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Purpose: Transcatheter arterial chemoembolization (TACE) is a common clinical treatment for hepatocellular carcinoma (HCC). However, hypoxia induction after treatment might trigger tumor invasiveness and metastasis. Although pterostilbene (PTS) has antitumor effects, its chemoprevention in HepG2 cells under hypoxia has not been investigated yet. In addition, the poor water solubility of raw PTS limits its clinical application. Here, we prepared nanoparticles of PTS (PSN) and compared their antihepatoma activities with those of raw PTS in HepG2 under hypoxic conditions., Materials and Methods: The PTS nanoparticle formulation was prepared by nanoprecipitation, using Eudragit ® e100 (EE) and polyvinyl alcohol (PVA) as carriers. We analyzed the physicochemical properties of raw PTS and PSN, including yield, encapsulation efficiency, water-solubility, particle size, morphology, crystalline-to-amorphous transformation, and molecular interaction between PTS and carriers. We also evaluated their antihepatoma activities under hypoxia treatment in HepG2 cells, including cell viability, hypoxia, and apoptosis., Results: The yield and encapsulation efficiency of PSN were 86.33% and >99%, respectively. The water solubility and drug release of PTS were effectively improved after nanoprecipitation corresponding to the reduction in particle size, amorphous transformation, and formation of hydrogen bonding with carriers. PSN had a better cytotoxic effect than raw PTS in HepG2 under pre- and post-hypoxia conditions. In addition, hypoxia- and apoptosis-related proteins in HepG2 cells under two different hypoxic conditions were significantly inhibited by PSN compared with the control group with hypoxia only, except for HIF-1α in the post-hypoxia group. PSN was also significantly better in inhibiting these proteins, except for Bcl2, under pre-hypoxic conditions., Conclusion: Our results suggested that PSN could improve the water solubility and drug release of PTS and enhance the efficacy of HCC treatment under hypoxic conditions., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Tzeng et al.)

Background: 7,3',4'-Trihydroxyisoflavone (734THI), a secondary metabolite derived from daidzein in soybean, possesses several biological activities, including antioxidant, skin whitening and anti-atopic dermatitis properties, but the poor aqueous solubility of 734THI has limited its application in medicine and cosmetic industry., Methods: The aim of the present study was to improve the physicochemical properties of 734THI using planetary ball mill preparation under a solvent-free process to improve its solubility and anti-pollutant activity., Results: 734THI nanoparticle powder (734THIN) was successfully prepared by the planetary ball mill technique using polyvinylpyrrolidone K30 as the excipient. 734THIN effectively increased the aqueous solubility and cellular uptake of 734THI by improving its physicochemical properties, including particle size reduction, crystalline-amorphous transformation and intermolecular hydrogen bonding with polyvinylpyrrolidone K30. In addition, 734THIN inhibited the overexpression of COX-2 and MMP-9 by downregulating MAPK pathway signaling in particulate matter-exposed HaCaT keratinocytes, while raw 734THI in PBS with low aqueous solubility did not show any anti-inflammatory or antiaging activity., Conclusion: 734THIN may be used as an additive in anti-pollutant skin care products for preventing particulate matter-induced inflammation and aging in skin., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells enables the attachment of leukocytes to the endothelium, which may lead to inflammation and the development of atherosclerosis. Magnolol is a major bioactive compound derived from the plant species Magnolia officinalis. In this study, we synthesized a novel nanoparticle formulation of magnolol to improve its water solubility and physicochemical properties, evaluated its effects on TNF-α-induced VCAM-1 expression in endothelial cells, and determined the signal transduction pathways involved. Our findings demonstrated that the magnolol nanoparticle system showed great improvements in physicochemical properties and water solubility owing to a reduction in particle size, transformation from a crystalline to amorphous structure, and the formation of hydrogen bonds with the nanoparticle carriers. In terms of its biological actions, magnolol nanoparticles attenuated TNF-α-induced VCAM-1 protein expression, promoter activity, and mRNA expression in endothelial cells in vitro. This was found to be mediated by the ERK, AKT, and NF-κB signaling pathways. In addition, magnolol nanoparticles inhibited TNF-α-induced leukocyte adhesion to endothelial cells, and suppressed TNF-α-induced VCAM-1 expression in the aortic endothelium of mice. In summary, since magnolol nanoparticles inhibit endothelial VCAM-1 expression and leukocyte adhesion to endothelial cells, this novel drug formulation may be a potentially useful therapeutic formulation to prevent the development of atherosclerosis and inflammatory diseases.

Exposure to particulate matter (PM), a major form of air pollution, can induce oxidative stress and inflammation and may lead to many diseases in various organ systems including the skin. Eupafolin, a flavonoid compound derived from Phyla nodiflora, has been previously shown to exhibit various pharmacological activities, including antioxidant and anti-inflammatory effects. Unfortunately, eupafolin is characterized by poor water solubility and skin penetration, which limits its clinical applications. To address these issues, we successfully synthesized a eupafolin nanoparticle delivery system (ENDS). Our findings showed that ENDS could overcome the physicochemical drawbacks of raw eupafolin with respect to water solubility and skin penetration, through reduction of particle size and formation of an amorphous state with hydrogen bonding. Moreover, ENDS was superior to raw eupafolin in attenuating PM-induced oxidative stress and inflammation in HaCaT keratinocytes, by mediating the antioxidant pathway (decreased reactive oxygen species production and nicotinamide adenine dinucleotide phosphate oxidase activity) and anti-inflammation pathway (decreased cyclooxygenase-2 expression and prostaglandin E2 production through downregulation of mitogen-activated protein kinase and nuclear factor-κB signaling). In summary, ENDS shows better antioxidant and anti-inflammatory activities than raw eupafolin through improvement of water solubility and skin penetration. Therefore, ENDS may potentially be used as a medicinal drug and/or cosmeceutical product to prevent PM-induced skin inflammation.

7,3',4'-Trihydroxyisoflavone (734THIF) is a secondary metabolite of daidzein and has been recently found to possess antioxidant, melanin inhibition, and skin cancer chemopreventive activities. However, the poor water solubility of 734THIF impedes its absorption and skin penetration and, therefore, limits its pharmacological effects when applied topically to the skin. We seek to use the nanoprecipitation method to prepare optimal eudragit E100 (EE)-polyvinyl alcohol (PVA)-loaded 734THIF nanoparticles (734N) to improve its physicochemical properties and thereby increase its water solubility, skin penetration, and biological activities. EE-PVA-loaded 734THIF nanoparticles (734N) were prepared, and their morphology and particle size were evaluated using a particle size analyzer and by electron microscopy. The drug loading and encapsulation efficiencies and in vitro solubility were determined using high-performance liquid chromatography. Hydrogen-bond formation was evaluated by (1)H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, and crystalline-to-amorphous transformation was determined by differential scanning calorimetry and X-ray diffractometry. In vitro skin penetration was analyzed using fresh pig skin mounted on Franz diffusion cells, and cytotoxicity against human keratinocyte HaCaT cells was evaluated using the MTT assay. Antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl-free radical scavenging ability. EE-PVA-loaded 734THIF nanoparticles showed good drug loading and encapsulation efficiencies and were characterized by improved physicochemical properties, including reduction in particle size, amorphous transformation, and intermolecular hydrogen-bond formation. This is associated with increased water solubility and enhanced in vitro skin penetration, with no cytotoxicity toward HaCaT cells. In addition, 734THIF nanoparticles retained their antioxidant activity. In conclusion, 734THIF nanoparticles are characterized by improved physicochemical properties, increased water solubility, and enhanced skin penetration, and these may have potential use in the future as a topical delivery formulation for the treatment of skin diseases.

Ethnopharmacological Relevance: Bupleurum chinense is a traditional Chinese medicinal herb which has been used to treat various inflammatory and infectious diseases, while Bupleurum kaoi is an endemic plant in Taiwan. We determined whether B. chinense and B. kaoi and their biologically active saikosaponin compounds possess anti-melanoma activity. In addition, we developed a novel saikosaponin-d nanoparticle system to improve its solubility, and evaluated its antiproliferative effects and molecular mechanisms in melanoma cells., Materials and Methods: Ethanolic extracts from B. chinense and B. kaoi were prepared, and their saikosaponin contents were determined by high performance liquid chromatography analysis. Saikosaponin-d nanoparticles were synthesized, and their physicochemical properties were evaluated by particle size analyzer, transmission electron microscopy, differential scanning calorimetry, X-ray diffractometry, and Fourier transform infrared spectroscopy. Human A375.S2 melanoma cells were cultured, and cell viability determined by the MTT assay. Apoptosis was evaluated by determination of mitochondrial membrane potential, and signal transduction pathways investigated by Western blotting., Results: Ethanolic extracts from B. kaoi showed more potent antiproliferative effect on human A375.S2 melanoma cells compared to B. chinense. The saikosaponin-a, -c and -d contents were higher in B. kaoi compared to B. chinense. Saikosaponin-d was the most potent compound in terms of anti-melanoma activity, and saikosaponin-d nanoparticles exhibited increased water solubility due to lowered particle size, amorphous transformation and intermolecular hydrogen bond formation with the excipient. Furthermore, saikosaponin-d nanoparticles showed enhanced antiproliferative activity against melanoma cells, and induced apoptosis through the mitochondrial pathway. The anti-melanoma activity was mediated by phosphorylation of JNK and p38, phosphorylation of p53, increased level of cytochrome c, and activation of caspase 9., Conclusions: B. kaoi contains higher saikosaponin content and shows greater anti-melanoma activity than B. chinense. Saikosaponin-d nanoparticles have improved solubility, and may have potential use in the future as a form of treatment for melanoma., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Resveratrol (RES), a well-known antioxidant and anti-inflammatory compound, is abundant in red wine and exerts numerous pharmacological effects, including hepatoprotection and cadioprotection. Unfortunately, RES is restricted in clinical application due to poor dissolution property and adsorption. In addition, red wine as a supplement for preventing disease is not recommended for patients with alcohol-related disorders. To address these limitations, we successfully developed a novel RES nanoparticle system (RESN) and demonstrated that RESN could circumvent the physicochemical drawbacks of raw RES with respect to dissolution, such as the reduction of particle size, amorphous transformation, and hydrogen-bond formation. In addition, we employed an animal model of CCl₄-induced hepatotoxicity to estimate the potential of the nanoparticle formulation to improve the hepatoprotective effect of orally administered RES. Our results demonstrated that RESN can diminish liver function markers (aspartate aminotransferase and alanine aminotransferase) by decreasing hepatocyte death due to CCl₄-induced hepatotoxicity in rats, when compared with RES administration. The effect was achieved by reducing oxidative stress (decreased reactive oxygen species and lipid peroxidation) and lowering inflammatory cytokines (decreased tumor necrosis factor-α and interleukin 1β) and protein expression (cyclooxygenase-2, inducible nitric oxide synthase, cytosolic phospholipase A2, and caspase-3). In conclusion, enhancement of the dissolution of RES through a nanoparticle engineering process can result in increased hepatoprotective effects mediated by antioxidant and anti-inflammatory activities. Consequently, we suggest that RESN deserves further study, perhaps in prophylaxis of chronic liver diseases.

Silymarin, a well known hepatoprotective drug, has been routinely used in treating liver disorders. However, its bioavailability and therapeutic efficiency are limited by the poor aqueous solubility. In this study, we used the nanoprecipitation technique to develop a nanoparticles system to improve the solubility of silymarin. The newly developed silymarin nanoparticles were characterized for mean particle size, morphology, intermolecular interaction, crystalline features and dissolution property, as well as assessing for antioxidant activities. Results indicated that a drastic change in the physiochemical properties of silymarin was noted in the form of nanoparticles, as displayed by the extremely small particle size (46.1 +/- 1.73 nm), the formation of intermolecular hydrogen bonding between silymarin and matrix of nanoparticles, and the rendering of amorphous state. These phenomena have contributed to the enhanced dissolution property of silymarin nanoparticles, as well as a greater potency in DPPH radical scavenging, anti-superoxide anion formation, and superoxide anion scavenging activities than the crude silymarin. The present study concludes that silymarin nanoparticles have an improved physicochemical property as demonstrated by an increased solubility and enhanced antioxidant activities.

The preparation of TiO(2) nanocrystallite powders coated with and without 9 mol% ZnO has been studied for cosmetic applications in sunscreens by a co-precipitation process using TiCl(4) and Zn(NO(3))(2)·6H(2)O as starting materials. XRD results show that the phases of anatase TiO(2) and rutile TiO(2) coexist for precursor powders without added ZnO (T-0Z) and calcined at 523 to 973 K for 2 h. When the T-0Z precursor powders are calcined at 1273 K for 2 h, only the rutile TiO(2) appears. In addition, when the TiO(2) precursor powders contain 9 mol% ZnO (T-9Z) are calcined at 873 to 973 K for 2 h, the crystallized samples are composed of the major phase of rutile TiO(2) and the minor phases of anatase TiO(2) and Zn(2)Ti(3)O(8). The analyses of UV/VIS/NIR spectra reveal that the absorption of the T-9Z precursor powders after being calcined has a red-shift effect in the UV range with increasing calcination temperature. Therefore, the TiO(2) nanocrystallite powders coated with 9 mol% ZnO can be used as the attenuate agent in the UV-A region for cosmetic applications in sunscreens.

Purpose: A novel naringenin-loaded nanoparticles system (NARN) was developed to resolve the restricted bioavailability of naringenin (NAR) and to enhance its hepatoprotective effects in vivo on oral administration., Materials and Methods: Physicochemical characterizations of NARN included assessment of particle size and morphology, powder X-ray diffraction, fourier transform infrared spectroscopy, and dissolution study. In addition, to evaluate its bioactivities and its oral treatment potential against liver injuries, we compared the hepatoprotective, antioxidant, and antiapoptotic effects of NARN and NAR on carbon tetrachloride (CCl(4))-induced hepatotoxicity in rats., Results: NARN had a significantly higher release rate than NAR and improved its solubility. NARN also exhibited more liver-protective effects compared to NAR with considerable reduction in liver function index and lipid peroxidation, in conjunction to a substantial increase in the levels of the antioxidant enzymes (P < 0.05). Moreover, NARN was able to significantly inhibit the activation of caspase-3, -8, and -9 signaling, whereas NAR only markedly inhibited caspase-3 and -9 (P < 0.05)., Conclusion: NARN effectively improved the release of NAR which resulted in more hepatoprotective effects mediated by its antioxidant and antiapoptotic properties. These observations also suggest that nanoformulation can improve the free drug's bioactivity on oral administration.

Cuscuta chinensis is a commonly used traditional Chinese medicine to nourish the liver and kidney. Due to the poor water solubility of its major constituents such as flavonoids and lignans, its absorption upon oral administration could be limited. The purpose of the present study was to use the nanosuspension method to prepare C. chinensis nanoparticles (CN), and to compare the hepatoprotective and antioxidant effects of C. chinensis ethanolic extract (CE) and CN on acetaminophen-induced hepatotoxicity in rats. An oral dose of CE at 125 and 250 mg/kg and CN at 25 and 50mg/kg showed a significant hepatoprotective effect relatively to the same extent (P<0.05) by reducing levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. These biochemical assessments were supported by rat hepatic biopsy examinations. In addition, the antioxidant activities of CE and CN both significantly increased superoxide dismutase, catalase, glutathione peroxidase, and reduced malondialdehyde (P<0.05). Moreover, the results also indicated that the hepatoprotective and antioxidant effects of 50 mg/kg CN was effectively better than 125 mg/kg CE (P<0.05), and an oral dose of CN that is five times as less as CE could exhibit similar levels of outcomes. In conclusion, we suggest that the nanoparticles system can be applied to overcome other water poorly soluble herbal medicines and furthermore to decrease the treatment dosage.

The purpose of this study was to develop quercetin-loaded nanoparticles (QUEN) by a nanoprecipitation technique with Eudragit E (EE) and polyvinyl alcohol (PVA) as carriers, and to evaluate the antioxidant effects of quercetin (QU) and of its nanoparticles. The novel QUEN systems were characterized by particle size and morphology, yield and encapsulation efficiency, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), (1)H nuclear magnetic resonance ((1)H NMR), and dissolution study. It was observed that the weight ratio of QU:EE:PVA at 1:10:10 carried a particle size of <85 nm, a particle distribution with polydispersity index <0.3, and its yield and encapsulation efficiency were over 99%. The results from XRD and DSC of the QUEN showed that the crystal of the drug might be converted to an amorphous state. The FT-IR and (1)H NMR demonstrated that QU formed intermolecular hydrogen bonding with carriers. The release of the drug from the QUEN was 74-fold higher compared with the pure drug. In addition, the antioxidant activity of the QUEN was more effective than pure QU on DPPH scavenging, anti-superoxide formation, superoxide anion scavenging, and anti-lipid peroxidation.