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Frontiers in Medicine 2021SARS-Cov2 has raised concerns among dermatologists regarding psoriasis and its respective treatments. Comorbidities, which induce the expression of the proprotease...
SARS-Cov2 has raised concerns among dermatologists regarding psoriasis and its respective treatments. Comorbidities, which induce the expression of the proprotease furin have been associated with severe course of COVID-19. Furin and angiotensin converting enzyme 2 (ACE2) play a major role in viral host cell entry of SARS-Cov2. To evaluate mRNA expression of Furin and ACE2 from blood cells in psoriasis patients, and whether systemic or topical treatment reduces expression levels. This observational translational study analyzed blood samples from patients from a clinical trial and samples retrieved from the biobank of the Psoriasis Registry Austria (PsoRA). Furin and ACE2 expression levels were analyzed prior to as well as 3 and 12-24 months after start of biologic treatment with either ustekinumab or secukinumab. Additionally, the study analyzed expression levels prior to, 6 days after start of dithranol treatment and 4-6 weeks after end of dithranol treatment. Furin mRNA expression was significantly increased at baseline in the biologic (4.9 ± 2.6 fold, < 0.0001) and in the dithranol group (2.7 ± 1.4 fold, < 0.001) compared to controls. There was a trend for arthritis patients to express more furin than patients with psoriatic skin involvement only (5.26 ± 2.30 vs. 3.48 ± 2.27, = 0.078). Analyzing furin mRNA expression after treatment initiation with secukinumab or ustekinumab revealed a normalization of levels after 3 and 12 to 24 months. Similar findings were obtained for patients treated with dithranol, with significantly decreased expression levels 6 days after start of dithranol treatment and also at follow-up, (4-6 weeks after dithranol treatment had been terminated). ACE2 expression levels did not differ from controls at any timepoint, regardless of biologic or topical treatment. Significantly overexpressed levels of furin were observed in untreated patients, and, thus, these patients may be at risk for infection and a severe course of COVID-19. However, the data indicate that successful therapeutic intervention in psoriasis, by systemic biologic or topical treatment, can efficiently reduce furin levels in blood cells, possibly limiting the risk of psoriasis patients for a severe COVID-19 course. ClinicalTrials.gov, identifier NCT02752672.
PubMed: 33644099
DOI: 10.3389/fmed.2021.624462 -
Frontiers in Microbiology 2020Influenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The...
Influenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The viral polymerases process the capped RNAs to produce short capped RNA fragments that are used as primers to initiate the transcription of viral mRNAs. This process, known as cap-snatching, can be targeted by antiviral therapeutics. Here, anthralin was identified as an inhibitor against influenza a virus (IAV) infection by targeting the cap-snatching activity of the viral polymerase. Anthralin, an FDA-approved drug used in the treatment of psoriasis, shows antiviral activity against IAV infection and . Importantly, anthralin significantly reduces weight loss, lung injury, and mortality caused by IAV infection in mice. The mechanism of action study revealed that anthralin inhibits the cap-binding function of PB2 subunit and endonuclease activity of PA. As a result, viral mRNA transcription is blocked, leading to the decreases in viral RNA replication and viral protein expression. In conclusion, anthralin has been demonstrated to have the potential of an alternative antiviral against influenza virus infection. Also, targeting the captive pocket structure that includes the N-terminus of PA endonuclease domain and the C-terminal of PB2 cap-binding domain of IAV RdRp may be an excellent strategy for developing anti-influenza drugs.
PubMed: 32132985
DOI: 10.3389/fmicb.2020.00178 -
PloS One 2019Equine glutathione transferase A3-3 (EcaGST A3-3) belongs to the superfamily of detoxication enzymes found in all higher organisms. However, it is also the most...
Equine glutathione transferase A3-3 (EcaGST A3-3) belongs to the superfamily of detoxication enzymes found in all higher organisms. However, it is also the most efficient steroid double-bond isomerase known in mammals. Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes the horse a suitable animal model for investigations of human steroidogenesis. Inhibition of the enzyme has potential for treatment of steroid-hormone-dependent disorders. Screening of a library of FDA-approved drugs identified 16 out of 1040 compounds, which at 10 μM concentration afforded at least 50% inhibition of EcaGST A3-3. The most potent inhibitors, anthralin, sennoside A, tannic acid, and ethacrynic acid, were characterized by IC50 values in the submicromolar range when assayed with the natural substrate Δ5-androstene-3,17-dione.
Topics: Animals; Anthralin; Enzyme Inhibitors; Ethacrynic Acid; Glutathione Transferase; Horses; Sennosides; Substrate Specificity; Tannins
PubMed: 30897163
DOI: 10.1371/journal.pone.0214160 -
Canadian Family Physician Medecin de... Apr 2005To review current understandings of and approaches to topical psoriasis therapies and to assess their efficacies and adverse effects. (Review)
Review
OBJECTIVE
To review current understandings of and approaches to topical psoriasis therapies and to assess their efficacies and adverse effects.
QUALITY OF EVIDENCE
Literature from 1987 to 2003, inclusive, was reviewed via MEDLINE using the search term "psoriasis" combined with "topical treatment." Articles were prioritized based on their level of evidence, favouring double-blind, randomized controlled trials over other comparison studies. Other studies were included where level I research was unavailable. No level III research was included.
MAIN MESSAGE
Psoriasis is very common and causes substantial morbidity. Because most psoriasis is mild to moderate, patients are well suited to outpatient topical therapy. Advances in topical treatments for psoriasis have kept pace with a rapidly evolving comprehension of its pathogenesis, making a review of current therapies useful for those who treat psoriasis. While research supports continued reliance on corticosteroids as first-line therapy, comparable efficacy has been shown for vitamin D analogues and topical retinoids, albeit with a slight increase in adverse effects.
CONCLUSION
The combination of steroids and vitamin D analogues or topical retinoids is perhaps the most promising current treatment. It seems to have increased efficacy and fewer side effects.
Topics: Administration, Topical; Adrenal Cortex Hormones; Anthralin; Anti-Inflammatory Agents; Dermatologic Agents; Drug Combinations; Humans; Psoriasis; Retinoids; Tars; Vitamin D
PubMed: 15856971
DOI: No ID Found -
International Journal of Nanomedicine 2024Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly...
Revolutionizing Psoriasis Topical Treatment: Enhanced Efficacy Through Ceramide/Phospholipid Composite Cerosomes Co-Delivery of Cyclosporine and Dithranol: In-Vitro, Ex-Vivo, and in-Vivo Studies.
PURPOSE
Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly treated with cyclosporine-A (CsA) and dithranol (DTH). CsA suppresses the activation of T-cells, immune cells involved in forming psoriatic lesions. Meanwhile, DTH is a potent anti-inflammatory and anti-proliferative drug that effectively reduces the severity of psoriasis symptoms such as redness, scaling, and skin thickness. CsA and DTH belong to BCS class II with limited oral bioavailability. We aim to develop a drug delivery system for topical co-delivery of CsA and DTH, exploring its therapeutic potential.
METHODS
Firstly, we developed a niosomal drug delivery system based on ceramide IIIB to form Cerosomes. Cerosomes were prepared from a mixture of Ceramide, hyaluronic acid, and edge activator using a thin-film hydration technique. To co-deliver CsA and DTH topically for the treatment of psoriasis. These two hydrophobic drugs encapsulated into our synthesized positively charged particle cerosomes.
RESULTS
Cerosomes had an average particle size of (222.36 nm± 0.36), polydispersity index of (0.415±0.04), Entrapment Efficiency of (96.91%± 0.56), and zeta potential of (29.36±0.38mV) for selected formula. In vitro, In silico, in vivo, permeation, and histopathology experiments have shown that cerosomes enhanced the skin penetration of both hydrophobic drugs by 66.7% compared to the CsA/DTH solution. Imiquimod (IMQ) induced psoriatic mice model was topically treated with our CsA/DTH cerosomes. We found that our formulation enhances the skin penetration of both drugs and reduces psoriasis area and severity index (PASI score) by 2.73 times and 42.85%, respectively, compared to the CsA/DTH solution. Moreover, it reduces the levels of proinflammatory cytokines, TNF-α, IL-10, and IL-6 compared to CsA/DTH solution administration.
CONCLUSION
The Cerosomes nano-vesicle-containing CsA/DTH represents a more promising topical treatment for psoriasis, giving new hope to individuals with psoriasis, compared to commercial and other conventional alternatives.
Topics: Humans; Animals; Mice; Anthralin; Cyclosporine; Phospholipids; Ceramides; Administration, Cutaneous; Psoriasis; Skin; Disease Models, Animal
PubMed: 38344440
DOI: 10.2147/IJN.S443812 -
Experimental Dermatology Jun 2021Topical dithranol is effective in autoimmune conditions like alopecia areata, inducing hair regrowth in a high percentage of cases. Exact mechanisms of dithranol in...
Topical dithranol is effective in autoimmune conditions like alopecia areata, inducing hair regrowth in a high percentage of cases. Exact mechanisms of dithranol in alopecia areata, with seemingly healthy epidermis besides altered hair follicles, are not well understood. To better understand dithranol's mechanisms on healthy skin, we analysed its effect on normal murine as well as xenografted human skin. We found a strong increase in mRNA expression of anti-microbial peptides (AMPs) (eg Lcn2, Defb1, Defb3, S100a8, S100a9), keratinocyte differentiation markers (eg Serpinb3a, Flg, Krt16, Lce3e) and inflammatory cytokines (eg Il1b and Il17) in healthy murine skin. This effect was paralleled by inflammation and disturbed skin barrier, as well as an injury response resulting in epidermal hyperproliferation, as observed in murine and xenografted adult human skin. This contact response and disturbed barrier induced by dithranol might lead via a vicious loop between AMPs such as S100a8/a9 (that led to skin swelling itself after topical application) and cytokines such as IL-1β to an immune suppressive environment in the skin. A better understanding of the skin's physiologic response to dithranol may open up new avenues for the establishment of novel therapeutics (including AMP-related/interfering molecules) for certain skin conditions, such as alopecia areata.
Topics: Alopecia Areata; Animals; Anthralin; Antimicrobial Peptides; Cytokines; Dermatologic Agents; Humans; Interleukin-1beta; Keratinocytes; Mice; Mice, Inbred BALB C
PubMed: 33629779
DOI: 10.1111/exd.14310 -
The Journal of Investigative Dermatology Apr 2000Anthralin is a widely used, topical therapy for psoriasis. Anti-proliferative and anti-inflammatory properties of anthralin have been identified. Little is known,...
Anthralin is a widely used, topical therapy for psoriasis. Anti-proliferative and anti-inflammatory properties of anthralin have been identified. Little is known, however, about differential sensitivities of targeted cell types and specific mechanisms of signaling pathway activation. We demonstrate that anthralin exerts potent effects on keratinocytes and mononuclear cells through strong induction of lipid peroxidation and JNK activation, a stress-induced signal transduction pathway. Lipid peroxidation was observed rapidly and half-maximal levels of lipid peroxidation were reached at a 10-fold lower concentration of anthralin for peripheral blood mononuclear cells vs normal keratinocytes. JNK activation was detected in peripheral blood mononuclear cells at a 40-fold lower anthralin dose compared with keratinocytes. For both cell types, selected inhibitors of lipid peroxidation prevented JNK activation. This study demonstrates that mononuclear leukocytes are markedly more sensitive than keratinocytes to anthralin-induced lipid peroxidation and JNK activation. We identify anthralin as a novel and potent inducer of JNK activation and demonstrate that this process is mediated, at least in part, by lipid peroxidation which is among the earliest and most proximate, membrane-related responses to anthralin yet described.
Topics: Administration, Topical; Anthralin; Anti-Inflammatory Agents; Enzyme Activation; Humans; Infant, Newborn; JNK Mitogen-Activated Protein Kinases; Keratinocytes; Leukocytes, Mononuclear; Lipid Peroxidation; MAP Kinase Kinase 4; Male; Mitogen-Activated Protein Kinase Kinases; Psoriasis
PubMed: 10733674
DOI: 10.1046/j.1523-1747.2000.00934.x -
Journal of the American Society For... May 2006A dry sample preparation strategy was previously established as a new method for matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS), so-called...
A dry sample preparation strategy was previously established as a new method for matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS), so-called solvent-free MALDI-MS. In this contribution, we examine systems that have been shown problematic with conventional solvent-based MALDI approaches. Problems frequently encountered are solubility, miscibility, and segregation effects during crystallization as a result of unfavorable analyte and matrix polarities. In all cases studied, solvent-free MALDI-MS simplified the measurement and improved the analysis. Solvent-free MALDI-MS enables more reliable results in well-known problematic systems such as polydimethylsiloxane with its segregation effects. However, even in highly compatible analyte/matrix systems such as polystyrene and dithranol, there were undesirable suppression effects when employing THF as solvent. Generally, the solvent-free method allows for more homogeneous analyte/matrix mixtures as well as higher shot-to-shot and sample-to-sample reproducibility. As a result, less laser power has to be applied, which yields milder MALDI conditions, reduced background signals, and provides better resolution of the analyte signals. Solvent-free MALDI-MS proved valuable for the characterization of nanosized material, e.g., fullereno-based structures, which indicated having an increased fragmentation-susceptibility. New analyte/matrix combinations (e.g., polyvinylpyrrolidone/dithranol) are accessible independent of solubility and compatibility in common solvents. An improved quantitation potential is recognized (e.g., insoluble polycyclic aromatic hydrocarbon against soluble dendrite precursor). The rapid and easy measurement of industrial products demonstrates the solvent-free method capable for improved throughput analysis of a variety of compounds (e.g., poly(butylmethacrylate) diol) in routine industrial analysis. Hence, this new MALDI method leads to qualitative and quantitative improvements, making it a powerful tool for analytical purposes, which may also prove to be valuable in future automation attempts.
Topics: Organic Chemicals; Polymers; Reproducibility of Results; Solvents; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 16540340
DOI: 10.1016/j.jasms.2006.01.007 -
International Journal of Nanomedicine 2020Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative...
PURPOSE
Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative strategies eradicating ROS may serve as effective and easy treatment options for psoriasis, while nanozymes with intrinsic antioxidant enzyme-like activity have not been explored for psoriasis treatment. The aim of this study is to fabricate β-cyclodextrins (β-CDs)-modified ceria nanoparticles (β-CDs/CeO NPs) with drug-loaded and multimimic-enzyme activities for combinational psoriasis therapy.
METHODS
The β-CDs/CeO NPs were synthesized by a hydrothermal method using unmodified β-CDs as a protecting agent. The structure, size and morphology were analyzed by dynamic light scattering, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. Considering the superoxide dismutase (SOD)- and catalase-mimetic activities, the in vitro antioxidant activity of the β-CDs/CeO2 NPs was investigated. After dithranol (DIT) was loaded, the drug-loading capacity and release profile were determined by UV-visible light spectrophotometer and high-performance liquid chromatography. The anti-psoriatic efficacy was studied in the imiquimod (IMQ)-induced mouse model on the basis of morphological evaluation, psoriasis area and severity index calculation (PASI), and inflammatory cytokine expression.
RESULTS
The average particle size of the blank β-CDs/CeO NPs was 60.89±0.32 nm with a polydispersity index (PDI) of 0.12, whereas that of the DIT-loaded NPs was 79.38±1.06 nm with a PDI of 0.27. TEM results showed the as-prepared NPs formed a uniform quasi-spherical shape with low polydispersity. XPS indicates synthesized NPs have a mixed Ce/Ce valence state. FTIR spectroscopy confirmed the presence of β-CDs and DIT in the NPs. Inhibition of superoxide anion rate by NPs could be reached to 79.4% in the presence of 200 µg/mL, and elimination of HO efficiency reached about 50% in the presence of 40 µg/mL, demonstrating excellent superoxide dismutase- and catalase-mimicking activities, thereby providing remarkable cryoprotection against ROS-mediated damage. Furthermore, β-CDs on the surface endowed the NPs with drug-loading function via host-guest interactions. The entrapment efficiency and drug loading of DIT are 94.7% and 3.48%, respectively. The in vitro drug release curves revealed a suitable release capability of DIT@β-CDs/CeO NPs under physiological conditions. In IMQ-induced psoriatic model, the DIT@β-CDs/CeO NPs exhibited excellent therapeutic effect.
CONCLUSION
This study may pave the way for the application of nanozyme β-CDs/CeO NPs as a powerful tool for psoriasis therapy.
Topics: Animals; Catalase; Cell Line; Cell Survival; Cerium; Combined Modality Therapy; Free Radical Scavengers; Hydrodynamics; Imiquimod; Male; Mice, Inbred BALB C; Nanoparticles; Particle Size; Photoelectron Spectroscopy; Psoriasis; Reactive Oxygen Species; Skin; Spectroscopy, Fourier Transform Infrared; Superoxide Dismutase; Tumor Necrosis Factor-alpha; beta-Cyclodextrins
PubMed: 32368038
DOI: 10.2147/IJN.S246783 -
International Journal of Molecular... Mar 2023Skin is a major administration route for drugs, and all transdermal formulations must be tested for their capability to overcome the cutaneous barrier. Therefore,...
Skin is a major administration route for drugs, and all transdermal formulations must be tested for their capability to overcome the cutaneous barrier. Therefore, developing highly reliable skin models is crucial for preclinical studies. The current in vitro models are unable to replicate the living skin in all its complexity; thus, to date, excised human skin is considered the gold standard for in vitro permeation studies. However, skin explants have a limited life span. In an attempt to overcome this problem, we used an innovative bioreactor that allowed us to achieve good structural and functional preservation in vitro of explanted human skin for up to 72 h. This device was then used to set up an in vitro inflammatory model by applying two distinct agents mimicking either exogenous or endogenous stimuli: i.e., dithranol, inducing the contact dermatitis phenotype, and the substance P, mimicking neurogenic inflammation. Our in vitro system proved to reproduce inflammatory events observed in vivo, such as vasodilation, increased number of macrophages and mast cells, and increased cytokine secretion. This bioreactor-based system may therefore be suitably and reliably used to simulate in vitro human skin inflammation and may be foreseen as a promising tool to test the efficacy of drugs and cosmetics.
Topics: Humans; Hydrodynamics; Skin; Administration, Cutaneous; Skin Absorption; Inflammation; Pharmaceutical Preparations
PubMed: 37047256
DOI: 10.3390/ijms24076284