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Journal Der Deutschen Dermatologischen... May 2019Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease-related to psoriasis. Its treatment is challenging, and little is known about the sustainability of... (Observational Study)
Observational Study
BACKGROUND
Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease-related to psoriasis. Its treatment is challenging, and little is known about the sustainability of different medications. The aim of this study was to analyze drug survival rates and drug discontinuation in the treatment of PPP under real-world conditions.
PATIENTS AND METHODS
Patients with PPP treated in the dermatology departments of five German university medical centers between 01/2005 and 08/2017 were included in our retrospective study. Drug survival of systemic therapies was assessed with Kaplan-Meier analysis and multivariate regression.
RESULTS
Overall, 347 patients with 935 treatment courses were identified. Within the group of non-biologic systemic agents, apremilast showed the highest median drug survival (15 months), followed by cyclosporine (12 months), the combination of acitretin and topical PUVA (9 months), MTX (8 months), acitretin monotherapy (6 months), alitretinoin (5 months), and fumaric acid esters (3 months). Among biologicals, the highest maintenance rate was detected for certolizumab pegol (restricted mean: 47.4 months), followed by infliximab (median: 26 months), golimumab (22 months), ustekinumab (21 months), adalimumab (18 months), secukinumab (9 months), and etanercept (8 months).
CONCLUSIONS
Biologicals and apremilast may serve as second-line options for treatment of PPP and should be further evaluated.
Topics: Adult; Biological Products; Dermatologic Agents; Drug Substitution; Female; Foot Dermatoses; Hand Dermatoses; Humans; Kaplan-Meier Estimate; Male; Middle Aged; PUVA Therapy; Psoriasis; Retrospective Studies; Time Factors; Treatment Outcome
PubMed: 30994260
DOI: 10.1111/ddg.13834 -
Journal of Cellular Physiology Jun 2012The biological actions of retinoids are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We have recently reported that decreased...
The biological actions of retinoids are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We have recently reported that decreased expression of RARα and RXRα has an important role in high glucose (HG)-induced cardiomyocyte apoptosis. However, the regulatory mechanisms of HG effects on RARα and RXRα remain unclear. Using neonatal cardiomyocytes, we found that ligand-induced promoter activity of RAR and RXR was significantly suppressed by HG. HG promoted protein destabilization and serine-phosphorylation of RARα and RXRα. Proteasome inhibitor MG132 blocked the inhibitory effect of HG on RARα and RXRα. Inhibition of intracellular reactive oxidative species (ROS) abolished the HG effect. In contrast, H(2)O(2) stimulation suppressed the expression and ligand-induced promoter activity of RARα and RXRα. HG promoted phosphorylation of ERK1/2, JNK and p38 MAP kinases, which was abrogated by an ROS inhibitor. Inhibition of JNK, but not ERK and p38 activity, reversed HG effects on RARα and RXRα. Activation of JNK by over expressing MKK7 and MEKK1, resulted in significant downregulation of RARα and RXRα. Ligand-induced promoter activity of RARα and RXRα was also suppressed by overexpression of MEKK1. HG-induced cardiomyocyte apoptosis was potentiated by activation of JNK, and prevented by all-trans retinoic acid and inhibition of JNK. Silencing the expression of RARα and RXRα activated the JNK pathway. In conclusion, HG-induced oxidative stress and activation of the JNK pathway negatively regulated expression/activation of RAR and RXR. The impaired RAR/RXR signaling and oxidative stress/JNK pathway forms a vicious circle, which significantly contributes to hyperglycemia induced cardiomyocyte apoptosis.
Topics: Alitretinoin; Animals; Animals, Newborn; Apoptosis; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Glucose; HEK293 Cells; Humans; Hyperglycemia; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 7; MAP Kinase Kinase Kinase 1; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocytes, Cardiac; Oxidants; Oxidative Stress; Phosphorylation; Promoter Regions, Genetic; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Kinase Inhibitors; RNA Interference; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptor alpha; Signal Transduction; Time Factors; Transcriptional Activation; Transfection; Tretinoin; p38 Mitogen-Activated Protein Kinases
PubMed: 21882190
DOI: 10.1002/jcp.23005 -
Annals of Surgery Aug 2016To determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema.
OBJECTIVE
To determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema.
BACKGROUND
9-cis RA promotes lymphangiogenesis in vitro and in vivo and has promise as a therapeutic agent to limit the development of postsurgical lymphedema.
METHODS
Lymphedema was induced in the right hind limb after a single fraction of 20 Gy radiation, popliteal lymphadenectomy, and lymphatic vessel ablation. Postoperatively, mice were randomly divided in to 2 groups that received daily intraperitoneal injections of either (1) an oil-based vehicle solution (control) or (2) 0.08 mg/kg of 9-cis RA dissolved in a vehicle solution. Outcome measures included paw thickness, lymphatic drainage, and lymphatic vessel density as measured by podoplanin immunohistochemistry and whole mount skin analysis.
RESULTS
Using our combined injury protocol, postsurgical lymphedema was observed 89% of the time. 9-cis RA-treated animals had less early postsurgical edema and significantly less paw lymphedema compared with vehicle-treated animals at all time-points (P < 0.001). 9-cis RA-treated animals had significantly faster lymphatic drainage as measured by indocyanine green clearance and increased lymphatic vessel density as measured by podoplanin immunohistochemistry (P < 0.001) and whole mount skin analysis (P < 0.05).
CONCLUSIONS
We have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans.
Topics: Alitretinoin; Animals; Antineoplastic Agents; Disease Models, Animal; Lymphangiogenesis; Lymphedema; Male; Mice; Mice, Transgenic; Postoperative Complications; Tretinoin
PubMed: 26655920
DOI: 10.1097/SLA.0000000000001525 -
European Journal of Immunology Jan 2021Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells,...
Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells, controlled by their corresponding nuclear receptors, VDR and RAR. Herein, after the establishment of a plasmablast differentiation culture, we investigated how both ligands modulate human naïve B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified naïve B cells resulted in a strong differentiation of CD27 CD38 plasmablasts and antibody secretion. The significant IgA response was preceded by a strong induction of α-germline transcription (GLT). Induction of αGLT and consecutively IgA secretion driven by calcitriol is a novel observation and we show by magnetic chromatin IP that this was mediated by recruitment of the VDR to the TGF-β promoter thus inducing TGF-β expression. Finally, as revealed by transcriptomic profiling calcitriol and 9cRA modulate several signals required for differentiation and isotype switching in a noncompeting but rather additive manner. Calcitriol and 9cRA participate in the control of the IgA response in human activated naïve B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction.
Topics: Adaptive Immunity; Alitretinoin; B-Lymphocytes; Binding Sites; CD40 Ligand; Calcitriol; Cell Differentiation; Cells, Cultured; GTP-Binding Proteins; Gene Expression; Humans; Immunoglobulin A; Immunoglobulin Class Switching; Interleukin-4; Ligands; Lymphocyte Activation; Plasma Cells; Promoter Regions, Genetic; Protein Glutamine gamma Glutamyltransferase 2; Receptors, Calcitriol; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; Transforming Growth Factor beta1; Transglutaminases; Vitamin D3 24-Hydroxylase
PubMed: 33107588
DOI: 10.1002/eji.202048557 -
Acta Dermato-venereologica May 2012This non-interventional observational open study (TOCCATA, sponsored by Basilea Pharmaceutica Germany) investigated the use of alitretinoin to treat chronic hand eczema...
This non-interventional observational open study (TOCCATA, sponsored by Basilea Pharmaceutica Germany) investigated the use of alitretinoin to treat chronic hand eczema under daily "real life" medical practice conditions in Germany. A total of 349 dermatologists through-out Germany enrolled 680 adult patients with chronic hand eczema. Patients were prescribed and treated with alitretinoin in accordance with the summary of product characteristics. The maximum observation duration was 24 weeks, with efficacy and safety parameters evaluated every 4 weeks. Efficacy was primarily evaluated by assessing disease severity according to the Physician Global Assessment. In total, 56.7% of patients achieved a Physician Global Assessment rating of "clear" or "almost clear" hands, with only small differences in patients with different morphological forms: hyperkeratotic-rhagadiform (59.2%), fingertip (52.2%) and vesicular (47.9%). This observational study demonstrates the effectiveness and tolerability of alitretinoin in everyday clinical practice in addition to the known efficacy and safety obtain-ed by randomized controlled clinical trials.
Topics: Adult; Alitretinoin; Chronic Disease; Eczema; Female; Hand Dermatoses; Humans; Keratolytic Agents; Male; Middle Aged; Severity of Illness Index; Tretinoin
PubMed: 22281779
DOI: 10.2340/00015555-1256 -
Lymphatic Research and Biology Feb 2019The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes...
BACKGROUND
The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes as well as a wide range of human diseases. In particular, FGFR3 has been implicated in the mechanism by which 9-cis retinoic acid (9-cisRA) induces lymphangiogenesis and improves lymphedema. The purpose of this study was to validate the efficacy of a novel small peptide FGFR3 inhibitor, peptide P3 (VSPPLTLGQLLS), and to elucidate the role of FGFR3 in 9-cisRA-induced lymphangiogenesis using this peptide.
METHODS AND RESULTS
Peptide P3 effectively inhibited FGFR3 phosphorylation. In vitro, peptide P3-mediated FGFR3 inhibition did not decrease lymphatic endothelial cell (LEC) proliferation, migration, or tubule formation. However, peptide P3-mediated FGFR3 inhibition did block 9-cisRA-stimulated LEC proliferation, migration, and tubule formation. In vivo, peptide P3-mediated FGFR3 inhibition was sufficient to inhibit 9-cisRA-induced tracheal lymphangiogenesis.
CONCLUSION
FGFR3 does not appear to be essential to nonpromoted LEC proliferation, migration, and tubule formation. However, FGFR3 may play a key role in LEC proliferation, migration, tubule formation, and postnatal in vivo lymphangiogenesis when pharmacologically induced by 9-cisRA. P3 may have the potential to be used as a precise regulatory control element for 9-cisRA-mediated lymphangiogenesis.
Topics: Alitretinoin; Amino Acid Sequence; Animals; Biological Assay; Cell Movement; Cell Proliferation; Endothelial Cells; Gene Expression Regulation; Humans; Lymphangiogenesis; Lymphedema; Mice; Mice, Transgenic; Oligopeptides; Phosphorylation; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Trachea
PubMed: 30648916
DOI: 10.1089/lrb.2018.0035 -
Acta Dermato-venereologica May 2013A Danish-Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic...
A Danish-Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis. Patients were recruited from 5 dermatology departments in Denmark, and data were obtained using a structured questionnaire and a systematic examination together with photographs, histopathological descriptions and blood samples for mutational analysis. Sixteen patients from 12 families with generalized or naevoid epidermolytic ichthyosis and ichthyosis bullosa of Siemens were identified. Five families had mutations in K1 and 6 families had mutations in K10. Nine patients had been treated with systemic retinoids (etretinate, acitretin, isotretinoin or alitretinoin), but only 3 patients had acceptable treatment responses and chose to continue therapy. In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%). We identified 4 novel disease-causing mutations.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; DNA Mutational Analysis; Denmark; Female; Genetic Predisposition to Disease; Humans; Hyperkeratosis, Epidermolytic; Infant; Keratin-1; Keratin-10; Male; Mutation; Pedigree; Phenotype; Prevalence; Retinoids; Skin; Surveys and Questionnaires; Treatment Outcome; Young Adult
PubMed: 22930352
DOI: 10.2340/00015555-1447 -
Gut Jan 2006Activated pancreatic stellate cells (PSCs) are implicated in the production of alcohol induced pancreatic fibrosis. PSC activation is invariably associated with loss of...
BACKGROUND AND AIMS
Activated pancreatic stellate cells (PSCs) are implicated in the production of alcohol induced pancreatic fibrosis. PSC activation is invariably associated with loss of cytoplasmic vitamin A (retinol) stores. Furthermore, retinol and ethanol are known to be metabolised by similar pathways. Our group and others have demonstrated that ethanol induced PSC activation is mediated by the mitogen activated protein kinase (MAPK) pathway but the specific role of retinol and its metabolites all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-RA) in PSC quiescence/activation, or its influence on ethanol induced PSC activation is not known. Therefore, the aims of this study were to (i) examine the effects of retinol, ATRA, and 9-RA on PSC activation; (ii) determine whether retinol, ATRA, and 9-RA influence MAPK signalling in PSCs; and (iii) assess the effect of retinol supplementation on PSCs activated by ethanol.
METHODS
Cultured rat PSCs were incubated with retinol, ATRA, or 9-RA for varying time periods and assessed for: (i) proliferation; (ii) expression of alpha smooth muscle actin (alpha-SMA), collagen I, fibronectin, and laminin; and (iii) activation of MAPKs (extracellular regulated kinases 1 and 2, p38 kinase, and c-Jun N terminal kinase). The effect of retinol on PSCs treated with ethanol was also examined by incubating cells with ethanol in the presence or absence of retinol for five days, followed by assessment of alpha-SMA, collagen I, fibronectin, and laminin expression.
RESULTS
Retinol, ATRA, and 9-RA significantly inhibited: (i) cell proliferation, (ii) expression of alpha-SMA, collagen I, fibronectin, and laminin, and (iii) activation of all three classes of MAPKs. Furthermore, retinol prevented ethanol induced PSC activation, as indicated by inhibition of the ethanol induced increase in alpha-SMA, collagen I, fibronectin, and laminin expression.
CONCLUSIONS
Retinol and its metabolites ATRA and 9-RA induce quiescence in culture activated PSCs associated with a significant decrease in the activation of all three classes of MAPKs in PSCs. Ethanol induced PSC activation is prevented by retinol supplementation.
Topics: Alitretinoin; Animals; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Dual Specificity Phosphatase 1; Enzyme Activation; Enzyme Inhibitors; Ethanol; Extracellular Matrix Proteins; Fibrosis; Immediate-Early Proteins; Mitogen-Activated Protein Kinases; Pancreas; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Tyrosine Phosphatases; Rats; Receptors, Retinoic Acid; Retinoid X Receptors; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin; Vanadates; Vitamin A
PubMed: 16043492
DOI: 10.1136/gut.2005.064543 -
PLoS Pathogens Mar 2022Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family...
Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family Member 4 (KIF4) plays an important role in HBV/HDV infection. We intended to explore host factors impacting the HBV life cycle that can be therapeutically addressed using siRNA library transfection and HBV/NLuc (HBV/NL) reporter virus infection in HepG2-hNTCP cells. KIF4 silencing resulted in a 3-fold reduction in luciferase activity following HBV/NL infection. KIF4 knockdown suppressed both HBV and HDV infection. Transient KIF4 depletion reduced surface and raised intracellular NTCP (HBV/HDV entry receptor) levels, according to both cellular fractionation and immunofluorescence analysis (IF). Overexpression of wild-type KIF4 but not ATPase-null KIF4 mutant regained the surface localization of NTCP and significantly restored HBV permissiveness in these cells. IF revealed KIF4 and NTCP colocalization across microtubule filaments, and a co-immunoprecipitation study revealed that KIF4 interacts with NTCP. KIF4 expression is regulated by FOXM1. Interestingly, we discovered that RXR agonists (Bexarotene, and Alitretinoin) down-regulated KIF4 expression via FOXM1-mediated suppression, resulting in a substantial decrease in HBV-Pre-S1 protein attachment to HepG2-hNTCP cell surface and subsequent HBV infection in both HepG2-hNTCP and primary human hepatocyte (PXB) (Bexarotene, IC50 1.89 ± 0.98 μM) cultures. Overall, our findings show that human KIF4 is a critical regulator of NTCP surface transport and localization, which is required for NTCP to function as a receptor for HBV/HDV entry. Furthermore, small molecules that suppress or alleviate KIF4 expression would be potential antiviral candidates targeting HBV and HDV entry.
Topics: Family; Hep G2 Cells; Hepatitis B virus; Hepatitis Delta Virus; Humans; Kinesins; Organic Anion Transporters, Sodium-Dependent; Retinoid X Receptors; Symporters; Virus Internalization
PubMed: 35312737
DOI: 10.1371/journal.ppat.1009983 -
Aging Mar 2020Alzheimer's disease (AD) is associated with the accumulation and deposition of a beta-amyloid (Αβ) peptide in the brain, resulting in increased neuroinflammation and...
Alzheimer's disease (AD) is associated with the accumulation and deposition of a beta-amyloid (Αβ) peptide in the brain, resulting in increased neuroinflammation and synaptic dysfunction. Intranasal delivery of targeted drugs to the brain represents a noninvasive pathway that bypasses the blood-brain barrier and minimizes systemic exposure. The aim of this study was to evaluate the therapeutic effect of intranasally delivered 9-cis retinoic acid (RA) on the neuropathology of an AD mouse model. Herein, we observed dramatically decreased Αβ deposition in the brains of amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice (APP/PS1) treated intranasally with 9-cis RA for 4 weeks compared to that in the brains of vehicle-treated mice. Importantly, intranasal delivery of 9-cis RA suppressed Αβ-associated astrocyte activation and neuroinflammation and ultimately restored synaptic deficits in APP/PS1 transgenic mice. These results support the critical roles of Αβ-associated neuroinflammation responses to synaptic deficits, particularly during the deposition of Αβ. Our findings provide strong evidence that intranasally delivered 9-cis RA attenuates neuronal dysfunction in an AD mouse model and is a promising therapeutic strategy for the prevention and treatment of AD.
Topics: Administration, Intranasal; Alitretinoin; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Astrocytes; Brain; Disease Models, Animal; Inflammation; Inflammation Mediators; Mice; Mice, Transgenic; Microglia; Presenilin-1
PubMed: 32209731
DOI: 10.18632/aging.102970