The anti-inflammatory activity of flavonoids and alkaloids from Sophora flavescens alleviates psoriasiform lesions: Prenylation and methoxylation beneficially enhance bioactivity and skin targeting.

The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.

Combining the dual antibacterial and regenerative activities of platelet-rich plasma with ß-lactams to mitigate MRSA-infected skin wounds.

The emergence of multidrug-resistant bacteria contributes to the necessity of developing novel infection treatment approaches. This study was designed to evaluate the antimicrobial and wound healing activities of platelet-rich plasma (PRP) in combination with ß-lactams (ampicillin and/or oxacillin) for the application on methicillin-resistant Staphylococcus aureus (MRSA)-infected skin. PRP was collected from the peripheral blood of healthy donors. The anti-MRSA activity was tested through a growth inhibition curve, colony-forming unit (CFU), and SYTO 9 assay. The PRP incorporation lowered the minimum inhibitory concentration (MIC) of ampicillin and oxacillin against MRSA. The combination of ß-lactams together with PRP showed a three-log CFU reduction of MRSA. The major components of PRP for eliminating MRSA were found to be the complement system and iron sequestration proteins, according to the proteomic analysis. The adhesive bacterial colony in the microplate was decreased from 2.9 × 107 to 7.3 × 105 CFU after the treatment of cocktails containing ß-lactams and PRP. The cell-based study indicated that keratinocyte proliferation was stimulated by PRP. The in vitro scratch and transwell experiments revealed that PRP improved keratinocyte migration. In the MRSA-infected mouse skin model, PRP appeared to show a synergistic effect for wound area reduction by 39% when combined with ß-lactams. The MRSA burden in the infected area was lessened two-fold after topical administration of the combined ß-lactams and PRP. PRP inhibited macrophage infiltration in the wound site to shorten the inflammatory phase and accelerate the initiation of the proliferative phase. No skin irritation was detected with the topical delivery of this combination. Our findings suggested that ß-lactams plus PRP was applicable to alleviate the problems associated with MRSA via dual antibacterial and regenerative activities.

TiO2-embedded mesoporous silica with lower porosity is beneficial to adsorb the pollutants and retard UV filter absorption: A possible application for outdoor skin protection.

The purpose of the current investigation was to develop multifunctional TiO2-embedded mesoporous silica incorporating avobenzone to protect against environmental stress through pollutant adsorption and UVA protection. We sought to explore the effect of the mesoporous porosity on the capability of contaminant capture and the suppression of avobenzone skin penetration. The porosity of the mesoporous silica was tuned by adjusting the ratio of template triblock copolymers (Pluronic P123 and F68). The Pluronic P123:F68 ratios of 3:1, 2:2, and 1:3 produced mesoporous silica with pore volumes of 0.66 (TiO2/SBA-L), 0.47 (TiO2/SBA-M), and 0.25 (TiO2/SBA-S) cm3/g, respectively. X-ray scattering and electron microscopy confirmed the SBA-15 structure of the as-prepared material had a size of 3-5 µm. The maximum adsorbability of fluoranthene and methylene blue was found to be 43% and 53% for the TiO2/SBA-S under UVA light, respectively. The avobenzone loaded into the mesoporous silica demonstrated the synergistic effect of in vitro UVA protection, reaching an UVA/UVB absorbance ratio of near 1.5 (Boots star rating = 5). The encapsulation of avobenzone into the TiO2/SBA-S lessened cutaneous avobenzone absorption from 0.76 to 0.50 nmol/mg, whereas no reduction was detected for the TiO2/SBA-L. The avobenzone-loaded TiO2/SBA-S hydrogel exhibited a greater improvement in skin barrier recovery and proinflammatory mediator mitigation compared to the SBA-S hydrogel (without TiO2). The cytokines/chemokines in the photoaged skin were reduced by two- to three-fold after TiO2/SBA-S treatment compared to the non-treatment control. Our data suggested that the mesoporous formulation with low porosity and a specific surface area showed effective adsorbability and UVA protection, with reduced UVA filter absorption. The versatility of the developed mesoporous system indicated a promising potential for outdoor skin protection.

Sophoraflavanone G from Sophora flavescens Ameliorates Allergic Airway Inflammation by Suppressing Th2 Response and Oxidative Stress in a Murine Asthma Model.

Sophoraflavanone G (SG), isolated from Sophora flavescens, has anti-inflammatory and anti-tumor bioactive properties. We previously showed that SG promotes apoptosis in human breast cancer cells and leukemia cells and reduces the inflammatory response in lipopolysaccharide-stimulated macrophages. We investigated whether SG attenuates airway hyper-responsiveness (AHR) and airway inflammation in asthmatic mice. We also assessed its effects on the anti-inflammatory response in human tracheal epithelial cells. Female BALB/c mice were sensitized with ovalbumin, and asthmatic mice were treated with SG by intraperitoneal injection. We also exposed human bronchial epithelial BEAS-2B cells to different concentrations of SG to evaluate its effects on inflammatory cytokine levels. SG treatment significantly reduced AHR, eosinophil infiltration, goblet cell hyperplasia, and airway inflammation in the lungs of asthmatic mice. In the lungs of ovalbumin-sensitized mice, SG significantly promoted superoxide dismutase and glutathione expression and attenuated malondialdehyde levels. SG also suppressed levels of Th2 cytokines and chemokines in lung and bronchoalveolar lavage samples. In addition, we confirmed that SG decreased pro-inflammatory cytokine, chemokine, and eotaxin expression in inflammatory BEAS-2B cells. Taken together, our data demonstrate that SG shows potential as an immunomodulator that can improve asthma symptoms by decreasing airway-inflammation-related oxidative stress.

The effectiveness of synthetic methoxylated isoflavones in delivering to the skin and alleviating psoriasiform lesions via topical absorption.

This study was conducted to appraise the possible potential of synthetic isoflavones (SIFs) on psoriasis treatment. A practical and easy-to-operate approach was employed in synthesizing a series of SIFs, considering that acquiring flavonoids from natural resources is usually expensive, time-consuming, and non-eco-friendly. Seven SIFs derived from daidzein were produced with differences in the location of the hydroxyl groups and degree of methoxylation. The in vitro and in vivo skin absorption of topically applied SIFs was estimated. Further, keratinocytes (HaCaT) were employed as the model to investigate the anti-inflammatory activity of the isoflavones. The lipophilicity was increased from SIF-1 to -7. Noteworthily, there was a parabolic relationship between lipophilicity and skin absorption, with SIF-5 (4',7-dihydroxyisoflavone, daidzein) and SIF-6 (7-hydroxy-3',4'-dimethoxyisoflavone, cladrin) demonstrating the highest retention in pig skin. The methoxylated isoflavone SIF-5 showed the greatest permeation into barrier-deficient skin among the compounds tested, with a 6- and 8-fold increase after lipid and protein removal. The cell-based study exhibited the capability of SIFs to restrain the overexpressed IL-6, IL-8, and CXCL1 in stimulated HaCaT. The therapeutic index (TI) predicted the potential candidates of SIF-5 and SIF-6 for topical application to treat psoriatic inflammation. The imiquimod (IMQ)-driven psoriasiform murine model manifested the inhibition of hyperplasia and immune cell infiltration by topically administered SIF-5 and SIF-6. The epidermal thickness of IMQ-treated skin was decreased from 172 to 40 µm by both isoflavones. This effect was comparable with that of betamethasone, the positive control. The topical treatment of SIF-6 significantly reduced cytokine/chemokine upregulation by IMQ. The methoxylated isoflavone with dramatic anti-inflammatory activity is promising for the development of an antipsoriatic agent.

A systematic comparison of the effect of topically applied anthraquinone aglycones to relieve psoriasiform lesion: The evaluation of percutaneous absorption and anti-inflammatory potency.

The anthraquinones derived from rhubarb are reported to have anti-inflammatory activity. The present study aimed to assess the topical application of rhubarb anthraquinone aglycones for psoriasis treatment. The antipsoriatic effect of five anthraquinones, including aloe-emodin, rhein, emodin, physcion, and chrysophanol, was compared to elucidate a structure-permeation relationship. Molecular modeling was employed to determine the physicochemical properties. Both macrophages (differentiated THP-1) and keratinocytes (HaCaT) were used to examine the anti-inflammatory activity in the cell-based study. The in vitro pig skin absorption showed that chrysophanol was the compound with the highest cutaneous accumulation. Topically applied rhein was detected to be largely delivered to the receptor compartment. The absorption of rhein was increased by 5-fold in the barrier-deficient skin as compared to intact skin. By stimulating macrophages with imiquimod (IMQ) to model the inflammation in psoriasis, it was found that the anthraquinones significantly reduced IL-6, IL-23, and TNF. The cytokine inhibition level was comparable for the five compounds. The anthraquinones suppressed cytokines by inhibiting the activation of MAPK and NF-κB signaling. The anthraquinones also downregulated IL-6, IL-8, and IL-24 in the inflammatory keratinocytes stimulated with TNF. Rhein and chrysophanol were comparable to curtail the STAT3 phosphorylation in keratinocytes induced by the conditioned medium of stimulated macrophages. The IMQ-induced psoriasiform mouse model demonstrated the improvement of scaling, erythema, and epidermal hyperplasia by topically applied rhein or chrysophanol. The epidermal acanthosis evoked by IMQ was reduced with rhein and chrysophanol by 3-fold. The histological profiles exhibit that both anthraquinone compounds diminished the number of macrophages and neutrophils in the lesional skin, skin-draining lymph node, and spleen. Rhein and chrysophanol showed multifunctional inhibition, by regulating several targets for alleviating psoriasiform inflammation.

Facile Biofilm Penetration of Cationic Liposomes Loaded with DNase I/Proteinase K to Eradicate Cutibacterium acnes for Treating Cutaneous and Catheter Infections.

BACKGROUND: The biofilm produced by Cutibacterium acnes is a major infection threat for skin and implanted catheters. Nanoparticles provide a new approach to eradicate biofilms. The present study evaluated the capability of cationic liposomes loaded with DNase I (DNS) and proteinase K (PK) to remove preformed C. acnes biofilms. METHODS: DNS and PK were able to target and disassemble the biofilm by degrading extracellular polymer substances (EPS). Soyaethyl morpholinium ethosulfate (SME) was used to render a positive charge and enhance the antibacterial activity of the liposomes. RESULTS: The cationic liposomes containing enzymes yielded monodisperse nanovesicles ranging between 95 and 150 nm. The entrapment efficiency of the enzymes in the liposomes achieved a value of 67-83%. All liposomal formulations suppressed planktonic C. acnes growth at a minimum inhibitory concentration (MIC) equal to the free SME in the solution. The enzyme in the liposomal form inhibited biofilm growth much better than that in the free form, with the dual enzyme-loaded liposomes demonstrating the greatest inhibition of 54% based on a crystal violet assay. The biofilm-related virulence genes PA380 and PA1035 were downregulated by the combined enzymes in the liposomes but not the individual DNS or PK. Scanning electron microscopy (SEM) and confocal microscopy displayed reduced C. acnes aggregates and biofilm thickness by the liposomal system. The liposomes could penetrate through about 85% of the biofilm thickness. The in vitro pig skin permeation also showed a facile delivery of liposomes into the epidermis, deeper skin strata, and hair follicles. The liposomes exhibited potent activity to eliminate C. acnes colonization in mouse skin and catheters in vivo. The colony-forming units (CFUs) in the catheter treated with the liposomes were reduced by 2 logs compared to the untreated control. CONCLUSION: The data suggested a safe application of the enzyme-loaded cationic liposomes as antibacterial and antibiofilm agents.

Tomatidine Improves Pulmonary Inflammation in Mice with Acute Lung Injury.

Tomatidine, which is isolated from green tomato, can ameliorate inflammation and oxidative stress in cells and animal experiments and has been shown to improve airway inflammation in a murine model of asthma. Here, we investigated whether tomatidine can ameliorate acute lung injury in mice. Mice were given tomatidine by intraperitoneal injection for 7 consecutive days, and then, lung injury was induced via intratracheal instillation of lipopolysaccharide (LPS). Tomatidine reduced inflammatory cytokine expressions in bronchoalveolar lavage fluid (BALF), attenuated neutrophil infiltration in the BALF and lung tissue, increased superoxide dismutase activity and glutathione levels, and alleviated myeloperoxidase expression in the lung tissue of mice with lung injury. Tomatidine also decreased inflammatory cytokine and chemokine gene expression in inflammatory lungs and attenuated the phosphorylation of mitogen-activated protein kinase and nuclear factor kappa B. Furthermore, tomatidine enhanced the production of heme oxygenase-1, decreased the secretion of inflammatory cytokines and chemokines in LPS-stimulated lung epithelial cells, and attenuated THP-1 monocyte adhesion. Our findings suggest that tomatidine attenuates oxidative stress and inflammation, improving acute lung injury in mice.

Helminthostachys zeylanica Water Extract Ameliorates Airway Hyperresponsiveness and Eosinophil Infiltration by Reducing Oxidative Stress and Th2 Cytokine Production in a Mouse Asthma Model.

Helminthostachys zeylanica is a traditional folk herb used to improve inflammation and fever in Taiwan. Previous studies showed that H. zeylanica extract could ameliorate lipopolysaccharide-induced acute lung injury in mice. The aim of this study was to investigate whether H. zeylanica water (HZW) and ethyl acetate (HZE) extracts suppressed eosinophil infiltration and airway hyperresponsiveness (AHR) in asthmatic mice, and decreased the inflammatory response and oxidative stress in tracheal epithelial cells. Human tracheal epithelial cells (BEAS-2B cells) were pretreated with various doses of HZW or HZE (1 µg/ml-10 µg/ml), and cell inflammatory responses were induced with IL-4/TNF-α. In addition, female BALB/c mice sensitized with ovalbumin (OVA), to induce asthma, were orally administered with HZW or HZE. The result demonstrated that HZW significantly inhibited the levels of proinflammatory cytokines, chemokines, and reactive oxygen species in activated BEAS-2B cells. HZW also decreased ICAM-1 expression and blocked monocytic cells from adhering to inflammatory BEAS-2B cells in vitro. Surprisingly, HZW was more effective than HZE in suppressing the inflammatory response in BEAS-2B cells. Our results demonstrated that HZW significantly decreased AHR and eosinophil infiltration, and reduced goblet cell hyperplasia in the lungs of asthmatic mice. HZW also inhibited oxidative stress and reduced the levels of Th2 cytokines in bronchoalveolar lavage fluid. Our findings suggest that HZW attenuated the pathological changes and inflammatory response of asthma by suppressing Th2 cytokine production in OVA-sensitized asthmatic mice.

Percutaneous absorption of resveratrol and its oligomers to relieve psoriasiform lesions: In silico, in vitro and in vivo evaluations.

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, ε-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 ε-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-1ß, IL-6, and CXCL8 secretion in activated keratinocytes. In vivo, topically applied ε-viniferin accumulated at higher levels than resveratrol (0.067 versus 0.029 nmol/mg) in psoriasis-like mouse skin with impaired barrier capacity. Topical ε-viniferin alleviated psoriasiform symptoms and reduced IL-23 secretion (by 58% vs. 37%) more effectively than resveratrol. ε-Viniferin has potential as an anti-inflammatory agent to prevent or treat psoriasis.

Development of flavanone and its derivatives as topical agents against psoriasis: The prediction of therapeutic efficiency through skin permeation evaluation and cell-based assay.

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-1ß 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.

Apoptotic or Antiproliferative Activity of Natural Products against Keratinocytes for the Treatment of Psoriasis.

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.

Sophoraflavanone G from Sophora flavescens induces apoptosis in triple-negative breast cancer cells.

BACKGROUND: A compound isolated from Sophora flavescens-sophoraflavanone G (SG)-showed anti-tumor and anti-inflammatory properties. We previously demonstrated that SG promoted apoptosis in human leukemia HL-60 cells. In the present study, we investigated the effects of SG on apoptosis in human breast cancer MDA-MB-231 cells, and explored the underlying molecular mechanisms. METHODS: MDA-MB-231 cells were treated with various SG concentrations, and cell viability was evaluated by MTT assay. Apoptotic signal proteins were detected by western blotting, and cell apoptosis was assessed using flow cytometry. RESULTS: Our results demonstrated that SG induced nuclear condensation, DNA fragmentation, reactive oxygen species production, and increased cell apoptosis in MDA-MB-231 cells. SG also suppressed migration and invasion, likely via blockage of the MAPK pathway. In the apoptotic signaling pathway, SG increased cleaved caspase-8, caspase-3, and caspase-9. SG treatment also decreased Bcl-2 and Bcl-xL expression, increased Bax expression, and prompted release of more cytochrome c from mitochondria to the cytoplasm in MDA-MB-231 cells. CONCLUSION: Overall, our findings suggest that SG might increase apoptosis, and decrease migration and invasion, in MDA-MB-231 cells through suppression of a MAPK-related pathway.

Protective mechanisms of resveratrol derivatives against TNF-α-induced inflammatory responses in rat mesangial cells.

INTRODUCTION: Resveratrol has been reported to alleviate inflammatory responses and oxidative stress in mesangial cells and in several types of renal injury in animal models. Previously, the active resveratrol derivatives from the roots of Vitis thunbergii Sieb. & Zucc. (Vitaceae) were shown to have significant anti-platelet and anti-oxidative activities. However, the anti-inflammatory mechanisms of these resveratrol derivatives in rat mesangial cells (RMCs) have not been clarified fully. METHODS: The protective mechanisms of resveratrol derivatives involved in tumor necrosis factor-α (TNF-α)-induced inflammatory responses were assessed by Western blot analysis, real-time PCR, and RT-PCR. The involvement of various signaling molecules in these responses was investigated using selective pharmacological inhibitors. RESULTS: Nontoxic concentrations of the resveratrol derivatives significantly attenuated cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2) expression in RMCs challenged by TNF-α. These resveratrol derivatives inhibited TNF-α-activated ERK1/2 and JNK1/2 without affecting p38 phosphorylation. Next, we demonstrated that TNF-α induced NF-κB activation, translocation, and promoter activity, which was inhibited by pretreatment with resveratrol derivatives in RMCs. CONCLUSION: The protective mechanisms of resveratrol derivatives against TNF-α-stimulated inflammatory responses via cPLA2/COX-2/PGE2 inhibition was caused by the attenuation of the JNK1/2, ERK1/2, and NF-κB signaling pathways in RMCs.

UV filter entrapment in mesoporous silica hydrogel for skin protection against UVA with minimization of percutaneous absorption.

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.

The Interplay Between Nanoparticles and Neutrophils.

The employment of nanoparticles has markedly increased in recent years for different applications such as aerospace technology, electronics, biology, and medicine. The exposure of nanoparticles to humans is inevitable nowadays. Neutrophils act as the predominant phagocytic cells for first-line defense to be recruited to an inflammatory site against xenobiotics. It is important to explore how neutrophils interact with nanoparticles to elicit immune responses. Different types of nanoparticles have been studied to reveal a potential interaction to neutrophils in vitro and in vivo. These mainly include metallic nanoparticles, polymeric nanoparticles, silica nanoparticles, lipid nanoparticles, and fullerenes. A number of investigations have reported the toxicity of nanoparticles induced by neutrophil activation. In this review we discuss data demonstrating recently recognized aspects of inflammation induced by overwhelmed neutrophils after nanoparticle treatment. Besides the dark side of the nanoparticles, some therapeutic nanoparticles are developed and beneficial in treating neutrophil-related diseases such as acute lung injury, vascular inflammation, and bacterial infection. Some nanoparticles can recruit neutrophils around tumor sites for immunotherapy. We also summarize how nanoparticles actively target neutrophils with therapeutic aims. This review provides a broad introduction to nanoparticle interplay with neutrophils and discusses in vitro and in vivo studies in which they have been evaluated.

Derivatization of honokiol by integrated acetylation and methylation for improved cutaneous delivery and anti-inflammatory potency.

A set of honokiol derivatives was synthesized to evaluate skin permeation and bioactivity. The reaction for derivatization included acetylation and methylation. The anti-inflammatory activity against neutrophils and macrophages was examined. The experimental setup for the assessment of cutaneous absorption was the in vitro Franz diffusion assembly. Honokiol and its derivatives significantly downregulated superoxide anion and elastase production in neutrophils, with honokiol showing the greatest inhibition. All derivatives could be completely hydrolyzed to the parent compounds after passing into the skin. The skin deposition of honokiol at an infinite dose (3mM) was 0.33nmol/mg 4'-O-acetylhonokiol (AH), and 2,4'-diacetylhonokiol (DAH) exhibited comparable or less absorption than honokiol. The integrated acetylation and methylation (2-O-acetyl-4'-O-methylhonokiol, AMH) led to a 10.5-fold improvement of absorption compared to honokiol. AMH was advantageous for the targeted cutaneous treatment due to the high skin deposition and minimal penetration across the skin (8.40nmol/cm2 compared to 93.49nmol/cm2 for honokiol). The predicted therapeutic index for superoxide and interleukin (IL)-6 inhibition was much higher for topically applied AMH than for the other penetrants tested. The total polarity surface and hydrogen bond acceptor number calculated by molecular modeling were the parameters used to anticipate the cutaneous absorption. Our data suggest that AMH is a potent and safe candidate for cutaneous inflammation therapy.

Elucidating the Skin Delivery of Aglycone and Glycoside Flavonoids: How the Structures Affect Cutaneous Absorption.

Flavonoids are bioactive phytochemicals that exhibit protective potential against cutaneous inflammation and photoaging. We selected eight flavonoid aglycones or glycosides to elucidate the chemistry behind their skin absorption capability through experimental and computational approaches. The skin delivery was conducted using nude mouse and pig skins mounted on an in vitro Franz cell assembly. The anti-inflammatory activity was examined using the O2•.

Honokiol suppresses formyl peptide-induced human neutrophil activation by blocking formyl peptide receptor 1.

Formyl peptide receptor 1 (FPR1) mediates bacterial and mitochondrial N-formyl peptides-induced neutrophil activation. Therefore, FPR1 is an important therapeutic target for drugs to treat septic or sterile inflammatory diseases. Honokiol, a major bioactive compound of Magnoliaceae plants, possesses several anti-inflammatory activities. Here, we show that honokiol exhibits an inhibitory effect on FPR1 binding in human neutrophils. Honokiol inhibited superoxide anion generation, reactive oxygen species formation, and elastase release in bacterial or mitochondrial N-formyl peptides (FPR1 agonists)-activated human neutrophils. Adhesion of FPR1-induced human neutrophils to cerebral endothelial cells was also reduced by honokiol. The receptor-binding results revealed that honokiol repressed FPR1-specific ligand N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein binding to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells. However, honokiol did not inhibit FPR2-specific ligand binding to FPR2 in human neutrophils. Furthermore, honokiol inhibited FPR1 agonist-induced calcium mobilization as well as phosphorylation of p38 MAPK, ERK, and JNK in human neutrophils. In conclusion, our data demonstrate that honokiol may have therapeutic potential for treating FPR1-mediated inflammatory diseases.

Water extract of Helminthostachys zeylanica attenuates LPS-induced acute lung injury in mice by modulating NF-κB and MAPK pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Previous studies showed that Helminthostachys zeylanica (L.) Hook. could reduce inflammatory responses in macrophage and brain astrocytes. AIM OF THE STUDY: In the present study, we evaluated whether an ethyl acetate extract (HZE) or a water extract (HZW) of H. zeylanica could reduce inflammatory responses in lung epithelial cells and ameliorate lipopolysaccharide (LPS)-induced acute lung injury in mice. METHODS: Human lung epithelial A549 cells were pre-treated with HZE or HZW (1-10µg/mL), then stimulated with LPS. BALB/c mice received oral HZW for 7 consecutive days, then an intratracheal instillation of LPS to induce lung injury. RESULTS: HZW reduced chemokine and proinflammatory cytokine production in LPS-activated A549 cells. HZW also suppressed ICAM-1 expression and reduced the adherence of acute monocytic leukemia cells to inflammatory A549 cells. HZE had less efficacy than HZW in suppressing inflammatory responses in A549 cells. In vivo, HZW significantly suppressed neutrophil infiltration and reduced the TNF-α and IL-6 levels in bronchoalveolar lavage fluid and serum from LPS-treated mice. HZW also modulated superoxide dismutase activity, glutathione, and myeloperoxidase activity in lung tissues from LPS-treated mice. HZW decreased the phosphorylation of mitogen-activated protein kinase and nuclear factor kappa B, and promoted heme oxygenase-1 expression in inflamed lung tissue from LPS-treated mice. CONCLUSION: Our findings suggested that HZW reduced lung injury in mice by reducing oxidative stress and inflammatory responses. HZW also reduced inflammatory responses in human lung epithelial cells.