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Resveratrol has been extensively reported as a potential compound to treat some skin disorders, including skin cancer, photoaging, allergy, dermatitis, melanogenesis, and microbial infection. There has been an increasing interest in the discovery of cosmetic application using resveratrol as the active ingredient because of its anti-aging and skin lightening activities. The naturally occurring derivatives of resveratrol also exert a beneficial effect on the skin. There are four groups of resveratrol derivatives, including hydroxylated compounds, methoxylated compounds, glycosides, and oligomers. The major mechanism of resveratrol and its derivatives for attenuating cutaneous neoplasia, photoaging and inflammation, are related with its antioxidative activity to scavenge hydroxyl radical, nitric oxide and superoxide anion. A systematic review was conducted to describe the association between resveratrol-related compounds and their benefits on the skin. Firstly, the chemical classification of resveratrol and its derivatives was introduced. In this review the cases which were treated for different skin conditions by resveratrol and the derivatives were also described. The use of nanocarriers for efficient resveratrol skin delivery is also introduced here. This review summarizes the cutaneous application of resveratrol and the related compounds as observed in the cell-based, animal-based and clinical models. The research data in the present study relates to the management of resveratrol for treating skin disorders and suggesting a way forward to achieve advancement in using it for cosmetic and dermatological purpose.

Redox and ultrasonic responsive copolymers MPEG-S-S-P(αN3CL-g-ibu7POSS)x-r-PCLy bearing grafted hydrophobic polyhedral oligomeric silsesquioxane (POSS) were synthesized through a click reaction between MPEG-S-S-P(αN3CL)x-r-PCLy and alkynyl POSS. The morphology revealed that the copolymers underwent micellization or dissociation transitions in response to the reducing agent and ultrasound treatment. The release rate could be substantially increased and adjusted remotely under ultrasound radiation in the presence of dithiothreitol. The nanoparticles exhibited slight toxicity against HeLa cells. After high-intensity focused ultrasound (HIFU) irradiation, DOX-loaded micelles effectively inhibited the proliferation of HeLa cells with a half-maximal inhibitory concentration of 1.1 μg mL−1, and enhanced cellular uptake.

Background It is important to explore the interaction between antibacterial nanoparticles and microbes for understanding bactericidal activity and developing novel applications. It is possible that the nanoparticulate size can govern the antibacterial potency. Purpose The purpose of this study was to evaluate the antimicrobial and antibiofilm properties of cetylpyridinium chloride (CPC)-decorated nanoemulsions against methicillin-resistant Staphylococcus aureus (MRSA). Methods The droplet size could be adjusted by varying the percentage of squalene, the main ingredient of the oily core. Results We fabricated cationic nanoemulsions of three different sizes, 55, 165, and 245 nm. The nanoemulsions showed greater storage stability than the self-assembled CPC micelles. The tested nanoemulsions exhibited more antimicrobial activity against Gram-positive bacteria than Gram-negative bacteria and fungi. The killing of MRSA was mainly induced by direct cell-membrane damage. This rupture led to the leakage of cytoplasmic DNA and proteins. The nanoemulsions might also degrade the DNA helix and disturb protein synthesis. The proteomic analysis indicated the significant downregulation of DNA-directed RNA polymerase (RNAP) subunits β and β'. The antibacterial effect of nanoemulsions increased with decreasing droplet size in the biofilm MRSA but not planktonic MRSA. The small-sized nanoemulsions had potent antibiofilm activity that showed a colony-forming unit (CFU) reduction of 10-fold compared with the control. The loss of total DNA concentration also negatively correlated with the nanoemulsion size. Conclusion The present report established a foundation for the development of squalene@CPC nanosystems against drug-resistant S. aureus.

Aim This paper reports on the incorporation of oleic acid (OA) within nanostructured lipid carriers (OA-NLC) to improve the anti-inflammatory effects in the presence of albumin. Materials and methods NLCs produced via hot high-shear homogenization/ultrasonication were characterized in terms of particle size, zeta potential, and toxicity. We examined the effects of OA-NLC on neutrophil activities. Dermatologic therapeutic potential was also elucidated by using a murine model of leukotriene B4-induced skin inflammation. Results In the presence of albumin, OA-NLC but not free OA inhibited superoxide generation and elastase release. Topical administration of OA-NLC alleviated neutrophil infiltration and severity of skin inflammation. Conclusion OA incorporated within NLC can overcome the interference of albumin, which would undermine the anti-inflammatory effects of OA. OA-NLC has potential therapeutic effects in topical ointments.

Background The rationale of this study is to combine the merits of both albumin nanoparticles and quantum dots (QDs) in improved drug tumor accumulation and strong fluorescence imaging capability into one carrier. However, premature drug release from protein nanoparticles and high toxicity of QDs due to heavy metal leakage are among challenging hurdles. Following this platform, we developed cancer nano-theranostics by coupling biocompatible albumin backbone to CdTe QDs and mannose moieties to enhance tumor targeting and reduce QDs toxicity. The chemotherapeutic water soluble drug pemetrexed (PMT) was conjugated via tumor-cleavable bond to the albumin backbone for tumor site-specific release. In combination, the herbal hydrophobic drug resveratrol (RSV) was preformulated as phospholipid complex which enabled its physical encapsulation into albumin nanoparticles. Results Albumin–QDs theranostics showed enhanced cytotoxicity and internalization into breast cancer cells that could be traced by virtue of their high fluorescence quantum yield and excellent imaging capacity. In vivo, the nanocarriers demonstrated superior anti-tumor effects including reduced tumor volume, increased apoptosis, and inhibited angiogenesis in addition to non-immunogenic response. Moreover, in vivo bioimaging test demonstrated excellent tumor-specific accumulation of targeted nanocarriers via QDs-mediated fluorescence. Conclusion Mannose-grafted strategy and QD-fluorescence capability were beneficial to deliver albumin nanocarriers to tumor tissues and then to release the anticancer drugs for killing cancer cells as well as enabling tumor imaging facility. Overall, we believe albumin–QDs nanoplatform could be a potential nano-theranostic for bioimaging and targeted breast cancer therapy. Electronic supplementary material The online version of this article (10.1186/s12951-019-0445-7) contains supplementary material, which is available to authorized users.

Antrodia cinnamomea exhibits anti-inflammatory, antioxidant, and immunomodulatory activities. We aimed to explore the antipsoriatic potential of 2,4-dimethoxy-6-methylbenzene-1,3-diol (DMD) derived from A. cinnamomea. The macrophages activated by imiquimod (IMQ) were used as the cell model for examining the anti-inflammatory effect of DMD in vitro. A significantly high inhibition of IL-23 and IL-6 by DMD was observed in THP-1 macrophages and bone marrow-derived mouse macrophages. The conditioned medium of DMD-treated macrophages could reduce neutrophil migration and keratinocyte overproliferation. DMD could downregulate cytokine/chemokine by suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs) and NF-κB. We also observed inhibition of GDAP1L1/Drp1 translocation from the cytoplasm to mitochondria by DMD intervention. Thus, mitochondrial fission could be a novel target for treating psoriatic inflammation. A psoriasiform mouse model treated by IMQ showed reduced scaling, erythema, and skin thickening after topical application of DMD. Compared to the IMQ stimulation only, the active compound decreased epidermal thickness by about 2-fold. DMD diminished the number of infiltrating macrophages and neutrophils and their related cytokine/chemokine production in the lesional skin. Immunostaining of the IMQ-treated skin demonstrated the inhibition of GDAP1LI and phosphorylated Drp1 by DMD. The present study provides insight regarding the potential use of DMD as an effective treatment modality for psoriatic inflammation.

Psoriasis is a chronic autoimmune skin disorder that involves keratinocyte hyperproliferation and inflammatory cell recruitment. A strategy to mitigate psoriatic lesions is to induce keratinocyte apoptosis for proliferation suppression. Herein we designed a nanoformulation capable of treating psoriasis via hyperthermia-induced apoptosis in response to near-infrared (NIR) irradiation. To this end, gold nanorods (GNRs) and isatin, which is an anti-inflammatory agent for synergizing antipsoriatic activity, were loaded into a poly (lactic-co-glycolic acid) (PLGA) matrix to form the nanocomplexes. The physicochemical and photothermal properties of the nanocomplexes were determined in terms of size, surface charge, NIR-absorbing feature, isatin release, keratinocyte uptake, and cytotoxicity. The nanocomplexes showed a spherical shape with an average size of about 180 nm. The GNR-loaded nanoparticles can efficiently convert NIR light at 0.42 W/cm2 into heat with an increased temperature of 10 °C. When combined with NIR exposure, the nanocomplexes were internalized into keratinocyte cytoplasm with an inhibition of keratinocyte viability to about 60%. Live/dead cell assay and flow cytometry confirmed that the nanocomplexes could serve as NIR-absorbers to specifically elicit keratinocyte apoptosis through caspase and poly ADP-ribose polymerase (PARP) pathways. The in vivo psoriasiform murine model indicated that the combined nanocomplexes and NIR inhibited epidermal hyperplasia and neutrophil infiltration. The overexpressed cytokines in the lesion could be recovered to normal baseline level after the photothermal management. The subcutaneous nanocomplexes remained in the skin for at least 5 days. The nanocomposites produced a negligible toxicity in the skin or liver of healthy mice. The photothermal nanosystems, as designed in this study, shed new light on the therapeutic approach against psoriasis.

Localized drug delivery to lung cancer can overcome the limitations of systemic nanocarriers including low drug amounts reaching lung tissues and severe off-target toxicity. The current work presented novel inhalable nanocomposites as noninvasive platforms for lung cancer therapy. Nanoparticulate liquid crystals (LCNPs) based on monoolein were developed for synergistic co-encapsulation of the cytotoxic chemotherapeutic drug, pemetrexed, and the phytoherbal drug, resveratrol (PEM-RES-LCNPs). For active tumor targeting, lactoferrin (LF) and chondroitin sulfate (CS), natural polymers with intrinsic tumor-targeting capabilities, were exploited to functionalize the surface of LCNPs using a layer-by-layer (LbL) self-assembly approach. To maximize their deep lung deposition, LF/CS-coated PEM-RES-LCNPs were then microencapsulated within various carriers to obtain inhalable nanocomposites via spray-drying techniques. The inhalable dry powder nanocomposites prepared using a mannitol-inulin-leucine (1:1:1 wt) mixture displayed superior in vitro aerosolization performance (2.72 μm of MMAD and 61.6% FPF), which ensured deep lung deposition. In lung cancer-bearing mice using urethane as a chemical carcinogen, the inhalable LF/CS-coated PEM-RES-LCNP nanocomposites showed superior antitumor activity as revealed by a considerable decrease of the average lung weight, reduced number and diameter of cancerous lung foci, decreased expression of VEGF-1, and increased expression of active caspase-3 as well as reduced Ki-67 expression compared to the spray-dried free PEM/RES powder mixture and positive control. Moreover, the in vivo fluorescence imaging confirmed successful lung deposition of the inhalable nanocomposites. Conclusively, the inhalable liquid crystalline nanocomposites elaborated in the current work could open new avenues for noninvasive lung cancer treatment.

Localized pulmonary delivery of anticancer agents to lungs has proven to be pioneering approach for lung cancer therapy. Hybrid lipid nanocore-protein shell nanoparticles (HLPNPs) coloaded with all-trans retinoic acid (ATRA) and genistein (GNS) were prepared via sequential solvent evaporation followed by nanoprecipitation of zein shell onto the lipid core. The outer protein shell of HLPNPs provided additional drug reservoir for encapsulation of ATRA/stearyl amine ion pair and enabled dual tumor-targeting with biotin and ATRA. Enhanced uptake and cytotoxic activity of HLPNPs against A549 lung cancer cells was confirmed. To improve their deep lung deposition, dual-targeted drug-loaded HLPNP nanocomposites were fabricated. The nanocomposites prepared using mannitol/HPβCD/leucine demonstrated favorable aerosolization (MMAD = 2.47 μm and FPF = 70.81%). In vivo, the inhalable nanocomposites were superior to aerosolized or i.v. nanoparticle suspension against lung carcinoma bearing mice. Overall, inhalable dual-targeted HLPNPs nanocomposites provided localized codelivery of GNS and ATRA for lung cancer therapy.

MXenes have gained rapidly increasing attention owing to their two-dimensional (2D) layered structures and unique mechanical and physicochemical properties. However, MXenes have some intrinsic limitations (e.g., the restacking tendency of the 2D structure) that hinder their practical applications. Transition metal chalcogenide (TMC) materials such as SnS, NiS, MoS2, FeS2, and NiSe2 have attracted much interest for energy storage and conversion by virture of their earth-abundance, low costs, moderate overpotentials, and unique layered structures. Nonetheless, the intrinsic poor electronic conductivity and huge volume change of TMC materials during the alkali metal-ion intercalation/deintercalation process cause fast capacity fading and poor-rate and poor-cycling performances. Constructing heterostructures based on metallic conductive MXenes and highly electrochemically active TMCs is a promising and effective strategy to solve these problems and enhance the electrochemical performances. This review highlights and discusses the recent research development of MXenes and hierarchical MXene/TMC heterostructures, with a focus on the synthesis strategies, surface/heterointerface engineering, and potential applications for lithium-ion batteries, sodium-ion batteries, lithium-sulfur batteries, supercapacitors, electrocatalysis, and photocatalysis. The critical challenges and perspectives of the future development of MXenes and hierarchical MXene/TMC heterostructures for electrochemical energy storage and conversion are forecasted. Nanyang Technological University The authors gratefully acknowledge the financial support from the Basic and Applied Basic Research Foundation of Guangdong Province (2020A1515110928), National Natural Science Foundation of China (51903040), New Faculty Startup Fund of China University of Geosciences (162301202670), and Nanyang Environment and Water Research Institute (Core Fund) at Nanyang Technological University, Singapore.

We investigated the feasibility of densely polyethylene glycol (PEG2000)-modified liposomes as mucus-penetrating particles (MPPs) for oral delivery of systemically absorbed peptides. The oral absorption of MPPs and mucoadhesive liposomes modified with glycol chitosan (GCS) was compared. In an in vitro artificial mucus model, the densely PEGylated liposomes showed mucus permeability. Intracellular uptake of liposomes was evaluated in a Caco-2 and mucus-secreting Caco-2/HT29 co-culture. Intracellular uptake of MPPs was unaffected by mucus in the co-culture system, whereas the cellular uptake of GCS-liposomes was lower with a mucus layer than in Caco-2 alone. Rat in vivo oral absorption of liposomes was evaluated by using fluorescein isothiocyanate dextran (FD) as a model peptide drug. Oral absorption was higher for densely PEGylated than for unmodified liposomes and was PEG-concentration dependent, but excessive PEGylation decreased FD blood concentration. PEGylated liposomes incorporating spermine (SPM) as an absorption enhancer were then designed and showed the highest in vivo absorption of FD of all tested formulations. The pharmacological effects of the oral liposomes were evaluated by using elcatonin and did not correlate with FD oral absorption. The non-PEGylated SPM liposomes showed the highest pharmacological effect, suggesting the need for drug-specific optimization of liposomal components and surface modifiers.

In the foreseeable future, coastal coral reef ecosystems are likely to face further increases in eutrophication. Lipids and fatty acids (FAs), as important components of corals, are becoming a hot topic to study the effects of eutrophication on corals. This study investigated the effects of nitrate (NO3–) enrichment (0, 5, 10, 20, and 40 μM) on the respiration, photosynthesis, and FA compositions of Pocillopora damicornis larvae. Our results showed that saturated FAs (SFAs) were the most abundant in P. damicornis larvae over all treatment groups, followed by polyunsaturated FAs (PUFAs). The unsaturated-to-SFA ratio (U/S) and unsaturation index (UI) reduced at low nitrate concentrations (20 μM). The UI and U/S levels were elevated due to the increased PUFAs levels and decreased SFA levels at higher nitrate concentrations. Compared with the N5 and N10 groups, the fluidity of the biomembrane of the larvae did not continue to decrease but instead increased at higher nitrate concentrations, indicating that the biomembrane restructuring in the larvae may have become ineffective. Moreover, respiration increased and the consumption of numerous lipids led to a significant decrease in TFAs. These could adversely affect the dispersal, settlement, and development of larvae. Overall, P. damicornis larvae can adapt to low levels of nitrate (

Resveratrol was shown to exert anti-inflammatory effects in experimental models of psoriasis. Several natural oligomers of resveratrol have been extracted from plants. We investigated the antipsoriatic activity of topical administration of resveratrol oligomers and explored the effect of the number of resveratrol subunits on skin absorption to establish the structure-permeation relationship (SPR). Three oligomers, e-viniferin (dimer), ampelopsin C (trimer) and vitisin A (tetramer), extracted from Vitis thunbergii root were compared to the resveratrol glycoside polydatin. Delivery to porcine skin was assessed in vitro using the Franz cell. Keratinocytes activated with imiquimod (IMQ) were utilized to evaluate cytokine/chemokine inhibition. Topical application of resveratrol and oligomers was characterized in vivo by assessing cutaneous absorption, skin physiology, proinflammatory mediator expression, and histopathology in IMQ-treated mice. Skin deposition decreased as the molecular size and lipophilicity of the permeants increased. Resveratrol exhibited highest absorption, followed by e-viniferin. The monomers resveratrol and polydatin exhibited higher flux across skin than the larger oligomers. In silico modeling revealed the permeants that strongly interacted with stratum corneum (SC) lipids exhibited lower transport to viable skin and the receptor compartment. In vitro, resveratrol and its derivatives had comparable ability to inhibit IMQ-induced IL-1β, IL-6, and CXCL8 secretion in activated keratinocytes. In vivo, topically applied e-viniferin accumulated at higher levels than resveratrol (0.067 versus 0.029 nmol/mg) in psoriasis-like mouse skin with impaired barrier capacity. Topical e-viniferin alleviated psoriasiform symptoms and reduced IL-23 secretion (by 58% vs. 37%) more effectively than resveratrol. e-Viniferin has potential as an anti-inflammatory agent to prevent or treat psoriasis.

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.

Aim: We aimed to develop nanoemulsions containing phosphodiesterase 4 inhibitor rolipram with different droplet sizes, to evaluate the anti-inflammatory effect against activated neutrophils and a related lung injury. Materials & methods: We prepared nanoemulsions of three different sizes, 68, 133 and 188 nm. Results: The nanoemulsion inhibited the superoxide anion but not elastase release in primary human neutrophils. The large-sized nanoemulsions were mostly internalized by neutrophils, resulting in the reduction of intracellular Ca2+ half-life. The peripheral organ distribution of near-infrared dye-tagged nanoemulsions increased, following the decrease in droplet diameter. Rolipram entrapment into intravenous nanoemulsions ameliorated pulmonary inflammation. The smallest droplet size showed improvement, compared with the largest size. Conclusion: We established a foundation for the development of nanoemulsions against inflamed lung disease.

Polycyclic aromatic hydrocarbons (PAHs) can induce skin toxicity. Although some investigations have been conducted to assess the skin toxicity of different PAHs, few comparisons using a series of PAHs with different ring numbers and arrangements have been done. We aimed to explore the skin absorption of 6 PAH compounds and their effect on cutaneous inflammation. In vitro skin permeation was rated by Franz cell with pig skin. Molecular docking was employed to compute the PAH interaction with stratum corneum (SC) lipids. Cultured keratinocytes were exposed to PAHs for analyzing cytotoxicity, cyclooxygenase (COX)-2, prostaglandin E2 (PGE2), chemokines, and differentiation proteins. The in vivo topical PAH exposure in mice was characterized by skin absorption, transepidermal water loss (TEWL), PGE2 level, and histology. The skin deposition from the aqueous vehicle increased following the increase of PAH lipophilicity and molecular size, with benzo[a]pyrene (5-ring PAH) showing the greatest absorption. Pyrene was the compound showing the highest penetration across the skin (flux). Although the PAHs fluoranthene, pyrene, chrysene, and 1,2-benzanthracene all had 4 rings, the skin permeation was quite different. 1,2-Benzanthracene showed the greatest absorption among the 4-ring compounds. The PAHs with higher absorption exhibited stronger interaction with SC lipids according to the in silico modeling. Chrysene and 1,2-benzanthracene generally showed the highest COX-2 and PGE2 expression, followed by benzo[a]pyrene. The lowest COX-2 and PGE2 upregulation was observed for naphthalene (2-ring PAH). A contrary tendency was detected for the upregulation of chemokines. Filaggrin and integrin β1 in keratinocytes were suppressed at a comparable level by all PAHs. The skin’s absorption of PAHs showed strong in vivo–in vitro correlation. 1,2-Benzanthracene and benzo[a]pyrene highly disrupted the skin barrier and elevated the inflammation in vivo. The tendency toward in vivo inflammation caused by various PAHs could be well predicted by the combined estimation using in vitro skin absorption and a keratinocyte bioassay. This study also established the structure–permeation relationship (SPR) of PAHs.

Twelve novel 7-diethylaminocoumarin-based 1,3,4-oxadiazole derivatives were synthesized via iodine-mediated oxidative cyclisation and confirmed by 1H NMR, 13C NMR and HRMS. The result of these derivatives' activities inhibiting acetylcholinesterase in vitro showed that 4 g and 4i had moderate inhibitory activities with 69.19% and 65.06%, respectively. The preliminary structure-activity relationships revealed that introduction of halogen atom on the para-position of phenyl of 7-diethylaminocoumarin-based 1,3,4-oxadiazole derivatives could enhance their activities. Molecular docking study suggested that 4 g possessed an optimal docking pose with interactions inside AChE.

Background/Aims: 2-O-methylmagnolol (MM1), a derivative of magnolol bearing one methoxy moiety, has been shown to display improved anti-tumor activity against skin cancers. In this study, we examined the anti-tumor effects of magnolol and MM1 on oral squamous cell carcinoma (OSCC). Methods: Trypane blue staining and clonogenic assays were performed to determine the cytotoxic effects of magnolol and MM1 in OSCC cells. Migration and matrigel invasion assays were carried out to examine the metastasis effects of magnolol and MM1 in OSCC cells. IL6-stimulation, Western blot, and immunohistochemistry were used to investigate the IL-6/STAT3 signaling and apoptosis. A bioluminescent mouse model of orthotopically implanted SAS cells was used to determine the anti-tumor activity of MM1 in vivo. Results: MM1 displays greater activity than magnolol on affecting the cytotoxicity, migration, and invasion of OSCC cells cultured in vitro. The improved anti-tumor activity of MM1 was shown to associate with its greater activity to inhibit STAT3 signaling and to induce apoptosis in the OSCC. In addition, we presented evidence that MM1 is effective in inhibiting the growth of orthotopic implanted OSCC cells in vivo. Conclusion: Our data indicate that MM1 displays greater anti-tumor activity than magnolol in OSCC and is an attractive agent to be further explored for its potential clinical application.

In recent years, green nanomedicines have made transformative difference in cancer therapy researches. Herein, we propose dual-functionalized spray-dried casein micelles (CAS-MCs) for combined delivery of two phytochemicals; berberine (BRB) and diosmin (DSN) as targeted therapy of hepatocellular carcinoma (HCC). The nanomicelles enabled parenteral delivery of the poorly soluble DSN via its encapsulation within their hydrophobic core. Moreover, sustained release of the water soluble BRB was attained by hydrophobic ion pairing with sodium deoxycholate followed by genipin crosslinking of CAS-MCs. Dual-active targeting of MCs, via conjugating both lactobionic acid (LA) and folic acid (FA), resulted in superior cytotoxicity and higher cellular uptake against HepG2 cells compared to single-targeted and non-targeted CAS-MCs. The dual-targeted DSN/BRB-loaded CAS-MCs demonstrated superior in vivo anti-tumor efficacy in HCC bearing mice as revealed by down regulation of cell necrosis markers (NF-κB and TNF-α), inflammatory marker COX2, inhibition of angiogenesis and induction of apoptosis. Histopathological analysis and immunohistochemical Ki67 staining confirmed the superiority of the dual-targeted micelles. Ex-vivo imaging showed preferential liver-specific accumulation of dual-targeted CAS-MCs. Overall, this approach combined the benefits of traditional herbal medicine with nanotechnology via LA/FA-CAS-MCs loaded with BRB and DSN as a promising nanoplatform for targeted HCC therapy.

The self-tumor targeting polymers, lactoferrin (LF) and hyaluronic acid (HA) were utilized to develop layer-by-layer (LbL) lipid nanoparticles (NPs) for dual delivery of berberine (BER) and rapamycin (RAP) to lung cancer. To control its release from the NPs, BER was hydrophobically ion paired with SLS prior to incorporation into NPs. Spherical HA/LF-LbL-RAP-BER/SLS-NPs 250.5 nm in diameter, with a surface charge of −18.5 mV were successfully elaborated. The NPs exhibited sequential release pattern with faster release of BER followed by controlled release of RAP which enables sensitization of lung tumor cells to the anti-cancer action of RAP. LbL coating of the NPs was found to enhance the drug cytotoxicity against A549 lung cancer cells as augmented by remarkable increase in their cellular internalization through CD44 receptors overexpressed by tumor cells. In vivo studies in lung cancer bearing mice have revealed the superior therapeutic activity of LbL-RAP-BER/SLS-NPs over the free drugs as demonstrated by 88.09% reduction in the average number of microscopic lung foci and 3.1-fold reduction of the angiogenic factor VEGF level compared to positive control. Overall, the developed HA/LF-LbL-coated lipid NPs could be potential carriers for targeted co-delivery of BER and RAP to lung cancer cells.

Etoposide (ETP), as a potential treatment for lung cancer, has limited application due to its poor solubility, and systemic side effects. In the current study, we propose inhalable boronate-targeted HSA nanocomposites for combined delivery of ETP and the herbal drug, berberine (BER) for localized therapy of lung cancer. First, ETP was pre-formulated as phospholipid complex (EPC) to enhance drug solubility and facilitate its encapsulation within the hydrophilic albumin nanoparticles (NPs). Second, EPC and BER were then co-loaded with high efficiency into HSA NPs as a synergistic therapy for lung cancer. The NPs displayed suitable size around 200 nm and sequential drug release pattern. Moreover, conjugation of aminophenylboronic acid (APBA) to HSA NPs resulted in enhanced cytotoxicity and internalization into A549 lung cancer cells, compared to non-targeted NPs or free drugs via binding to sialic acid residues over-expressed by cancer cells. Using mannitol as a spray-drying carrier, the developed inhalable nanocomposites demonstrated deep pulmonary deposition, confirmed by small MMAD (2.112 μm) and high FPF (77.86%). In vivo investigations in lung cancer animal models revealed the superior anti-tumor efficacy of the inhalable nanocomposites. Overall, the inhalable APBA-HSA nanocomposites offered an alternative strategy for systemic delivery of ETP and BER in lung cancer therapy.

Real-time monitoring and controlled release of drugs are key factors in drug delivery. In this study, versatile fluorescence triple-responsive block-graft copolymers PNiPAAm-S-S-P(αN3CL-g-alkyne)n with a disulfide (S S) bond as a junction point between the hydrophilic and hydrophobic chains bearing cholesteryl- and pyrenyl- side groups were synthesized. The polymer was temperature-sensitive with a lower critical solution temperature in the range of 36 °C to 44 °C. When the polymer solution was treated with reducing agents and exposed to ultrasound, significant hydrolysis of the amide bonds was noted. The partial destruction of micelles in the presence of a reducing agent and ultrasound was observed through transmission electron microscopy. The copolymers containing cholesteryl and pyrenyl possessed highly drug loading content and entrapment efficiency. Above the lower critical solution temperature, the release rate could be greatly increased and adjusted remotely under high- intensity focused ultrasound in the presence of dithiothreitol. The nanoparticles exhibited slight toxicity against HeLa cells in the concentration range of 10–300 μg mL−1. Doxorubicin (DOX)-loaded micelles facilitated the uptake of DOX by HeLa cells and were predominantly retained in the cytoplasm.

Aim: Whether the obesity prevention by chemicals or surgeries in already obese patients is the better choice remains controversial. We aimed to compare the effect of orally silibinin-loaded nanocarriers and Roux-en-Y gastric bypass surgery on hepatic fibrosis in high-fat feeding-induced obese rats. Methodology: The developed nanocarriers included self-emulsifying drug delivery system (SNEDDS) and nanostructured lipid carriers (NLC). Results: A significant decrease in collagen production and lipid droplet formation was observed upon nanosystem and bariatric surgery than the rats treated with silibinin control suspension. Stage 3 fibrosis was present in 33% of the obese rats. This percentage could be minimized to 0% by SNEDDS and NLC. Following oral administration, SNEDDS and NLC resulted in 3.5- and 2.9-fold increase, respectively, in bioavailability compared with the reference suspension. Conclusion: Nanomedicine prevention provided a comparable efficiency to ameliorate liver steatosis as Roux-en-Y gastric bypass due to the improvement of silibinin dissolution and gastrointestinal permeation.

The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application.

C67H49Cl3N6O18, triclinic, P1̄ (no. 2), a = 12.3281(4) Å, b = 15.8887(5) Å, c = 16.9037(6) Å, α = 89.015(2)°, β = 77.885(3)°, γ = 72.021(3)°, V = 3075.20(19) Å3, Z = 2, R gt(F) = 0.0658, wR ref(F 2) = 0.1558, T = 291.2(3) K.

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 μM. Inhibition was increased in the order of curcumin &lt, DMC &lt, BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 μM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.

Ching-Yun Hsu,1,2,* Shih-Chun Yang,3,4,* Calvin T Sung,5 Yi-Han Weng,4 Jia-You Fang2,4,6,7 1Department of Nutrition and Health Sciences, 2Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, 3Department of Cosmetic Science, Providence University, Taichung, 4Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taiwan; 5School of Medicine, University of California, Riverside, CA, USA; 6Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, 7Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taiwan *These authors contributed equally to this work Abstract: Pathogens usually invade hair follicles when skin infection occurs. The accumulated bacteria in follicles are difficult to eradicate. The present study aimed to assess the cutaneous and follicular delivery of chloramphenicol (Cm)-loaded liposomes and the antibacterial activity of these liposomes against methicillin-resistant Staphylococcus aureus (MRSA). Skin permeation was conducted by in vitro Franz diffusion cell. The anti-MRSA potential was checked using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), a well diffusion test, and intracellular MRSA killing. The classic, dimyristoylphosphatidylcholine (DMPC), and deoxycholic acid (DA) liposomes had a vesicle size of 98, 132, and 239 nm, respectively. The incorporation of DMPC or DA into the liposomes increased the bilayer fluidity. The malleable vesicles containing DMPC and DA showed increased follicular Cm uptake over the control solution by 1.5- and 2-fold, respectively. The MIC and MBC of DA liposomes loaded with Cm were 62.5 and 62.5–125 µg/mL, comparable to free Cm. An inhibition zone about 2-fold higher was achieved by DA liposomes as compared to the free control at a Cm dose of 0.5 mg/mL. DA liposomes also augmented antibacterial activity on keratinocyte-infected MRSA. The deformable liposomes had good biocompatibility against keratinocytes and neutrophils (viability >80%). In vivo administration demonstrated that DA liposomes caused negligible toxicity on the skin, based on physiological examination and histology. These data suggest the potential application of malleable liposomes for follicular targeting and the treatment of MRSA-infected dermatologic conditions. Keywords: chloramphenicol, malleable liposomes, deoxycholic acid, hair follicle, MRSA, antibacterial activity

Acute lung injury (ALI) is a respiratory disease that is associated with neutrophil activation. Neutrophil elastase released from activated neutrophils has been reported to cause lung tissue damage and contribute to the inflammatory response in ALI. In this study, aqueous extracts of Kochia scoparia fruits, a traditional botanical medicine and food garnish in Asia, showed a selective inhibitory effect on human neutrophil elastase (IC50, 79.53 ± 4.26 μg mL−1). Using bioactivity-guided fractionation, the polysaccharide fraction (KSWP, molecular weight > 300 kDa) was identified, and its protective effects against ALI were investigated. The results showed that KSWP protected mice from lipopolysaccharide-induced ALI by reducing elastase activity, neutrophil infiltration, pro-inflammatory cytokines, and neutrophil NET formation. In addition, KSWP showed high safety parameters in toxicity tests. These results conclusively demonstrate the high potency of KSWP as a component of functional foods or botanical products in the prevention of ALI.

Remodelling of lymphatic vessels in tumours facilitates metastasis to lymph nodes. The growth factors VEGF-C and VEGF-D are well known inducers of lymphatic remodelling and metastasis in cancer. They are initially produced as full-length proteins requiring proteolytic processing in order to bind VEGF receptors with high affinity and thereby promote lymphatic remodelling. The fibrinolytic protease plasmin promotes processing of VEGF-C and VEGF-D in vitro, but its role in processing them in cancer was unknown. Here we explore plasmin’s role in proteolytically activating VEGF-D in vivo, and promoting lymphatic remodelling and metastasis in cancer, by co-expressing the plasmin inhibitor α2-antiplasmin with VEGF-D in a mouse tumour model. We show that α2-antiplasmin restricts activation of VEGF-D, enlargement of intra-tumoural lymphatics and occurrence of lymph node metastasis. Our findings indicate that the fibrinolytic system influences lymphatic remodelling in tumours which is consistent with previo...

Aim: Nanovesicles (NVs) conjugating ligands can deliver to the specific nidus. We designed a nanosystem targeting the injectable niosomes to liver for examining biodistribution. Methodology: Vitamin A and antiplatelet-derived growth factor receptor antibody were employed as the ligands to be taken by hepatic stellate cells. The biodistribution in rats was visualized by bioimaging. Results: A significant liver accumulation was detected for antibody-embedded NVs at 2 h after dosing. The vitamin A embedded NVs exhibited a delayed targeting to the liver (5 h). The spleen, intestine and kidneys were the nontargeted organs where the vitamin A loaded niosomes largely accumulated. The antibody-loaded NVs could deliver to the spleen, kidneys and lungs. The antibody-loaded nanocarriers increased silibinin uptake to lungs by fourfold than the plain NVs. Conclusion: The results have practical application for better designing of active targeting nanocarriers.

Background: Vascular endothelial growth factor (VEGF) is upregulated by hypoxia and is a crucial stimulator for choroidal neovascularization (CNV) in age-related macular degeneration and pathologic myopia, as well as retinal neovascularization in proliferative diabetic retinopathy. Retinal and choroidal endothelial cells play key roles in the development of retinal and CNV, and subsequent fibrosis. At present, the effects of gold nanoparticles (AuNPs) on the VEGF-induced choroid-retina endothelial (RF/6A) cells are still unknown. In our study, we investigated the effects of AuNPs on RF/6A cell viabilities and cell adhesion to fibronectin, a major ECM protein of fibrovascular membrane. Furthermore, the inhibitory effects of AuNPs on RF/6A cell migration induced by VEGF and its signaling were studied. Methods: The cell viability assay was used to determine the viability of cells treated with AuNPs. The migration of RF/6A cells was assessed by the Transwell migration assay. The cell adhesion to fibronectin was examined by an adhesion assay. The VEGF-induced signaling pathways were determined by western blotting. Results: The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay revealed no cytotoxicity of AuNPs on RF/6A cells. AuNPs inhibited VEGF-induced RF/6A cell migration in a concentration-dependent manner but showed no significant effects on RF/6A cell adhesion to fibronectin. Inhibitory effects of AuNPs on VEGF-induced Akt/eNOS were found. Conclusions: These results suggest that AuNPs are an effective inhibitor of VEGF-induced RF/6A cell migration through the Akt/eNOS pathways, but they have no effects on their cell viabilities and cell adhesion to fibronectin.

Methicillin-resistant Staphylococcus aureus (MRSA) is the primary microbe responsible for skin infections that are particularly difficult to eradicate. This study sought to inhibit planktonic and biofilm MRSA using furanoquinone-derived compounds containing imine moiety. A total of 19 furanoquinone analogs were designed, synthesized, and assessed for anti-MRSA potency. Among 19 compounds, (Z)-4-(hydroxyimino)naphtho[1,2-b]furan-5(4H)-one (HNF) and (Z)-4-(acetoxyimino)naphtho[1,2-b]furan-5(4H)-one (ANF) showed antibacterial activity superior to the others based on an agar diffusion assay. HNF and ANF exerted a bactericidal effect with a minimum inhibitory concentration (MIC) of 9.7 ∼ 19.5 and 2.4 ∼ 9.7 μg/ml, respectively. Both compounds were able to reduce the MRSA count by 1,000-fold in biofilm as compared to the control. In vivo efficacy was evaluated using a mouse model of skin infection. Topical application of lead compounds significantly suppressed abscess occurrence and the MRSA burden, and also ameliorated the skin-barrier function. The biochemical assay indicated the compounds’ inhibition of DNA polymerase and gyrase. In silico docking revealed a favorable interaction of the compounds with DNA polymerase and gyrase although the binding was not very strong. The total DNA analysis and proteomic data suggested a greater impairment of some proteins by HNF than ANF. In general, HNF and ANF were similarly potent in MRSA inhibition in vitro and in vivo. The findings demonstrated that there was room for structural modification of furanoquinone compounds that could be used to identify anti-MRSA agent candidates.

Natural products or herbs can be used as an effective therapy for treating psoriasis, an autoimmune skin disease that involves keratinocyte overproliferation. It has been demonstrated that phytomedicine, which is used for psoriasis patients, provides some advantages, including natural sources, a lower risk of adverse effects, and the avoidance of dissatisfaction with conventional therapy. The herbal products’ structural diversity and multiple mechanisms of action have enabled the synergistic activity to mitigate psoriasis. In recent years, the concept of using natural products as antiproliferative agents in psoriasis treatment has attracted increasing attention in basic and clinical investigations. This review highlights the development of an apoptotic or antiproliferatic strategy for natural-product management in the treatment of psoriasis. We systematically introduce the concepts and molecular mechanisms of keratinocyte-proliferation inhibition by crude extracts or natural compounds that were isolated from natural resources, especially plants. Most of these studies focus on evaluation through an in vitro keratinocyte model and an in vivo psoriasis-like animal model. Topical delivery is the major route for the in vivo or clinical administration of these natural products. The potential use of antiproliferative phytomedicine on hyperproliferative keratinocytes suggests a way forward for generating advances in the field of psoriasis therapy.

Photo-cleavable polymers containing 5-hydroxy-2-nitrobenzyl alcohol (ONB) junction point between the target molecule of folic acid (FA) and the hydrophobic poly(4-substituted-ɛ-caprolactone) (PXCLn) chain were synthesized. FA –terminated ONB-PXCLn polymers formed micelles with critical micelle concentration (CMC) 1.2 – 64.3 mg L−1. Fluorescence emission spectroscopy indicated the release of Nile red encapsulated FA-ONB-PXCLn micelles in response to irradiation. Light-triggered bursts released were observed for drug-loaded FA-ONB-PXCLn micelles. The nanoparticles exhibited nonsignificant toxicity at concentrations up to 300 µg mL−1. Flow cytometry revealed that the uptake of folate-targeted doxorubicin (DOX) -encapsulated micelles by HeLa cells was faster than that of free DOX.

TiO2 acts as an inorganic sunscreen and photocatalyst to protect humans from environmental pollutants. We incorporated TiO2 into mesoporous silica (SBA-15) for skin application to prevent environmental stresses including UVA irradiation and pollutant invasion. Organic ultraviolet (UV)A filters such as avobenzone and oxybenzone were then loaded into mesoporous support for synergistic sunscreen efficiency. The as-prepared formulations with different TiO2 amounts (10 %-50 %) were fabricated. The pore size decreased from 4.72 to 4.00 nm following the increase in TiO2 percentage. TiO2/SBA-15 captured about 60 % fluoranthene and 80 % furfural within 3 h with no significant difference due to different TiO2 content. The in vitro photoprotection assessed by UVA/UVB ratio exhibited the increase in Boots star rating from 2 to 3 to 5 by entrapment of avobenzone into TiO2/SBA-15. Thirty-percent TiO2/SBA-15 in hydrogel decreased avobenzone and oxybenzone deposition by 70 % and 80 % compared to free form, respectively. Avobenzone and TiO2 supplementation to SBA-15 significantly alleviated skin cell death and neutrophil recruitment in the photoaged mouse skin compared to the SBA-15 application alone. Compared to the UVA-irradiated skin, 30 % TiO2/SBA-15 showed a 2.5- and 3.1-fold decline in IL-1β and IL-6 levels, respectively. The TiO2/SBA-15 hybrid was considered non-irritant based on results of cytotoxicity assay, skin histology, and cutaneous barrier function. Our data indicate that the versatile mesoporous silica is an effective system for topical use in sunscreen and skin protection.

Zih-Chan Lin,1,* Chiang-Wen Lee,2,3,* Ming-Horng Tsai,4 Horng-Huey Ko,5 Jia-You Fang,1,2 Yao-Chang Chiang,6,7 Chan-Jung Liang,8,9 Lee-Fen Hsu,10 Stephen Chu-Sung Hu,11,12 Feng-Lin Yen5,8,13 1Graduate Institute of BioMedical Sciences, Chang Gung University, 2Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, 3Division of Basic Medical Sciences, Department of Nursing, Chang Gung Institute of Technology and Chronic Diseases and Health Promotion Research Center, Chiayi, 4Division of Neonatology and Pediatric Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Yunlin, 5Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 6Center for Drug Abuse and Addiction, China Medical University Hospital, 7Center for Drug Abuse and Addiction, China Medical University, Taichung, 8Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, 9Center for Lipid Biosciences, Kaohsiung Medical University Hospital, 10Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, 11Department of Dermatology, College of Medicine, Kaohsiung Medical University, 12Department of Dermatology, Kaohsiung Medical University Hospital, 13Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, Republic of China *These authors contributed equally to this work Abstract: 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. Keywords: eupafolin, nanoparticles, particulate matter, oxidative stress, cyclooxygenase-2, keratinocytes

Eupafolin is a major bioactive compound derived from the methanolic extract of the medicinal herb Phyla nodiflora, which has been used in traditional Chinese medicine to treat various inflammatory diseases. Recently, particulate air pollutants have been shown to induce inflammation of the skin. In this study, we seek to determine whether eupafolin can inhibit the production of inflammatory mediators in a human skin keratinocyte cell line exposed to particulate air pollutants (particulate matter, PM), and determine the molecular mechanisms involved.Human keratinocyte HaCaT cells were treated with PM in the presence or absence of eupafolin. Cyclooxygenase-2 (COX-2) protein and gene expression levels were determined by Western blotting, RT-PCR and luciferase activity assay. Prostaglandin E2 (PGE2) production was evaluated by the enzyme immunoassay method. Generation of intracellular reactive oxygen species (ROS) was measured by the dichlorofluorescin (DCFH) oxidation assay, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was determined by a chemiluminescence assay. For in vivo studies, COX-2 expression in the skin of BALB/c nude mice was analyzed by immunohistochemistry.Eupafolin inhibited PM-induced COX-2 protein and gene expression and PGE2 production in HaCaT cells. In addition, eupafolin suppressed PM-induced intracellular ROS generation, NADPH oxidase activity, MAPK (ERK, JNK and p38) activation and NK-κB activation. In vivo studies showed that topical treatment with eupafolin inhibited COX-2 expression in the epidermal keratinocytes of PM-treated mice.Eupafolin exerts anti-inflammatory and antioxidant effects on skin keratinocytes exposed to particulate air pollutants, and may have potential use in the treatment or prevention of air pollutant-induced inflammatory skin diseases in the future.

BACKGROUND The serum uric acid (SUA) is the end-product from the metabolic breakdown of purine nucleotides. It has been considered to be a prognostic factor for malignant tumor in several researches. However, its prognostic value in patients with esophageal squamous cell carcinoma (ESCC) has not been elucidated. METHODS We retrospectively reviewed the records of 209 ESCC patients who underwent R0 esophagectomy. A receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off value for pre-operative SUA levels and to divide the ESCC patients into two groups. Furthermore, we analyzed the pre-operative serum uric acid (SUA) levels and its relationship with the clinicopathological parameters and the prognosis of 209 ESCC patients. RESULTS Optimal cut-off value for pre-operative SUA in ROC analysis was 304.5 μ mol/l (sensitivity 67.46%, specificity 65.06%). SUA low- or high-levels were associated with gender (P< 0.001), smoking status (P< 0.001), pN statues (P= 0.003) and TNM stage (P= 0.010). SUA levels, tumor differentiation and pTNM stage were independent predictors of ESCC patient survival in a multivariate analysis. CONCLUSIONS The pre-operative level of SUA is an independent prognostic predictor in ESCC patients who undergo R0 esophagectomy and patients with higher SUA level may have an unfavorable survival probability.

As a continuing effort to elucidate the impact of structure modification upon cutaneous absorption behavior, we attempted to assess the skin permeation of magnolol by methylation and acetylation.Diacetylmagnolol and 2-O-acetyl-2'-O-methylmagnolol (AMM) were designed and synthesized in this study. The anti-inflammatory activity against stimulated neutrophils and keratinocytes was evaluated to check the bioactivity of the analogues. In vitro skin absorption was investigated using nude mouse and pig skin models at both equimolar and saturated doses.Magnolol generally showed the strongest anti-inflammatory potential, followed by diacetylmagnolol and AMM. The antibacterial activity was observed for magnolol and diacetylmagnolol but not AMM. Diacetylmagnolol and AMM could be partly hydrolyzed to magnolol and 2-O-methylmagnolol after entering the skin. The hydrolysis rate of diacetylmagnolol was faster than that of AMM. The lipophilicity played a crucial role in cutaneous absorption, with AMM exhibiting the highest skin deposition. AMM accumulation within nude mouse skin was about 2.5-fold greater than that of magnolol and diacetylmagnolol. On the other hand, the transdermal penetration across the skin was lessened by methylation and esterification. This led to a superior skin targeting of AMM. Although the pharmacological activity of AMM was low, the high skin uptake and bioconversion into 2-O-methylmagnolol in the skin contributed to a greater therapeutic index (TI, skin deposition x inflammatory inhibition percentage) compared to the others. The accumulation of AMM in the hair follicles was 77.12 nmol/cm(2), which was significantly greater than that with magnolol (44.84 nmol/cm(2)) and diacetylmagnolol (26.96 nmol/cm(2)). The synthetic analogues were tolerable to the nude mouse skin.Based on the experimental results, we may suggest topically applied AMM as a potent and safe candidate for the treatment of cutaneous inflammation.

New dual-stimuli-responsive and bio-recognizable glycopolymers (Glyco-ONB-s-s-PXCL) containing a photodegradable 5-hydroxy-2-nitrobenzyl alcohol (ONB), and a redox-cleavable disulfide (-s-s-) as junction point between bio-recognizable hydrophilic sugar molecule (Glyco) and hydrophobic poly(4-substituted-e-caprolactone) (PXCL) chains were synthesized using a combination of ring-opening polymerization and nucleophilic substitution reactions. When the polymer solution was exposed to ultraviolet (UV) irradiation and/or the reducing agent DL-dithiothreitol (DTT), substantial structural and morphological changes were observed in the particles. The polymers formed micelles in the aqueous solution, had hydrodynamic sizes ≤200 nm, and were spherical. Under the combined stimulation of UV irradiation and DTT, the micellar nanoparticles dissociated and the loaded molecules could be released from the assemblies more efficiently than under the stimulation of only one of the two stimuli. Selective lectin binding experiments confirmed that glucosylated Gluco-ONB-s-s-PXCL can be used for bio-recognition. The nanoparticles exhibited nonsignificant toxicity against HeLa cells at concentrations of ≤300 μg mL−1. The DOX-loaded Gluco-ONB-s-s-PMCL20 micelles effectively inhibited the proliferation of HeLa cells with a half-maximal inhibitory concentration (IC50) of 1.5 μg mL−1.

Herein we report promoted anti-cancer activity via a combination strategy of synergistic chemotherapy/retinoid-based breast cancer therapy with shell-stabilized micellar green nanomedicine. Amphiphilic zein-chondroitin sulfate (ChS)-based copolymeric micelles (PMs) were successfully developed via carbodiimide coupling for concomitant delivery of etoposide (ETP) and all-trans retinoic acid (ATRA) to breast cancer. The micelles exhibited low critical micellar concentration (CMC) of 0.008 mg/mL with high encapsulation efficiencies of ETP and ATRA (61.2 and 84.29%, respectively). Calcium-mediated crosslinking of the anionic ChS micellar shell resulted in prolonged drug release with small micellar size of 222.7 nm. The micelles exhibited augmented internalization into MCF-7 breast cancer cells by virtue of ChS binding affinity to CD44 receptors overexpressed by cancer cells. Consequently, the ETP/ATRA-loaded micelles exhibited synergistic cytotoxicity against breast cancer cells as revealed by their significantly lower IC50, combination index (CI), and higherdose reduction index (DRI) in comparison to the free ETP and free ATRA or their combination. Micelles displayed superiority in reducing tumor volume, decreasing proliferation, and promoting necrosis in mice bearing Ehrlich Ascites Tumor (EAT) upon comparison to free ETP and free ATRA or their combination. Overall, the developed green zein-ChS micelles offer a promising platform for tumor-targeted delivery of hydrophobic therapeutic agents.

Flavonoids inhibit skin inflammation. Previous study suggests that the flavonoids with flavanone backbone were beneficial to penetrate into the skin. We aimed to investigate the possibility of psoriasis treatment by topically applied flavanone and its derivatives including naringenin, hesperetin, 6-hydroxyflavanone, flavanone, and 6-bromoflavone. The skin absorption of the compounds was determined by Franz cells. Molecular modeling was used to compute the physicochemical and molecular parameters of the penetrants in order to elucidate the correlation between structure and permeation. Among the compounds tested, flavanone showed the greatest skin absorption. The in vitro skin absorption predicted efficient skin targeting of 6-bromoflavone with minimal risk of circulation absorption. The permeation of naringenin was remarkably enhanced 13-fold in the barrier-defective skin mimicking inflamed skin. The penetrants with fewer hydrogen bond number, total polarity surface, and molecular volume were advantageous for facile skin absorption. In the cell-based study, IL-1β inhibition in imiquimod (IMQ)-stimulated keratinocytes was increased following the increase in compound lipophilicity. Naringenin, a flavanone analog with three hydroxyl moieties, could suppress IL-6 overexpression to baseline control. We assessed the anti-inflammatory potency of the chemicals in comparison with tacrolimus as reference in a psoriasis-like mouse model. Flavanone was found to mitigate scaling and epidermal hyperplasia at a higher level than naringenin. Flavanone lessened IL-6 overexpression by 80% in the psoriasiform plaque. The skin barrier function recorded by transepidermal water loss (TEWL) was recovered by naringenin but not flavanone. The experimental data indicate that naringenin and flavanone are potential candidates for anti-psoriatic therapy.

Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids show anti-inflammatory activity for treating inflamed skin diseases, but their efficacy remains low. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis model. OA played dual roles in the nanocarriers as both the active ingredient and lipid matrix in the nanoparticulate core. OA nanoparticles but not free OA could restrain calcium mobilization in activated neutrophils. The inhibition level of superoxide anion and elastase by cilomilast-loaded OA nanocarriers approximated that of free forms. In the mouse model, the intradermal nanosystems reduced imiquimod-induced epidermal thickening from 230.4 to 63.1 μm. Transepidermal water loss was decreased from 30.2 to 11.3 g/m2/h by integrated nanocarriers. The nanosystems mitigated neutrophil infiltration and hyperproliferation in the psoriasiform lesion via decreased expression of cytokines and chemokines. Statement of Significance The long-term therapy for psoriasis is unsatisfactory due to the possible adverse effects and inefficiency after prolonged use. Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids such as oleic acid (OA) show anti-inflammatory activity for treating inflamed skin diseases. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. OA is also ideal for incorporation into nanoparticles to enhance particulate emulsification, drug entrapment, and biocompatibility. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis lesion. OA nanocarriers are indigenous to prevent neutrophil activation and the deterioration of psoriatic lesion. Cilomilast incorporation in OA nanocarriers could further mitigate the clinical score and suppressing proinflammatory mediators.

Fish oil has been broadly reported as a potential supplement to ameliorate the severity of some skin disorders such as photoaging, skin cancer, allergy, dermatitis, cutaneous wounds, and melanogenesis. There has been increasing interest in the relationship of fish oil with skin protection and homeostasis, especially with respect to the omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). The other PUFAs, such as α-linolenic acid (ALA) and linoleic acid (LA), also show a beneficial effect on the skin. The major mechanisms of PUFAs for attenuating cutaneous inflammation are the competition with the inflammatory arachidonic acid and the inhibition of proinflammatory eicosanoid production. On the other hand, PUFAs in fish oil can be the regulators that affect the synthesis and activity of cytokines for promoting wound healing. A systemic review was conducted to demonstrate the association between fish oil supplementation and the benefits to the skin. The following describes the different cosmetic and therapeutic approaches using fatty acids derived from fish oil, especially ALA, LA, DHA, and EPA. This review summarizes the cutaneous application of fish oil and the related fatty acids in the cell-based, animal-based, and clinical models. The research data relating to fish oil treatment of skin disorders suggest a way forward for generating advances in cosmetic and dermatological uses.

Bio-recognizable and photocleavable amphiphilic glycopolymers and prodrugs containing photodegradable linkers (i.e. 5-hydroxy-2-nitrobenzyl alcohol) as junction points between bio-recognizable hydrophilic glucose (or maltose) and hydrophobic poly(α-azo-e-caprolactone)-grafted alkyne or drug chains were synthesized by combining ring-opening polymerization, nucleophilic substitution, and “click” post-functionalization with alkynyl-pyrene and 2-nitrobenzyl-functionalized indomethacin (IMC). The block-grafted glycocopolymers could self-assemble into spherical photoresponsive micelles with hydrodynamic sizes of

8‑Methoxypsoralen (8-MOP) in combination with ultraviolet A (PUVA) is a photochemotherapy for management of psoriasis. 8-MOP is a natural compound from Psoralea corylifolia. The present work was undertaken to evaluate the percutaneous absorption of five compounds derived from P. corylifolia, and to further explore the inhibitory effect on psoriasis-like lesions generated by imiquimod stimulation in a mouse model. 8-MOP, psoralen, isopsoralen, psoralidin, and bakuchiol were comparatively tested for in vitro skin permeation, keratinocyte apoptosis, and in vivo antipsoriatic potency. The pig ear skin deposition of 8-MOP, isopsoralen, and bakuchiol at an equimolar dose was 0.47, 0.58, and 0.50 nmol/mg, respectively, which was comparable and higher than that of psoralen (0.25 nmol/mg) and psoralidin (0.14 nmol/mg). Psoralidin and bakuchiol were absorbed into the skin without further penetration across the skin. Besides experimental data of physicochemical properties, the hydrogen bond number, total polarity surface, and stratum corneum lipid docking calculated could explain the correlation of the penetrant structure with the skin permeability. The antiproliferative activity against keratinocytes was stronger for 8-MOP and isopsoralen than the others. Topical application of PUVA by using 8-MOP and isopsoralen on imiquimod-induced plaque significantly reduced transepidermal water loss from 55 to 33 and 38 g/m2/h, respectively. The epidermal thickening elicited by imiquimod (117 μm) was decreased to 62 and 26 μm by 8-MOP and isopsoralen application. IL-6 expression in psoriasiform skin was downregulated by isopsoralen but not 8-MOP. Isopsoralen may be a potential candidate for PUVA therapy.

Pulmonary delivery of drug nanocarriers can overcome the shortcomings of systemic cancer therapy via the enhanced permeability and retention (EPR) based-nanomedicine. Herein, inhalable multi-compartmental nanocomposites with the capability for both localized and modulated release of the hydrophobic mTOR inhibitor, rapamycin (RAP) and the hydrophilic herbal drug, berberine (BER) have been developed for lung cancer therapy. Two types of multi-compartmental nanocarriers were fabricated by enveloping BER hydrophobic ion pair-lipid nanocore within a shell of RAP-phospholipid complex bilayer to reduce the delivery gap between the two drugs. To further enhance their tumor targeting, the nanocarriers were layer-by-layer coated by cationic lactoferrin and anionic hyaluronate resulting in enhanced internalization and cytotoxicity against lung cancer cells. The inhalable nanocomposites fabricated by spray-drying of multi-compartmental nanocarriers exhibited favorable aerosolization efficiency (MMAD of 3.28 µm and FPF of 55.5%). The powerful anti-cancer efficacy of inhalable nanocomposites in lung cancer bearing mice compared to the inhaled free drugs was revealed by remarkable decrease in lung weight, and reduction in both number and diameters of lung adenomatous foci and angiogenic markers compared to positive control. Overall, localized delivery of RAP and BER to tumor cells via inhalable multi-compartmental nanocomposites holds great promise in management of lung cancer.

The UVA absorbers such as avobenzone are widely used for sunlight protection; however, they show a significant skin penetration. The aim of the present study was to formulate UVA absorbers into mesoporous silicas (MSs) for enhanced UVA protection with reduced percutaneous absorption. Two MSs prepared with different structure-directing agents (Pluronic P123 as single MS and combined Pluronic P123-Pluronic F68 as hybrid MS) were synthesized in this study. The hybrid MS exhibited higher specific surface area (853 m2/g) than the single MS (764 m2/g). The particle sizes of single MS and hybrid MS were about 1 and 1.5 μm, respectively. The adsorbed avobenzone had greatly decreased crystallinity compared with free avobenzone. The in vitro photoprotection determined by UVA/UVB ratio showed that the MS-loaded avobenzone in hydrogel endowed a synergistic effect on UVA protection compared to the free avobenzone. The skin absorption test using Franz diffusion cell indicated that the skin permeation of avobenzone and oxybenzone from MSs in semisolid preparations was one-third to one-half of those from free control. This effect was observed by using both pig skin and UVA-damaged nude mouse skin as the penetration barriers. Topical application of hybrid MS on nude mouse skin before UVA irradiation had prevented the increased transepidermal water loss (TEWL), furrow formation, keratinocyte apoptosis, and neutrophil infiltration. Our findings conclude that MSs containing avobenzone or oxybenzone effectively ameliorated UVA-induced skin disruption and reduced the possible toxicity elicited by percutaneous penetration.

Phytochemicals present in vegetables, fruits, and herbs are believed to reduce the risk of several major diseases including cardiovascular or neurodegenerative disorders. The roots of the fern Helminthostachys zeylanica (L.) Hook. (Ophioglossaceae) have been used for centuries in the treatment of inflammation and as a folk medicine in several countries. The plant has been shown to possess an array of medicinal properties, including antioxidants and anti-inflammatory activities. Moreover, a rising level of matrix metalloproteinase-9 (MMP-9) has been found in blood fluid of these patients suffering from brain inflammatory diseases, which may be considered an inflammatory biomarker in several inflammatory diseases including the central nervous system (CNS) inflammation. Previously, we have demonstrated the signaling mechanisms of bradykinin (BK)-induced MMP-9 expression in brain astrocytes. Herein, we evaluate the effects of H. zeylanica extracts on BK-induced MMP-9 expression in brain astrocytes and its influencing mechanism. The results showed that H. zeylanica extracts, including E0, E1, and E2 significantly reduce MMP-9 induced by BK in brain astrocytes (RBA-1 cells). These H. zeylanica extracts can inhibit BK-stimulated phosphorylation of c-Src, Pyk2, and PKC(α/δ). Moreover, BK-stimulated NADPH oxidase (Nox)-derived reactive oxygen species (ROS) generation has also been attenuated by pretreatment with these extracts, suggesting that the H. zeylanica extracts have an antioxidative activity. We further demonstrated that the H. zeylanica extracts blocked activation of MAPKs (e.g., ERK1/2 and p38 MAPK) by BK. These data indicated that the H. zeylanica extracts may be has anti-inflammatory activity by reducing BK-induced ROS-dependent MMP-9 expression via these related pathways in brain astrocytes.

Dual-sensitive block copolymers, PNiPAAm-b-PNBTMC, were synthesized via the ring-opening polymerization of 3-methyl-3-nitrobenzyl-trimethylene carbonate (NBTMC) bearing numerous 2-nitro-benzoxycarbonyl photolabile groups with a PNiPAAm macroinitiator in the presence of an organocatalyst, 1,5,7-triazobicyclo-[4.4.0]dec-5-ene (TBD). When the polymer solutions were exposed to ultraviolet (UV) irradiation, we observed significant changes in the structure and morphology of the particles. Fluorescence spectroscopy studies revealed that the copolymers underwent micellization or dissociation transitions in water in response to temperature changes and UV irradiation. No significant toxicity of these nanoparticles was found at concentrations up to 300 μg mL − 1 .