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Molecules (Basel, Switzerland) Sep 2022The heterodimeric complex between retinoic X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most important and...
The heterodimeric complex between retinoic X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most important and predominant regulatory systems, controlling lipid metabolism by binding to specific DNA promoter regions. X-ray and molecular dynamics (MD) simulations have revealed the average conformation adopted by the RXRα-PPARγ heterodimer bound to DNA, providing information about how multiple domains communicate to regulate receptor properties. However, knowledge of the energetic basis of the protein-ligand and protein-protein interactions is still lacking. Here we explore the structural and energetic mechanism of RXRα-PPARγ heterodimer bound or unbound to DNA and forming complex with co-crystallized ligands (rosiglitazone and 9--retinoic acid) through microsecond MD simulations, molecular mechanics generalized Born surface area binding free energy calculations, principal component analysis, the free energy landscape, and correlated motion analysis. Our results suggest that DNA binding alters correlated motions and conformational mobility within RXRα-PPARγ system that impact the dimerization and the binding affinity on both receptors. Intradomain correlated motions denotes a stronger correlation map for RXRα-PPARγ-DNA than RXRα-PPARγ, involving residues at the ligand binding site. In addition, our results also corroborated the greater role of PPARγ in regulation of the free and bound DNA state.
Topics: Alitretinoin; Carrier Proteins; DNA; Humans; Ligands; Molecular Dynamics Simulation; PPAR gamma; Rosiglitazone
PubMed: 36144514
DOI: 10.3390/molecules27185778 -
Clinical and Experimental Dermatology Dec 2022For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids...
For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.
Topics: Adult; Humans; Female; Acitretin; Isotretinoin; Alitretinoin; Hyperostosis; Ichthyosis
PubMed: 35988035
DOI: 10.1111/ced.15382 -
Medicina (Kaunas, Lithuania) Jul 2022Darier disease is an autosomal dominant disorder with dark crusty patches and is classified as hereditary acantholytic dermatosis. Keratotic papules and crust are often...
Darier disease is an autosomal dominant disorder with dark crusty patches and is classified as hereditary acantholytic dermatosis. Keratotic papules and crust are often present on the scalp, forehead, chest, back, upper arms, elbows, groin, and behind the ears, predominantly in seborrheic areas. A 48-year-old male patient presented skin lesions with pruritus on the trunk and both upper and lower extremities. He first noticed the lesion 15 years before. On physical examination, there were multiple erythematous papules with crust on the trunk and red-brown colored keratotic plaque on both extremities. The suspected histopathological diagnosis was psoriasis vulgaris. The patient's skin lesions and pruritus were significantly improved after the psoriasis treatment. While continuing psoriasis treatment, the patient showed sudden worsening of the skin lesions on the scalp, abdomen, and fingernails (V-shaped nicks) with pruritus. Punch biopsy was performed on the abdominal lesion again and the final diagnosis was Darier disease. The patient was then treated using alitretinoin while maintaining the use of guselkumab for psoriasis. There are only a few cases that we found in which patients with Darier disease also had psoriasis. We report this rare case of Darier disease with psoriasis and propose that an additional biopsy might be necessary for accurate diagnosis and proper treatment.
Topics: Biopsy; Darier Disease; Humans; Male; Middle Aged; Pruritus; Psoriasis; Skin
PubMed: 35888621
DOI: 10.3390/medicina58070902 -
Acta Dermato-venereologica Sep 2022This non-interventional, observational, longitudinal study describes treatment patterns of atopic dermatitis (AD) in Sweden. Data from 3 Swedish registries were merged,... (Observational Study)
Observational Study
This non-interventional, observational, longitudinal study describes treatment patterns of atopic dermatitis (AD) in Sweden. Data from 3 Swedish registries were merged, and included patients who received an AD diagnosis (during the period 1997 to 2019) and had AD treatment prescribed (during the period 2006 to 2020). Treatment persistence, treatment sequencing, time-to-event analysis, and 12-month prevalence were analysed. Overall, data for 99,885 patients with AD were included, of whom 4,086 (4.1%) received systemic treatments. Median persistence rates were 12.6 (95% CI 11.9, 13.4) months for methotrexate, 10.8 (9.1, 13.0) months for azathioprine, 5.6 (3.8, 6.2) months for mycophenolate, 5.1 (4.4, 5.7) months for alitretinoin and 3.4 (3.2, 3.7) months for cyclosporine. Median (Q1, Q3) time from first secondary care visit for AD to first systemic treatment was 5.8 (2.2, 11.0) years overall and 4.4 (1.3, 9.1) years in the Stockholm region. Methotrexate was a prominent first- and second-line treatment used during the period 2006 to 2020. Dupilumab was introduced during the study period and was increasingly used as first- or second-line therapy over time. The 12-month prevalence of AD generally remained steady, with a gradual increase observed over time for the overall population. A steep increase was observed in Stockholm from 2011. This study shows that a small proportion of patients with AD are offered systemic treatments in Sweden, with long periods in secondary care prior to systemic treatments and low persistence on systemic treatments. Regional differences highlight a need for national treatment guidelines.
Topics: Dermatitis, Atopic; Humans; Longitudinal Studies; Methotrexate; Retrospective Studies; Secondary Care; Sweden
PubMed: 35818736
DOI: 10.2340/actadv.v102.1986 -
Annals of Dermatology Jun 2022
PubMed: 35721329
DOI: 10.5021/ad.2022.34.3.235 -
Skin Health and Disease Jun 2022While treatment options exist for solitary or disseminated Kaposi sarcoma (KS) disease, there are currently no standardized clinical treatment guidelines for cutaneous...
BACKGROUND
While treatment options exist for solitary or disseminated Kaposi sarcoma (KS) disease, there are currently no standardized clinical treatment guidelines for cutaneous KS.
OBJECTIVE
This systematic review seeks to identify safe and effective topical treatments for cutaneous KS lesions.
METHODS
We conducted a systematic review using peer-reviewed articles from January 1970 to September 2021 published in the PubMed/MEDLINE and EMBASE databases.
RESULTS
From the initial search that yielded 590 studies, 34 met the inclusion criteria and were selected. Of the 34 studies, seven were clinical trials, 26 were case reports/series and one was a multicentre study. A total of 634 patients were included in our review. The three most common topical treatments used for cutaneous KS were imiquimod, alitretinoin and timolol. Topical alitretinoin was used in three case reports and three clinical trials. Topical imiquimod was used in eight case reports, one prospective phase II cohort study and one comparative single-blinded non-controlled clinical study. Topical timolol was used in nine case reports/series. Our review also identified reports of less widely used topical treatments for cutaneous KS. These include topical diphencyprone (DPCP), all--retinoic-acid, rapamycin and bleomycin-dimethylsulfoxide (BLM-DMSO) which achieved variable response rates but have not been widely studied.
CONCLUSION
Topical alitretinoin, imiquimod and timolol demonstrated positive responses for cutaneous KS and the treatments were well tolerated. These three topical treatment modalities could be considered by clinicians when treating cutaneous KS.
PubMed: 35677916
DOI: 10.1002/ski2.107 -
Indian Journal of Dermatology 2022
PubMed: 35656238
DOI: 10.4103/ijd.ijd_280_21 -
JAAD Case Reports Jun 2022
PubMed: 35600571
DOI: 10.1016/j.jdcr.2022.04.006 -
Lymphatic Research and Biology Dec 2022Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged...
Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged lymphatic vessels fail to adequately regenerate and lymphatic obstruction leads to fluid and protein accumulation in the interstitial space and chronic lymphedema develops as a result. There are currently no effective pharmacological agents that reduce the risk of developing lymphedema or treat pre-existing lymphedema, and management is largely palliative. The present study investigated the efficacy of various 9- retinoic acid (9- RA) dosing strategies in reducing postsurgical lymphedema by utilizing a well-established mouse tail lymphedema model. Short-duration treatment with 9- RA did not demonstrate a significant reduction in postoperative tail volume, nor an improvement in lymphatic clearance. However, long-term treatment with 9- RA resulted in decreased overall tail volume, dermal thickness, and epidermal thickness, with an associated increase in functional lymphatic clearance and lymphatic vessel density, assessed by LYVE-1 immunostaining, compared with control. These effects were seen at the site of lymphatic injury, with no significant changes observed in uninjured sites such as ear skin and the diaphragm. Given the reported results indicating that 9- RA is a potent promoter of lymphangiogenesis and improved lymphatic clearance at sites of lymphatic injury, investigation of postoperative 9- RA administration to patients at high risk of developing lymphedema may demonstrate positive efficacy and reduced rates of postsurgical lymphedema.
Topics: Mice; Humans; Animals; Duration of Therapy; Lymphatic Vessels; Alitretinoin; Lymphangiogenesis; Lymphedema; Disease Models, Animal
PubMed: 35584281
DOI: 10.1089/lrb.2021.0073 -
Contact Dermatitis Oct 2022
Randomized Controlled Trial
Efficacy and safety of oral alitretinoin versus oral azathioprine in patients with severe chronic hand eczema: Results from a prematurely discontinued randomized controlled trial.
Topics: Administration, Oral; Alitretinoin; Azathioprine; Chronic Disease; Dermatitis, Allergic Contact; Dermatologic Agents; Eczema; Hand Dermatoses; Humans; Treatment Outcome
PubMed: 35567385
DOI: 10.1111/cod.14161