scholarly journals Serine Protease-Mediated Cutaneous Inflammation: Characterization of an Ex Vivo Skin Model for the Assessment of Dexamethasone-Loaded Core Multishell-Nanocarriers

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 862
Author(s):  
Janna Frombach ◽  
Fiorenza Rancan ◽  
Katharina Kübrich ◽  
Fabian Schumacher ◽  
Michael Unbehauen ◽  
...  
Keyword(s):  
Serine Protease ◽  
Ex Vivo ◽  
Biological Effects ◽  
Skin Barrier ◽  
Fold Increase ◽  
Transepidermal Water Loss ◽  
Moderate Increase ◽  
Skin Model ◽  
Proinflammatory Mediators ◽  
Anti Inflammatory

Standard experimental set-ups for the assessment of skin penetration are typically performed on skin explants with an intact skin barrier or after a partial mechanical or chemical perturbation of the stratum corneum, but they do not take into account biochemical changes. Among the various pathological alterations in inflamed skin, aberrant serine protease (SP) activity directly affects the biochemical environment in the superficial compartments, which interact with topically applied formulations. It further impacts the skin barrier structure and is a key regulator of inflammatory mediators. Herein, we used short-term cultures of ex vivo human skin treated with trypsin and plasmin as inflammatory stimuli to assess the penetration and biological effects of the anti-inflammatory drug dexamethasone (DXM), encapsulated in core multishell-nanocarriers (CMS-NC), when compared to a standard cream formulation. Despite a high interindividual variability, the combined pretreatment of the skin resulted in an average 2.5-fold increase of the transepidermal water loss and swelling of the epidermis, as assessed by optical coherence tomography, as well as in a moderate increase of a broad spectrum of proinflammatory mediators of clinical relevance. The topical application of DXM-loaded CMS-NC or DXM standard cream revealed an increased penetration into SP-treated skin when compared to untreated control skin with an intact barrier. Both formulations, however, delivered sufficient amounts of DXM to effectively suppress the production of interleukin-6 (IL-6), interleukin-8 (IL-8) and Thymic Stromal Lymphopoietin (TSLP). In conclusion, we suggest that the herein presented ex vivo inflammatory skin model is functional and could improve the selection of promising drug delivery strategies for anti-inflammatory compounds at early stages of development.

scholarly journals Bile acid bio-nanoencapsulation improved drug targeted-delivery and pharmacological effects via cellular flux: 6-months diabetes preclinical study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Armin Mooranian ◽  
Susbin Raj Wagle ◽  
Bozica Kovacevic ◽  
Ryu Takechi ◽  
John Mamo ◽  
...  
Keyword(s):  
Bile Acid ◽  
Targeted Delivery ◽  
Oral Delivery ◽  
Ex Vivo ◽  
Biological Effects ◽  
Protective Effects ◽  
Β Cells ◽  
Positive Effects ◽  
Anti Inflammatory

AbstractThe antilipidemic drug, probucol (PB), has demonstrated potential applications in Type 2 diabetes (T2D) through its protective effects on pancreatic β-cells. PB has poor solubility and bioavailability, and despite attempts to improve its oral delivery, none has shown dramatic improvements in absorption or antidiabetic effects. Preliminary data has shown potential benefits from bile acid co-encapsulation with PB. One bile acid has shown best potential improvement of PB oral delivery (ursodeoxycholic acid, UDCA). This study aimed to examine PB and UDCA microcapsules (with UDCA microcapsules serving as control) in terms of the microcapsules’ morphology, biological effects ex vivo, and their hypoglycemic and antilipidemic and anti-inflammatory effects in vivo. PBUDCA and UDCA microcapsules were examined in vitro (formulation studies), ex vivo and in vivo. PBUDCA microcapsules exerted positive effects on β-cells viability at hyperglycemic state, and brought about hypoglycemic and anti-inflammatory effects on the prediabetic mice. In conclusion, PBUDCA co-encapsulation have showed beneficial therapeutic impact of dual antioxidant-bile acid effects in diabetes treatment.

scholarly journals Annexin 1 and Melanocortin Peptide Therapy for Protection Against Ischaemic-Reperfusion Damage in the Heart

2006 ◽  
Vol 6 ◽  
pp. 1008-1023 ◽  
Author(s):  
F.N.E. Gavins ◽  
G. Leoni ◽  
S.J. Getting
Keyword(s):  
Biological Effects ◽  
Western World ◽  
Protective Effects ◽  
Ischaemic Injury ◽  
Endogenous Peptides ◽  
Animal Models Of Disease ◽  
Annexin 1 ◽  
Proinflammatory Mediators ◽  
Melanocortin Peptides ◽  
Anti Inflammatory

Cardiovascular disease is a major cause of mortality within the western world affecting 2.7 million British people. This review highlights the beneficial effects of naturally occurring hormones and their peptides, in myocardial ischaemic-injury (MI) models, a disease pathology in which cytokines and neutrophils play a causal role. Here we discuss two distinct classes of endogenous peptides: the steroid inducible annexin 1 and the melanocortin peptides. Annexin 1 and the melanocortins counteract the most important part of the host inflammatory response, namely, the process of leukocyte extravasation, as well as release of proinflammatory mediators. Their biological effects are mediated via the seven transmembrane G-protein-coupled receptors, the fMLP receptor family (or FPR), and the melanocortin receptors, respectively. Pharmacological analysis has demonstrated that the first 24 amino acids of the N-terminus (termed Ac2-26) are the most active region. Both exogenous annexin 1 and its peptides demonstrate cardioprotectiveness and continuing work is required to understand this annexin 1/FPR relationship fully. The melanocortin peptides are derived from a precursor molecule called the POMC protein. These peptides display potent anti-inflammatory effects in human and animal models of disease. In MI, the MC3R has been demonstrated to play an important role in mediating the protective effects of these peptides. The potential anti-inflammatory role for endogenous peptides in cardiac disease is in its infancy. The inhibition of cell migration and release of cytokines and other soluble mediators appears to play an important role in affording protection in ischaemic injury and thus may lead to potential therapeutic targets.

scholarly journals Ex Vivo Live Full-Thickness Porcine Skin Model as a Versatile In Vitro Testing Method for Skin Barrier Research

2021 ◽  
Vol 22 (2) ◽  
pp. 657
Author(s):  
Jee-Hyun Hwang ◽  
Haengdueng Jeong ◽  
Nahyun Lee ◽  
Sumin Hur ◽  
Nakyum Lee ◽  
...  
Keyword(s):  
Barrier Function ◽  
Ex Vivo ◽  
Animal Experiments ◽  
Skin Barrier ◽  
Skin Barrier Function ◽  
Protective Effects ◽  
Skin Model ◽  
Porcine Skin ◽  
Single Exposure ◽  
Cosmetic Ingredients

Since the European Union (EU) announced their animal testing ban in 2013, all animal experiments related to cosmetics have been prohibited, creating a demand for alternatives to animal experiments for skin studies. Here, we investigated whether an ex vivo live porcine skin model can be employed to study the safety and skin barrier-improving effects of hydroxyacids widely used in cosmetics for keratolytic peels. Glycolic acid (1–10%), salicylic acid (0.2–2%), and lactobionic acid (1.2–12%) were used as representative substances for α-hydroxyacid (AHA), β-hydroxyacid (BHA), and polyhydroxyacid (PHA), respectively. When hydroxyacids were applied at high concentrations on the porcine skin every other day for 6 days, tissue viability was reduced to 50–80%, suggesting that the toxicity of cosmetic ingredients can be evaluated with this model. Based on tissue viability, the treatment scheme was changed to a single exposure for 20 min. The protective effects of a single exposure of hydroxyacids on skin barrier function were evaluated by examining rhodamine permeability and epidermal structural components of barrier function using immunohistochemistry (IHC) and immunofluorescence (IF) staining. Lactobionic acid (PHAs) improved skin barrier function most compared to other AHAs and BHAs. Most importantly, trans-epidermal water loss (TEWL), an important functional marker of skin barrier function, could be measured with this model, which confirmed the significant skin barrier-protective effects of PHAs. Collectively, we demonstrated that the ex vivo live full-thickness porcine skin model can be an excellent alternative to animal experiments for skin studies on the safety and efficacy of cosmetic ingredients.

scholarly journals Anti-Inflammatory Activity and Mechanism of Isookanin, Isolated by Bioassay-Guided Fractionation from Bidens pilosa L.

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 255
Author(s):  
Ying-Ji Xin ◽  
Soojung Choi ◽  
Kyung-Baeg Roh ◽  
Eunae Cho ◽  
Hyanggi Ji ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Biological Effects ◽  
Biological Properties ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Activator Protein 1 ◽  
Bidens Pilosa ◽  
Proinflammatory Mediators ◽  
Bioassay Guided Fractionation ◽  
Anti Inflammatory

Bidens pilosa L. (Asteraceae) has been used historically in traditional Asian medicine and is known to have a variety of biological effects. However, the specific active compounds responsible for the individual pharmacological effects of Bidens pilosa L. (B. pilosa) extract have not yet been made clear. This study aimed to investigate the anti-inflammatory phytochemicals obtained from B. pilosa. We isolated a flavonoids-type phytochemical, isookanin, from B. pilosa through bioassay-guided fractionation based on its capacity to inhibit inflammation. Some of isookanin’s biological properties have been reported; however, the anti-inflammatory mechanism of isookanin has not yet been studied. In the present study, we evaluated the anti-inflammatory activities of isookanin using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We have shown that isookanin reduces the production of proinflammatory mediators (nitric oxide, prostaglandin E2) by inhibiting the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated macrophages. Isookanin also inhibited the expression of activator protein 1 (AP-1) and downregulated the LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun NH2-terminal kinase (JNK) in the MAPK signaling pathway. Additionally, isookanin inhibited proinflammatory cytokines (tumor necrosis factor-a (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β)) in LPS-induced THP-1 cells. These results demonstrate that isookanin could be a potential therapeutic candidate for inflammatory disease.

scholarly journals Preliminary Assessment of the Anti-Inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6630
Author(s):  
Daria D. Vaulina ◽  
Kira I. Stosman ◽  
Konstantin V. Sivak ◽  
Andrey G. Aleksandrov ◽  
Nikolai B. Viktorov ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Inflammatory Activity ◽  
Preliminary Evaluation ◽  
Moderate Increase ◽  
Biodistribution Studies ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
The Brain

Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [11C]MPbP (4′-[11С]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [18F]F-IV in a rodent model of neuroinflammation. [18F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by 18F-fluoroethylation of the precursor with Boc-protecting group (15) with [18F]2-fluoro-1-bromoethane ([18F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [18F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [11C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [18F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.

scholarly journals Proteoglycan Combined with Hyaluronic Acid and Hydrolyzed Collagen Restores the Skin Barrier in Mild Atopic Dermatitis and Dry, Eczema-Prone Skin: A Pilot Study

2021 ◽  
Vol 22 (19) ◽  
pp. 10189
Author(s):  
Young In Lee ◽  
Sang Gyu Lee ◽  
Jemin Kim ◽  
Sooyeon Choi ◽  
Inhee Jung ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Hyaluronic Acid ◽  
Barrier Function ◽  
Ex Vivo ◽  
Therapeutic Option ◽  
Skin Barrier ◽  
Transepidermal Water Loss ◽  
Skin Barrier Function ◽  
Hydrolyzed Collagen

Dry and eczema-prone skin conditions such as atopic dermatitis and xerotic eczema primarily indicate an impaired skin barrier function, which leads to chronic pruritus. Here, we investigated the effects of a novel emollient containing H.ECMTM liposome, which contains a soluble proteoglycan in combination with hydrolyzed collagen and hyaluronic acid. A prospective, single-arm study was conducted on 25 participants with mild atopic dermatitis or dry skin to assess the hydration and anti-inflammatory effect of the novel emollient applied daily over four weeks. All efficacy parameters, including itching severity, transepidermal water loss, and skin hydration, improved significantly after four weeks. The in vitro and ex vivo studies confirmed the restoration of the skin’s barrier function. The study revealed the clinical and laboratory efficacy of H.ECMTM liposome in reducing itching and improving the skin’s barrier integrity. Thus, the use of H.ECMTM liposome can be considered a therapeutic option for dry and eczema-prone skin.

scholarly journals Salicylate and Procyanidin-Rich Stem Extracts of Gaultheria procumbens L. Inhibit Pro-Inflammatory Enzymes and Suppress Pro-Inflammatory and Pro-Oxidant Functions of Human Neutrophils Ex Vivo

2019 ◽  
Vol 20 (7) ◽  
pp. 1753 ◽  
Author(s):  
Piotr Michel ◽  
Sebastian Granica ◽  
Anna Magiera ◽  
Karolina Rosińska ◽  
Małgorzata Jurek ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Biological Effects ◽  
Total Content ◽  
In Vitro Models ◽  
Human Neutrophils ◽  
Attractive Alternative ◽  
Anti Inflammatory ◽  
Model Components ◽  
Gaultheria Procumbens

Salicylate-rich plants are an attractive alternative to synthetic anti-inflammatory drugs due to a better safety profile and the advantage of complementary anti-inflammatory and antioxidant effects of the co-occurring non-salicylate phytochemicals. Here, the phytochemical value and biological effects in vitro and ex vivo of the stems of one of such plants, Gaultheria procumbens L., were evaluated. The best extrahent for effective recovery of the active stem molecules was established in comparative studies of five extracts. The UHPLC-PDA-ESI-MS3, HPLC-PDA, and UV-photometric assays revealed that the selected acetone extract (AE) accumulates a rich polyphenolic fraction (35 identified constituents; total content 427.2 mg/g dw), mainly flavanols (catechins and proanthocyanidins; 201.3 mg/g dw) and methyl salicylate glycosides (199.9 mg/g dw). The extract and its model components were effective cyclooxygenase-2, lipoxygenase, and hyaluronidase inhibitors; exhibited strong antioxidant capacity in six non-cellular in vitro models (AE and procyanidins); and also significantly and dose-dependently reduced the levels of reactive oxygen species (ROS), and the release of cytokines (IL-1β, IL-8, TNF-α) and proteinases (elastase-2, metalloproteinase-9) in human neutrophils stimulated ex vivo by lipopolysaccharide (LPS) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). The cellular safety of AE was demonstrated by flow cytometry. The results support the application of the plant in traditional medicine and encourage the use of AE for development of new therapeutic agents.

scholarly journals Investigating the Early Events after Skin-Barrier Disruption Using Microdialysis—A Human Ex Vivo Skin Model

Dermato ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 47-58
Author(s):  
Katrine Baumann ◽  
Niels Peter Hell Knudsen ◽  
Anne-Sofie Østergaard Gadsbøll ◽  
Anders Woetmann ◽  
Per Stahl Skov
Keyword(s):  
Interstitial Fluid ◽  
Ex Vivo ◽  
Skin Barrier ◽  
Microdialysis Sampling ◽  
Sample Analysis ◽  
Skin Model ◽  
Barrier Disruption ◽  
Gm Csf ◽  
Tnf Α ◽  
Subsequent Sample

Skin-barrier restoration following abrasive trauma is facilitated by mediator release from skin-resident cells, a process that has been investigated primarily in mice or simplified human systems with previous studies focusing on a limited number of biomarkers. Here, we demonstrate how early events caused by skin-barrier disruption can be studied in a human ex vivo skin model. Ten relevant biomarkers were recovered from the interstitial fluid by skin microdialysis with subsequent sample analysis using a multiplex platform. As a control, the biomarker profiles obtained from microdialysis sampling were compared to profiles of skin biopsy homogenates. We found that nine (GM-CSF, CXCL1/GROα, CXCL8/IL-8 CXCL10/IP-10, IL-1α, IL-6, MIF, TNF-α, and VEGF) of the 10 biomarkers were significantly upregulated in response to abrasive trauma. Only dialysate levels of CCL27/CTACK were unaffected by skin abrasion. Biomarker levels in the homogenates corresponded to dialysate levels for CCL27/CTACK, CXCL1/GROα, CXCL8/IL-8, and IL-6. However, IL-1α showed an inverse trend in response to trauma, and biopsy levels of MIF were unchanged. GM-CSF, CXCL10/IP-10, TNF-α, and VEGF were not detected in the biopsy homogenates. Our results suggest that the human ex vivo skin model is a reliable approach to study early events after disruption of the skin barrier.

scholarly journals Echinochrome A Treatment Alleviates Atopic Dermatitis-like Skin Lesions in NC/Nga Mice via IL-4 and IL-13 Suppression

Marine Drugs ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. 622
Author(s):  
Hyeong Rok Yun ◽  
Sang Woo Ahn ◽  
Bomin Seol ◽  
Elena A. Vasileva ◽  
Natalia P. Mishchenko ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Clinical Symptoms ◽  
Sea Urchins ◽  
Skin Barrier ◽  
Skin Lesions ◽  
Transepidermal Water Loss ◽  
Interleukin 4 ◽  
Barrier Dysfunction ◽  
Echinochrome A ◽  
Anti Inflammatory

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which skin barrier dysfunction leads to dryness, pruritus, and erythematous lesions. AD is triggered by immune imbalance and oxidative stress. Echinochrome A (Ech A), a natural pigment isolated from sea urchins, exerts antioxidant and beneficial effects in various inflammatory disease models. In the present study, we tested whether Ech A treatment alleviated AD-like skin lesions. We examined the anti-inflammatory effect of Ech A on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like lesions in an NC/Nga mouse model. AD-like skin symptoms were induced by treatment with 1% DNCB for 1 week and 0.4% DNCB for 5 weeks in NC/Nga mice. The results showed that Ech A alleviated AD clinical symptoms, such as edema, erythema, and dryness. Treatment with Ech A induced the recovery of epidermis skin lesions as observed histologically. Tewameter® and Corneometer® measurements indicated that Ech A treatment reduced transepidermal water loss and improved stratum corneum hydration, respectively. Ech A treatment also inhibited inflammatory-response-induced mast cell infiltration in AD-like skin lesions and suppressed the expression of proinflammatory cytokines, such as interferon-γ, interleukin-4, and interleukin-13. Collectively, these results suggest that Ech A may be beneficial for treating AD owing to its anti-inflammatory effects.

scholarly journals Effect of Cannabidiol (CBD) on Canine Inflammatory Response: An Ex Vivo Study on LPS Stimulated Whole Blood

2021 ◽  
Vol 8 (9) ◽  
pp. 185
Author(s):  
Enrico Gugliandolo ◽  
Patrizia Licata ◽  
Alessio Filippo Peritore ◽  
Rosalba Siracusa ◽  
Ramona D’Amico ◽  
...  
Keyword(s):  
Veterinary Medicine ◽  
Inflammatory Response ◽  
Whole Blood ◽  
Ex Vivo ◽  
Biological Effects ◽  
Treated Group ◽  
Ex Vivo Model ◽  
Group A ◽  
Anti Inflammatory ◽  
First Time

The use of cannabidiol (CBD) for animal species is an area of growing interest, for example for its anti-inflammatory and immuno-modulating properties, even though all of its biological effects are still not fully understood, especially in veterinary medicine. Therefore, the aim of this study was to investigate the anti-inflammatory and immuno-modulating properties of CBD for the first time directly in canine inflammatory response. We used an ex vivo model of LPS-stimulated whole dog blood. We stimulated the whole blood from healthy dogs with LPS 100 ng/mL for 24 h in the presence or not of CBD 50 and 100 μg/mL. We observed a reduction in IL-6 and TNF-α production from the group treated with CBD, but non-altered IL-10 levels. Moreover, we also observed from the CBD-treated group a reduction in Nf-κB and COX-2 expression. In conclusion, we demonstrated for the first time the anti-inflammatory and immuno-modulating properties of CBD directly in dogs’ immune cells, using a canine ex vivo inflammatory model. The results obtained from these studies encourage further studies to better understand the possible therapeutic role of CBD in veterinary medicine.

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