19.7 and 26.6 degrees C, respectively. A hydrogel with stronger strength was obtained by alginate coupling (AP) according to SEM images and viscosity kinetics as compared to PF. Both liposomes and hydrogels could sustain the release of cisplatin to a certain level. The drug release from the vehicles decreased in the order of PF > liposomes > or = AP > or = PF/liposomes > AP/liposomes. The burst release effect of cisplatin was inhibited when using the AP/liposomes composite system as the vehicle. Formulations were administered intratumorally in melanoma-bearing mice. The respective liposomes or hydrogels did not increase cisplatin accumulation in melanomas compared to the control (aqueous solution). PF/liposomes and AP/liposomes, respectively, increased cisplatin deposition by 2.5- and 4.4-fold. To our best of knowledge, the present work is the first report to investigate the drug delivery from PF-alginate conjugates.
Skin as a route for drug delivery has been extensively investigated. However, because of the pred... more Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical application is limited. One strategy to solve this problem of drug permeation via skin is the use of prodrugs. Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to its parent active drug. Prodrugs can enhance dermal/transdermal drug delivery via different mechanisms, including increased skin partitioning, increased aqueous solubility, and reduced crystallization, etc. Besides the prodrug itself, the optimization of vehicle is important as well. The prodrug partitioning between skin and vehicle as well as prodrug-vehicle interaction may influence the enhancing efficacy on skin permeation. This review explores the synthesis and enhancing mechanisms of prodrugs for topical drug delivery. The prodrugs categorized by the therapeutic use of the parent drugs, including anticancer drugs, analgesics, anti-inflammatory drugs and vitamins, are systemically introduced in this review.
European Journal of Pharmaceutical Sciences, Jun 1, 2002
Nonivamide, a so-called synthetic capsaicin, is a substitute for capsaicin which has a similar ch... more Nonivamide, a so-called synthetic capsaicin, is a substitute for capsaicin which has a similar chemical structure and pharmacological activities as those of capsaicin. The purposes of this study were to explore the in vivo pharmacodynamic responses of nonivamide in hydrogels using Wistar rat as an animal model and to correlate the in vivo results with in vitro topical application. The incorporation of Pluronic F-127 polymer into hydrogels resulted in retarded release of nonivamide. Chitosan and carboxymethylcellulose hydrogels produced higher levels of in vitro nonivamide permeation and skin distribution. The in vivo effects of nonivamide on skin perturbation and vasodilation were found to differ depending on dose and duration after topical application. Quantification of transepidermal water loss was demonstrated to correlate with the measured in vitro skin distribution of nonivamide. The various doses of nonivamide in the hydrogels did not markedly influence erythematous reactions of skin as determined by colorimetric measurements. Hydrogel formulations of nonivamide delivered more drug to the skin and produced greater pharmacodynamic activities than did cream bases of capsaicin.
Four anthraquinones, physcion (1), emodin (2), citreorosein (3) and anthraglycoside B (6), and tw... more Four anthraquinones, physcion (1), emodin (2), citreorosein (3) and anthraglycoside B (6), and two stilbenes, resveratrol (4), and piceid (5), were isolated previously from the root of Polygonum cuspidatum. These bioactive compounds were examined for their antityrosinase potency. No antityrosinase activity was detected with treatment using stilbenes. On the other hand, the anthraquinones showed moderate to strong inhibition of tyrosinase. Physcion exhibited the most potent tyrosinase inhibition among the four anthraquinones examined, which was comparable to kojic acid. The ability of anthraquinones to permeate the skin was also examined. Based on the same thermodynamic activity, physcion showed a higher permeation compared with emodin (48-fold), suggesting it as a potent candidate for dermal use. As naturally occurring tyrosinase inhibitors, anthraquinones from P. cuspidatum may be useful as skin-whitening agents to inhibit tyrosinase for dermal use.
Corrigendum to "Coumarin derivatives, but not coumarin itself, cause skin irritation via topical ... more Corrigendum to "Coumarin derivatives, but not coumarin itself, cause skin irritation via topical delivery". Toxicology letters 226(2014) 173-181
Coumarin and its derivatives are widely employed as a fragrance in cosmetics and skin care produc... more Coumarin and its derivatives are widely employed as a fragrance in cosmetics and skin care products. The skin absorption level and possible disruption to the skin by topical application of coumarins were evaluated in this study. Percutaneous absorption of osthole, daphnoretin, coumarin, byakangelicin, and 7-hydroxycoumarin was assessed in vitro and in vivo. Skin physiology measurements and immunoblotting were utilized as methodologies for validating toxicity. The relationship between structures and permeation/toxicity of coumarins was elucidated. Both equimolar concentration and saturated solubility in 30% ethanol were used as the applied dose. Osthole with the most lipophilic characteristic demonstrated the greatest skin accumulation, followed by coumarin and 7-hydroxycoumarin. Coumarin was the permeant with the highest flux across the skin. The trend of in vivo deposition was consistent with that of the in vitro profiles. Skin uptake of osthole was 8-fold higher than that of coumarin. Hair follicles played a significant role as a pathway for transport of coumarin according to the examination of follicular accumulation. Osthole and 7-hydroxycoumarin slightly, but significantly, enhanced transepidermal water loss after a consecutive 5-day administration. The immunoblotting profiling verified the role of proliferation in skin damage induced by osthole, byakangelicin, and 7-hydroxycoumarin. The proliferation-related proteins examined in this work included glucose-regulated proteins, cytokeratin, and C-myc. Daphnoretin and coumarin showed a negligible alteration on protein biomarkers. The experimental results suggested that skin irritation caused by coumarins was mainly derived from the analogs but not from coumarin itself.
The application of lipid nano/submicron emulsions as topical drug carrier systems for the percuta... more The application of lipid nano/submicron emulsions as topical drug carrier systems for the percutaneous absorption of flurbiprofen was investigated. The lipid emulsions were made up of isopropyl myristate (IPM), soybean oil, or coconut oil as the oil phase, egg lecithin as the predominant emulsifier, and double-distilled water as the external phase. Stearylamine (SA) and deoxycholic acid (DA) also were used to produce positively and negatively charged emulsions. To evaluate the physicochemical properties of the lipid emulsions, particle size by laser light scattering, the image of atomic force microscopy, and relaxation time values by Nuclear Magnetic Resonance (NMR) were determined. The in vitro permeation data showed that incorporation of SA significantly reduced the topical delivery of flurbiprofen. On the other hand, incorporation of DA exhibited no or a negligible effect on drug permeation. Enhancement of drug absorption was observed when adding oleic acid as part of the oil phase. The in vivo topical application of flurbiprofen from selected lipid emulsions showed a similar trend to the in vitro status. Furthermore, the intersubject variability was considerably reduced by lipid emulsions than by aqueous suspensions in both the in vitro and in vivo experiments. The irritant profiles of lipid emulsions showed that IPM elicited higher irritation than soybean oil. The incorporation of oleic acid also produced skin disruption. The results in the present study suggest the feasibility of lipid emulsions for the topical delivery of flurbiprofen.
European Journal of Pharmaceutics and Biopharmaceutics, Mar 1, 2008
Temperature-sensitive hydrogels composed of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (... more Temperature-sensitive hydrogels composed of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) and chitosan + hyaluronic acid (CPNHA) were grafted in order to examine their physicochemical characteristics, in vitro drug release, and in vivo pharmacodynamics. The sol-gel transition behavior was investigated by UV/visible spectrophotometry, differential scanning calorimetry, and viscometry. A slight difference in the transition temperatures was observed among these polymer systems, with CPN and CPNHA exhibiting higher temperatures compared with PNIPAAm. A zeta potential determination revealed a positive charge for the CPN hydrogel, whereas no or only a negligible charge was observed for PNIPAAm and CPNHA. The entanglement of CPN hydrogels observed using scanning electronic microscopy showed the densest cross-linkage structure, followed by CPNHA and PNIPAAm. Both hydrophilic and lipophilic drugs, including nalbuphine, indomethacin, and the nalbuphine prodrug, were used as model drugs in an in vitro drug release experiment. All 3 hydrogels significantly prolonged drug release. The release rate of hydrophilic nalbuphine increased in the order CPN < CPNHA < PNIPAAm. The drug release of these hydrogels exhibited a trend opposite to that of lipophilic drugs. A cold ethanol tail-flick study was utilized in order to examine the antinociceptive activity of intravenous nalbuphine. CPN and CPNHA prolonged the analgesic duration of nalbuphine with no influence on the onset time. The loading of nalbuphine in the CPNHA hydrogel exhibited the longest analgesic duration (4 h) among the 3 hydrogels tested.
HPLC/UPLC assay of flavonoid fraction in polar extracts from various parts of medicinal spice Cro... more HPLC/UPLC assay of flavonoid fraction in polar extracts from various parts of medicinal spice Crocus sativus L.
Background/objectives Low-grade chronic inflammation in visceral adipose tissue and the intestine... more Background/objectives Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts. Methods We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked...
Diphencyprone (DPCP) is a therapeutic agent for treating alopecia areata. To improve skin absorpt... more Diphencyprone (DPCP) is a therapeutic agent for treating alopecia areata. To improve skin absorption and follicular targeting nanostructured lipid carriers (NLCs) were developed. Nanoparticles were characterized by size, zeta potential, molecular environment, differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). In vitro and in vivo skin absorption experiments were performed. Fluorescence and confocal microscopes for imaging skin distribution were used. NLCs with different designs were 208 ~ 265 nm with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 77% DPCP encapsulation. NLCs incorporating a cationic surfactant or more soybean phosphatidylcholine (SPC) showed higher lipophilicity compared to typical NLCs by Nile red emission. All NLCs tested revealed controlled DPCP release; burst release was observed for control. The formulation with more SPC provided 275 μg/g DPCP skin retention, which was greater than control and other NLCs. Intersubject deviation was reduced after DPCP loading into NLCs. Cyanoacrylate skin biopsy demonstrated greater follicular deposition for NLCs with more SPC compared to control. Cationic NLCs but not typical or SPC-containing carriers were largely internalized into keratinocytes. In vivo skin retention of NLCs with more SPC was higher than free control. Confocal imaging confirmed localization of NLCs in follicles and intercellular lipids of stratum corneum. This work encourages further investigation of DPCP absorption using NLCs with a specific formulation design.
New thermosensitive hydrogels of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) were p... more New thermosensitive hydrogels of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) were prepared and evaluated for use in the delivery of the platinum drugs, cisplatin and carboplatin. The effects of polymers containing different ratios of chitosan on the physicochemical and drug release characteristics were examined. The sol-gel transition temperature of the hydrogels was determined by differential scanning calorimetry (DSC) and viscometry. Discrepancies in the transition temperature among the various polymer systems were more pronounced when determined by viscosity compared by DSC, with the CPN showing a higher transition temperature than PNIPAAm. The cross-sectional structure and surface topography of the hydrogels were examined by scanning electronic microscopy (SEM) and atomic force microscopy (AFM), respectively. The incorporation of chitosan further increased the entanglement of the hydrogel network. An increase in the chitosan ratio in the polymers (CPN-H) also increased the cross-linking structure. A smoother surface of hydrogel matrices was observed for CPN compared with PNIPAAm. All hydrogels tested significantly reduced drug release compared with an aqueous solution. The release rate of platinum drugs from PNIPAAm was retarded at the late stage. CPN matrices could continuously deliver platinum drugs during the experiment. The rate of release from CPN-H was generally slower than that from hydrogels and had a lower chitosan ratio (CPN-L), presumably due to the more-tortuous pathways in the hydrogels. Thermosensitive hydrogels like those prepared in this study may be a promising carrier for the delivery of platinum drugs, as the drug release can be controlled and sustained using CPN networks.
Pluronic F127 (PF127) is a copolymer which forms thermosensitive hydrogels. Hyaluronic acid (HA) ... more Pluronic F127 (PF127) is a copolymer which forms thermosensitive hydrogels. Hyaluronic acid (HA) was grafted to PF127 to form a new hydrogel matrix (HP) for delivery of cisplatin and carboplatin. The physicochemical properties and drug delivery of the graft were examined in this study. HP system (20% HP copolymer in water) exhibited a similar sol-gel transition temperature (28.3°C) as PF127 system (20% PF127 copolymer in water) but with a shorter gelling process. A stronger structure was obtained by HP system according to scanning electron microscopic (SEM) images and viscosity kinetics. In vitro release test showed the sustained-release characteristics of hydrogels entrapped with cisplatin and carboplatin. The drug release rate from HP hydrogel was slower than that from PF127 hydrogel. The reduction of drug release by HP system as compared to the control solution was more significant for cisplatin than for carboplatin. Such a thermosensitive hydrogel may be advantageous as an injectable therapeutic formulation for anticancer treatment.
Aim: Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and ... more Aim: Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and severity of psoriasis. Although the therapy of psoriasis remain elusive, targeting treatment to reduce oxidative stress is considered a potential option. Our study demonstrates the anti-inflammatory effects of a natural furocoumarin, imperatorin, on activated human neutrophils and imiquimod-induced psoriasiform dermatitis in mice. Results: Imperatorin inhibited superoxide anion generation, neutrophil adhesion, and migration in formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. Further studies showed that imperatorin induced a decrease in cAMP-specific phosphodiesterase (PDE) activity and increased intracellular cAMP levels and protein kinase A (PKA) activity in human neutrophils. The enzyme activities of PDE4 subtypes, but not PDE3 and PDE7, were inhibited by imperatorin. Furthermore, imperatorin inhibited the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK), and c-Jun N-terminal kinase (JNK),as well as Ca2+ mobilization in fMLF-stimulated neutrophils. These suppressive effects of imperatorin on cell responses and signaling were reversed by PKA inhibitor, suggesting that cAMP/PKA is involved in the anti-inflammatory effects of imperatorin. In vivo studies of imiquimod- and interleukin-23-induced mouse psoriasiform dermatitis demonstrated that imperatorin alleviated skin desquamation, epidermal thickening, keratinocyte hyperproliferation, and neutrophil infiltration. Innovation and Conclusion: Our results demonstrate that imperatorin inhibits human neutrophil respiratory burst, adhesion, and migration through the elevation of cAMP/PKA to inhibit Akt, ERK, JNK, and Ca2+ mobilization. Imperatorin is a natural inhibitor of PDE4A/B/C and may serve as a lead for developing new therapeutics to treat neutrophilic psoriasis.
In clinical use, Taxillus genus plants could be placed by Viscum genus plants. But, they belong t... more In clinical use, Taxillus genus plants could be placed by Viscum genus plants. But, they belong to different genera of Loranthaceae. The genus of Viscum, the plants of Loranthaceae family, are photosynthetic shrubby, hemiparasites on the tree branches. Viscum coloratum has commonly been used for Chinese medicine as a curative for a number of ailments such as hemorrhage, pleurisy, gout, heart disease, epilepsy, arthritis and hypertension. 1,2) In our research, we found oleanolic acid showed significantly anti-inflammatory activitiy in V. articulatum. 3) Oleanolic acid concentration-dependently inhibited superoxide anion generation by human neutrophils in response to fMLP (formyl-L-methionyl-Lleucyl-L-phenylalanine), but not to PMA (phorbol myristate acetate). It suggested that the inhibitory effect of oleanolic acid was through protein kinase C-independent pathway. In a previous screening for the inhibitory activities on superoxide anion generation in fMLP-stimulated human neutrophils by Viscum and Taxillus medicinal plants, V. coloratum also exhibited the strong inhibition. From V. coloratum, two new and thirty-nine known compounds were isolated and characterized. This paper deals with the structural
In the long history of traditional Chinese medicine, single herbs and complex formulas have been ... more In the long history of traditional Chinese medicine, single herbs and complex formulas have been suggested to increase lifespan. However, the identification of single molecules responsible for lifespan extension has been challenging. Here, we collected a list of traditional Chinese medicines with potential longevity properties from pharmacopeias. By utilizing the mother enrichment program, we systematically screened these traditional Chinese medicines and identified a single herb, Psoralea corylifolia, that increases lifespan in Saccharomyces cerevisiae. Next, twenty-two pure compounds were isolated from Psoralea corylifolia. One of the compounds, corylin, was found to extend the replicative lifespan in yeast by targeting the Gtr1 protein. In human umbilical vein endothelial cells, RNA sequencing data showed that corylin ameliorates cellular senescence. We also examined an in vivo mammalian model, and found that corylin extends lifespan in mice fed a high-fat diet. Taken together, t...
Indigo naturalis is effective in treating nail psoriasis coexisting with microorganism infections... more Indigo naturalis is effective in treating nail psoriasis coexisting with microorganism infections. This study examines the antimicrobial effects of indigo naturalis prepared from Strobilanthes formosanus Moore. Eight bacterial and seven fungal strains were assayed using the agar diffusion method to examine the effects of indigo naturalis and its bioactive compounds. The bioactive compounds of indigo naturalis were purified sequentially using GFC, TLC, and HPLC. Their structures were identified using mass spectrometry and NMR spectroscopy. UPLC-MS/MS was applied to compare the metabolome profiles of indigo naturalis ethyl-acetate (EA) extract and its source plant, Strobilanthes formosanus Moore. The results of in vitro antimicrobial assays showed that indigo naturalis EA-extract significantly (≥1 mg/disc) inhibits Gram-positive bacteria (Staphylococcus aureus, S. epidermis and methicillin-resistant S. aureus (MRSA)) and mildly inhibits non-dermatophytic onychomycosis pathogens (Aspergillus fumigates and Candida albicans), but has little effect on dermatophyes. Isatin and tryptanthrin were identified as the bioactive compounds of indigo naturalis using S. aureus and S. epidermis as the bioassay model. Both bioactive ingredients had no effect on all tested fungi. In summary, indigo naturalis prepared from Strobilanthes formosanus Moore exhibits
Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, head... more Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, headache, diarrhea, and stroke. Magnolol is a phenolic compound extracted from M. officinalis, with proven antibacterial, antioxidant, anti-inflammatory, and anticancer activities. In this study, we modified magnolol to synthesize a methoxylated derivative, 2-O-methylmagnolol (MM1), and investigated the use of MM1, and magnolol in the treatment of liver cancer. We found that both magnolol and MM1 exhibited inhibitory effects on the growth, migration, and invasion of hepatocellular carcinoma (HCC) cell lines and halted the cell cycle at the G1 phase. MM1 also demonstrated a substantially better tumor-suppressive effect than magnolol. Further analysis suggested that by inhibiting class I histone deacetylase expression in HCC cell lines, magnolol and MM1 induced p21 expression and p53 activation, thereby causing cell cycle arrest and inhibiting HCC cell growth, migration, and invasion. Subsequently, we verified the significant tumor-suppressive effects of magnolol and MM1 in an animal model. Collectively, these findings demonstrate the anti-HCC activities of magnolol and MM1 and their potential for clinical use.
Journal of Biomaterials Science-polymer Edition, 2009
The aim of this work was to evaluate the use of Pluronic F127 (PF) hydrogels incorporating liposo... more The aim of this work was to evaluate the use of Pluronic F127 (PF) hydrogels incorporating liposomes and/or grafted with alginate (AP) for the parenteral delivery of cisplatin. The physicochemical properties such as scanning electron microscopy (SEM), polarity and sol-gel transition temperature, as well as in vitro drug release of developed hydrogels were examined. The sol-gel temperature of PF, PF with liposomes and AP was 26.4, 19.7 and 26.6 degrees C, respectively. A hydrogel with stronger strength was obtained by alginate coupling (AP) according to SEM images and viscosity kinetics as compared to PF. Both liposomes and hydrogels could sustain the release of cisplatin to a certain level. The drug release from the vehicles decreased in the order of PF &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; liposomes &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = AP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = PF/liposomes &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; AP/liposomes. The burst release effect of cisplatin was inhibited when using the AP/liposomes composite system as the vehicle. Formulations were administered intratumorally in melanoma-bearing mice. The respective liposomes or hydrogels did not increase cisplatin accumulation in melanomas compared to the control (aqueous solution). PF/liposomes and AP/liposomes, respectively, increased cisplatin deposition by 2.5- and 4.4-fold. To our best of knowledge, the present work is the first report to investigate the drug delivery from PF-alginate conjugates.
Skin as a route for drug delivery has been extensively investigated. However, because of the pred... more Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical application is limited. One strategy to solve this problem of drug permeation via skin is the use of prodrugs. Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to its parent active drug. Prodrugs can enhance dermal/transdermal drug delivery via different mechanisms, including increased skin partitioning, increased aqueous solubility, and reduced crystallization, etc. Besides the prodrug itself, the optimization of vehicle is important as well. The prodrug partitioning between skin and vehicle as well as prodrug-vehicle interaction may influence the enhancing efficacy on skin permeation. This review explores the synthesis and enhancing mechanisms of prodrugs for topical drug delivery. The prodrugs categorized by the therapeutic use of the parent drugs, including anticancer drugs, analgesics, anti-inflammatory drugs and vitamins, are systemically introduced in this review.
European Journal of Pharmaceutical Sciences, Jun 1, 2002
Nonivamide, a so-called synthetic capsaicin, is a substitute for capsaicin which has a similar ch... more Nonivamide, a so-called synthetic capsaicin, is a substitute for capsaicin which has a similar chemical structure and pharmacological activities as those of capsaicin. The purposes of this study were to explore the in vivo pharmacodynamic responses of nonivamide in hydrogels using Wistar rat as an animal model and to correlate the in vivo results with in vitro topical application. The incorporation of Pluronic F-127 polymer into hydrogels resulted in retarded release of nonivamide. Chitosan and carboxymethylcellulose hydrogels produced higher levels of in vitro nonivamide permeation and skin distribution. The in vivo effects of nonivamide on skin perturbation and vasodilation were found to differ depending on dose and duration after topical application. Quantification of transepidermal water loss was demonstrated to correlate with the measured in vitro skin distribution of nonivamide. The various doses of nonivamide in the hydrogels did not markedly influence erythematous reactions of skin as determined by colorimetric measurements. Hydrogel formulations of nonivamide delivered more drug to the skin and produced greater pharmacodynamic activities than did cream bases of capsaicin.
Four anthraquinones, physcion (1), emodin (2), citreorosein (3) and anthraglycoside B (6), and tw... more Four anthraquinones, physcion (1), emodin (2), citreorosein (3) and anthraglycoside B (6), and two stilbenes, resveratrol (4), and piceid (5), were isolated previously from the root of Polygonum cuspidatum. These bioactive compounds were examined for their antityrosinase potency. No antityrosinase activity was detected with treatment using stilbenes. On the other hand, the anthraquinones showed moderate to strong inhibition of tyrosinase. Physcion exhibited the most potent tyrosinase inhibition among the four anthraquinones examined, which was comparable to kojic acid. The ability of anthraquinones to permeate the skin was also examined. Based on the same thermodynamic activity, physcion showed a higher permeation compared with emodin (48-fold), suggesting it as a potent candidate for dermal use. As naturally occurring tyrosinase inhibitors, anthraquinones from P. cuspidatum may be useful as skin-whitening agents to inhibit tyrosinase for dermal use.
Corrigendum to "Coumarin derivatives, but not coumarin itself, cause skin irritation via topical ... more Corrigendum to "Coumarin derivatives, but not coumarin itself, cause skin irritation via topical delivery". Toxicology letters 226(2014) 173-181
Coumarin and its derivatives are widely employed as a fragrance in cosmetics and skin care produc... more Coumarin and its derivatives are widely employed as a fragrance in cosmetics and skin care products. The skin absorption level and possible disruption to the skin by topical application of coumarins were evaluated in this study. Percutaneous absorption of osthole, daphnoretin, coumarin, byakangelicin, and 7-hydroxycoumarin was assessed in vitro and in vivo. Skin physiology measurements and immunoblotting were utilized as methodologies for validating toxicity. The relationship between structures and permeation/toxicity of coumarins was elucidated. Both equimolar concentration and saturated solubility in 30% ethanol were used as the applied dose. Osthole with the most lipophilic characteristic demonstrated the greatest skin accumulation, followed by coumarin and 7-hydroxycoumarin. Coumarin was the permeant with the highest flux across the skin. The trend of in vivo deposition was consistent with that of the in vitro profiles. Skin uptake of osthole was 8-fold higher than that of coumarin. Hair follicles played a significant role as a pathway for transport of coumarin according to the examination of follicular accumulation. Osthole and 7-hydroxycoumarin slightly, but significantly, enhanced transepidermal water loss after a consecutive 5-day administration. The immunoblotting profiling verified the role of proliferation in skin damage induced by osthole, byakangelicin, and 7-hydroxycoumarin. The proliferation-related proteins examined in this work included glucose-regulated proteins, cytokeratin, and C-myc. Daphnoretin and coumarin showed a negligible alteration on protein biomarkers. The experimental results suggested that skin irritation caused by coumarins was mainly derived from the analogs but not from coumarin itself.
The application of lipid nano/submicron emulsions as topical drug carrier systems for the percuta... more The application of lipid nano/submicron emulsions as topical drug carrier systems for the percutaneous absorption of flurbiprofen was investigated. The lipid emulsions were made up of isopropyl myristate (IPM), soybean oil, or coconut oil as the oil phase, egg lecithin as the predominant emulsifier, and double-distilled water as the external phase. Stearylamine (SA) and deoxycholic acid (DA) also were used to produce positively and negatively charged emulsions. To evaluate the physicochemical properties of the lipid emulsions, particle size by laser light scattering, the image of atomic force microscopy, and relaxation time values by Nuclear Magnetic Resonance (NMR) were determined. The in vitro permeation data showed that incorporation of SA significantly reduced the topical delivery of flurbiprofen. On the other hand, incorporation of DA exhibited no or a negligible effect on drug permeation. Enhancement of drug absorption was observed when adding oleic acid as part of the oil phase. The in vivo topical application of flurbiprofen from selected lipid emulsions showed a similar trend to the in vitro status. Furthermore, the intersubject variability was considerably reduced by lipid emulsions than by aqueous suspensions in both the in vitro and in vivo experiments. The irritant profiles of lipid emulsions showed that IPM elicited higher irritation than soybean oil. The incorporation of oleic acid also produced skin disruption. The results in the present study suggest the feasibility of lipid emulsions for the topical delivery of flurbiprofen.
European Journal of Pharmaceutics and Biopharmaceutics, Mar 1, 2008
Temperature-sensitive hydrogels composed of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (... more Temperature-sensitive hydrogels composed of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) and chitosan + hyaluronic acid (CPNHA) were grafted in order to examine their physicochemical characteristics, in vitro drug release, and in vivo pharmacodynamics. The sol-gel transition behavior was investigated by UV/visible spectrophotometry, differential scanning calorimetry, and viscometry. A slight difference in the transition temperatures was observed among these polymer systems, with CPN and CPNHA exhibiting higher temperatures compared with PNIPAAm. A zeta potential determination revealed a positive charge for the CPN hydrogel, whereas no or only a negligible charge was observed for PNIPAAm and CPNHA. The entanglement of CPN hydrogels observed using scanning electronic microscopy showed the densest cross-linkage structure, followed by CPNHA and PNIPAAm. Both hydrophilic and lipophilic drugs, including nalbuphine, indomethacin, and the nalbuphine prodrug, were used as model drugs in an in vitro drug release experiment. All 3 hydrogels significantly prolonged drug release. The release rate of hydrophilic nalbuphine increased in the order CPN < CPNHA < PNIPAAm. The drug release of these hydrogels exhibited a trend opposite to that of lipophilic drugs. A cold ethanol tail-flick study was utilized in order to examine the antinociceptive activity of intravenous nalbuphine. CPN and CPNHA prolonged the analgesic duration of nalbuphine with no influence on the onset time. The loading of nalbuphine in the CPNHA hydrogel exhibited the longest analgesic duration (4 h) among the 3 hydrogels tested.
HPLC/UPLC assay of flavonoid fraction in polar extracts from various parts of medicinal spice Cro... more HPLC/UPLC assay of flavonoid fraction in polar extracts from various parts of medicinal spice Crocus sativus L.
Background/objectives Low-grade chronic inflammation in visceral adipose tissue and the intestine... more Background/objectives Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts. Methods We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked...
Diphencyprone (DPCP) is a therapeutic agent for treating alopecia areata. To improve skin absorpt... more Diphencyprone (DPCP) is a therapeutic agent for treating alopecia areata. To improve skin absorption and follicular targeting nanostructured lipid carriers (NLCs) were developed. Nanoparticles were characterized by size, zeta potential, molecular environment, differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). In vitro and in vivo skin absorption experiments were performed. Fluorescence and confocal microscopes for imaging skin distribution were used. NLCs with different designs were 208 ~ 265 nm with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 77% DPCP encapsulation. NLCs incorporating a cationic surfactant or more soybean phosphatidylcholine (SPC) showed higher lipophilicity compared to typical NLCs by Nile red emission. All NLCs tested revealed controlled DPCP release; burst release was observed for control. The formulation with more SPC provided 275 μg/g DPCP skin retention, which was greater than control and other NLCs. Intersubject deviation was reduced after DPCP loading into NLCs. Cyanoacrylate skin biopsy demonstrated greater follicular deposition for NLCs with more SPC compared to control. Cationic NLCs but not typical or SPC-containing carriers were largely internalized into keratinocytes. In vivo skin retention of NLCs with more SPC was higher than free control. Confocal imaging confirmed localization of NLCs in follicles and intercellular lipids of stratum corneum. This work encourages further investigation of DPCP absorption using NLCs with a specific formulation design.
New thermosensitive hydrogels of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) were p... more New thermosensitive hydrogels of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) were prepared and evaluated for use in the delivery of the platinum drugs, cisplatin and carboplatin. The effects of polymers containing different ratios of chitosan on the physicochemical and drug release characteristics were examined. The sol-gel transition temperature of the hydrogels was determined by differential scanning calorimetry (DSC) and viscometry. Discrepancies in the transition temperature among the various polymer systems were more pronounced when determined by viscosity compared by DSC, with the CPN showing a higher transition temperature than PNIPAAm. The cross-sectional structure and surface topography of the hydrogels were examined by scanning electronic microscopy (SEM) and atomic force microscopy (AFM), respectively. The incorporation of chitosan further increased the entanglement of the hydrogel network. An increase in the chitosan ratio in the polymers (CPN-H) also increased the cross-linking structure. A smoother surface of hydrogel matrices was observed for CPN compared with PNIPAAm. All hydrogels tested significantly reduced drug release compared with an aqueous solution. The release rate of platinum drugs from PNIPAAm was retarded at the late stage. CPN matrices could continuously deliver platinum drugs during the experiment. The rate of release from CPN-H was generally slower than that from hydrogels and had a lower chitosan ratio (CPN-L), presumably due to the more-tortuous pathways in the hydrogels. Thermosensitive hydrogels like those prepared in this study may be a promising carrier for the delivery of platinum drugs, as the drug release can be controlled and sustained using CPN networks.
Pluronic F127 (PF127) is a copolymer which forms thermosensitive hydrogels. Hyaluronic acid (HA) ... more Pluronic F127 (PF127) is a copolymer which forms thermosensitive hydrogels. Hyaluronic acid (HA) was grafted to PF127 to form a new hydrogel matrix (HP) for delivery of cisplatin and carboplatin. The physicochemical properties and drug delivery of the graft were examined in this study. HP system (20% HP copolymer in water) exhibited a similar sol-gel transition temperature (28.3°C) as PF127 system (20% PF127 copolymer in water) but with a shorter gelling process. A stronger structure was obtained by HP system according to scanning electron microscopic (SEM) images and viscosity kinetics. In vitro release test showed the sustained-release characteristics of hydrogels entrapped with cisplatin and carboplatin. The drug release rate from HP hydrogel was slower than that from PF127 hydrogel. The reduction of drug release by HP system as compared to the control solution was more significant for cisplatin than for carboplatin. Such a thermosensitive hydrogel may be advantageous as an injectable therapeutic formulation for anticancer treatment.
Aim: Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and ... more Aim: Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and severity of psoriasis. Although the therapy of psoriasis remain elusive, targeting treatment to reduce oxidative stress is considered a potential option. Our study demonstrates the anti-inflammatory effects of a natural furocoumarin, imperatorin, on activated human neutrophils and imiquimod-induced psoriasiform dermatitis in mice. Results: Imperatorin inhibited superoxide anion generation, neutrophil adhesion, and migration in formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. Further studies showed that imperatorin induced a decrease in cAMP-specific phosphodiesterase (PDE) activity and increased intracellular cAMP levels and protein kinase A (PKA) activity in human neutrophils. The enzyme activities of PDE4 subtypes, but not PDE3 and PDE7, were inhibited by imperatorin. Furthermore, imperatorin inhibited the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK), and c-Jun N-terminal kinase (JNK),as well as Ca2+ mobilization in fMLF-stimulated neutrophils. These suppressive effects of imperatorin on cell responses and signaling were reversed by PKA inhibitor, suggesting that cAMP/PKA is involved in the anti-inflammatory effects of imperatorin. In vivo studies of imiquimod- and interleukin-23-induced mouse psoriasiform dermatitis demonstrated that imperatorin alleviated skin desquamation, epidermal thickening, keratinocyte hyperproliferation, and neutrophil infiltration. Innovation and Conclusion: Our results demonstrate that imperatorin inhibits human neutrophil respiratory burst, adhesion, and migration through the elevation of cAMP/PKA to inhibit Akt, ERK, JNK, and Ca2+ mobilization. Imperatorin is a natural inhibitor of PDE4A/B/C and may serve as a lead for developing new therapeutics to treat neutrophilic psoriasis.
In clinical use, Taxillus genus plants could be placed by Viscum genus plants. But, they belong t... more In clinical use, Taxillus genus plants could be placed by Viscum genus plants. But, they belong to different genera of Loranthaceae. The genus of Viscum, the plants of Loranthaceae family, are photosynthetic shrubby, hemiparasites on the tree branches. Viscum coloratum has commonly been used for Chinese medicine as a curative for a number of ailments such as hemorrhage, pleurisy, gout, heart disease, epilepsy, arthritis and hypertension. 1,2) In our research, we found oleanolic acid showed significantly anti-inflammatory activitiy in V. articulatum. 3) Oleanolic acid concentration-dependently inhibited superoxide anion generation by human neutrophils in response to fMLP (formyl-L-methionyl-Lleucyl-L-phenylalanine), but not to PMA (phorbol myristate acetate). It suggested that the inhibitory effect of oleanolic acid was through protein kinase C-independent pathway. In a previous screening for the inhibitory activities on superoxide anion generation in fMLP-stimulated human neutrophils by Viscum and Taxillus medicinal plants, V. coloratum also exhibited the strong inhibition. From V. coloratum, two new and thirty-nine known compounds were isolated and characterized. This paper deals with the structural
In the long history of traditional Chinese medicine, single herbs and complex formulas have been ... more In the long history of traditional Chinese medicine, single herbs and complex formulas have been suggested to increase lifespan. However, the identification of single molecules responsible for lifespan extension has been challenging. Here, we collected a list of traditional Chinese medicines with potential longevity properties from pharmacopeias. By utilizing the mother enrichment program, we systematically screened these traditional Chinese medicines and identified a single herb, Psoralea corylifolia, that increases lifespan in Saccharomyces cerevisiae. Next, twenty-two pure compounds were isolated from Psoralea corylifolia. One of the compounds, corylin, was found to extend the replicative lifespan in yeast by targeting the Gtr1 protein. In human umbilical vein endothelial cells, RNA sequencing data showed that corylin ameliorates cellular senescence. We also examined an in vivo mammalian model, and found that corylin extends lifespan in mice fed a high-fat diet. Taken together, t...
Indigo naturalis is effective in treating nail psoriasis coexisting with microorganism infections... more Indigo naturalis is effective in treating nail psoriasis coexisting with microorganism infections. This study examines the antimicrobial effects of indigo naturalis prepared from Strobilanthes formosanus Moore. Eight bacterial and seven fungal strains were assayed using the agar diffusion method to examine the effects of indigo naturalis and its bioactive compounds. The bioactive compounds of indigo naturalis were purified sequentially using GFC, TLC, and HPLC. Their structures were identified using mass spectrometry and NMR spectroscopy. UPLC-MS/MS was applied to compare the metabolome profiles of indigo naturalis ethyl-acetate (EA) extract and its source plant, Strobilanthes formosanus Moore. The results of in vitro antimicrobial assays showed that indigo naturalis EA-extract significantly (≥1 mg/disc) inhibits Gram-positive bacteria (Staphylococcus aureus, S. epidermis and methicillin-resistant S. aureus (MRSA)) and mildly inhibits non-dermatophytic onychomycosis pathogens (Aspergillus fumigates and Candida albicans), but has little effect on dermatophyes. Isatin and tryptanthrin were identified as the bioactive compounds of indigo naturalis using S. aureus and S. epidermis as the bioassay model. Both bioactive ingredients had no effect on all tested fungi. In summary, indigo naturalis prepared from Strobilanthes formosanus Moore exhibits
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