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ATPR regulates human mantle cell lymphoma cells differentiation via SOX11/CyclinD1/Rb/E2F1.
Xu, X, Zhang, T, Zhang, M, Li, L, Deng, G, Lu, Z, Zhang, Z, Du, Y, Feng, Y, Feng, X, et al
Cellular signalling. 2022;:110280
Abstract
Mantle cell lymphoma (MCL) is a lymphoproliferative disorder that lacks reliable therapeutic options. Therefore, new treatment approaches for targeting novel biological pathways are required. 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) synthesized by our group previously has been proven to have higher solubility and superior differentiation effects compared to those of conventional all-trans retinoic acid in acute myeloid leukemia. ATPR induces differentiation and inhibits the proliferation of acute promyelocytic leukemia. However, whether ATPR induces differentiation of MCL cells to normal immune cells has not been investigated. In this study, the proliferation of JEKO-1 cells was completely repressed, and differentiation was activated after ATPR treatment. The neural transcription factor SOX11 was further found to be highly expressed in MCL, but was downregulated by ATPR. After silencing SOX11 in vitro and in vivo, the malignant proliferation and inhibited differentiation of JEKO-1 cells were reversed, whereas the overexpression of SOX11 exacerbated the malignant phenotype of JEKO-1 cells. We also have added additional MCL cell lines (MINO) to complete the key pilot experiments. In addition, the CyclinD1/Rb/E2F1 axis was involved in MCL and was regulated by ATPR. In conclusion, ATPR promoted JEKO-1 cell differentiation via SOX11/CyclinD1/Rb/E2F1. This study provides experimental foundation for developing differentiation therapy for MCL with ATPR.
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2.
The Role of Vitamin A in Wound Healing.
Polcz, ME, Barbul, A
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2019;(5):695-700
Abstract
Vitamin A is an essential micronutrient that comes in multiple forms, including retinols, retinals, and retinoic acids. Dietary vitamin A is absorbed as retinol from preformed retinoids or as pro-vitamin A carotenoids that are converted into retinol in the enterocyte. These are then delivered to the liver for storage via chylomicrons and later released into the circulation and to its biologically active tissues bound to retinol-binding protein. Vitamin A is a crucial component of many important and diverse biological functions, including reproduction, embryological development, cellular differentiation, growth, immunity, and vision. Vitamin A functions mostly through nuclear retinoic acid receptors, retinoid X receptors, and peroxisome proliferator-activated receptors. Retinoids regulate the growth and differentiation of many cell types within skin, and its deficiency leads to abnormal epithelial keratinization. In wounded tissue, vitamin A stimulates epidermal turnover, increases the rate of re-epithelialization, and restores epithelial structure. Retinoids have the unique ability to reverse the inhibitory effects of anti-inflammatory steroids on wound healing. In addition to its role in the inflammatory phase of wound healing, retinoic acid has been demonstrated to enhance production of extracellular matrix components such as collagen type I and fibronectin, increase proliferation of keratinocytes and fibroblasts, and decrease levels of degrading matrix metalloproteinases.
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3.
[Drug therapy of acne inversa].
Schneider-Burrus, S, Arpa, E, Kors, C, Stavermann, T, Sabat, R, Kokolakis, G
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2018;(1):58-63
Abstract
Acne inversa is a chronic inflammatory destructive skin disease that affects about 1% of the population. The therapy should be personalized and consists of surgical and conservative procedures. Antibiotics are administered either topically or systemically. Combination therapy with clindamycin and rifampicin for 10-12 weeks can be very effective. Furthermore, TNF-α inhibitors show adequate efficacy and can be recommended. Adalimumab is the only approved drug product for systemic treatment of acne inversa. The efficacy of retinoids is controversial. Isotretinoin cannot be recommended for the treatment of acne inversa; however, acitretin has been proven to be more effective. Immune-modulating substances, like dapsone, cyclosporine A, methotrexate, colchicine, or corticosteroids, can be considered; however, the study data are insufficient for recommendation. Hormonal therapies can influence the course of the disease. Antiseptics are applied independent of the stage of disease. Patients should be informed about triggering factors.
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4.
Pathogenesis of Endometriosis: Roles of Retinoids and Inflammatory Pathways.
Taylor, RN, Kane, MA, Sidell, N
Seminars in reproductive medicine. 2015;(4):246-56
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Abstract
Endometriosis is a nonmalignant, but potentially metastatic, gynecological condition manifested by the extrauterine growth of inflammatory endometrial implants. Ten percent of reproductive-age women are affected and commonly suffer pelvic pain and/or infertility. The theories of endometriosis histogenesis remain controversial, but retrograde menstruation and metaplasia each infer mechanisms that explain the immune cell responses observed around the ectopic lesions. Recent findings from our laboratories and others suggest that retinoic acid metabolism and action are fundamentally flawed in endometriotic tissues and even generically in women with endometriosis. The focus of our ongoing research is to develop medical therapies as adjuvants or alternatives to the surgical excision of these lesions. On the basis of concepts put forward in this review, we predict that the pharmacological actions and anticipated low side-effect profiles of retinoid supplementation might provide a new treatment option for the long-term management of this chronic and debilitating gynecological disease.
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5.
Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review.
Blok, JL, van Hattem, S, Jonkman, MF, Horváth, B
The British journal of dermatology. 2013;(2):243-52
Abstract
Hidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of this inflammatory skin disease is largely unknown, the important role of the immune system has been demonstrated in both experimental and clinical studies. Clinicians are therefore increasingly prescribing systemic treatments with immunosuppressive agents, but the more traditionally used systemic retinoids, especially isotretinoin, also remain relatively common therapies. In order to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, a systematic search was performed using the Medline and Embase databases. All published papers concerning systemic retinoids or immunosuppressive treatments for HS in adults were included. The primary endpoints were the percentages of significant responders, moderate responders and nonresponders. Other endpoints were the relapse rate and adverse events. In total 87 papers were included, comprising 518 patients with HS who were treated with systemic retinoids, biological agents or another immunosuppressive agents, including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was low and differed between the agents, making direct comparisons difficult. However, based on the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin was also effective in HS, although the quality of the evidence was low. The therapeutic effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the effectiveness of acitretin, and to identify the most effective immunosuppressive agents in HS.
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6.
Treatment of cutaneous T-cell lymphoma with retinoids.
Zhang, C, Duvic, M
Dermatologic therapy. 2006;(5):264-71
Abstract
Retinoids are biologic regulators of differentiation, proliferation, apoptosis, and immune response. Retinoids (all-trans retinoic acid, 13-cis-retinoic acid, and the synthetic analogs isotretinoin, etretinate, and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphomas (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid X receptor retinoid to be approved by the Food and Drug Administration for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Use of retinoids in future long-term clinical trials and their eventual application in CTCL regiments will require strategies to decrease the side effects of existing retinoids, identify novel receptor subtype-selective retinoids with better therapeutic index, and explore biologically based synergistic combination therapies with other active agents.
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7.
Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma.
Zhang, C, Duvic, M
Dermatologic therapy. 2003;(4):322-30
Abstract
Retinoids, natural and synthetic derivatives of vitamin A, are biological regulators of differentiation, proliferation, apoptosis, and immune response. Retinoic-acid-receptor-selective retinoids (all-trans retinoic acid, 13-cis-retinoic acid, and the synthetic analogs isotretinoin, etretinate and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphoma (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid-X-receptor retinoid to be approved by the FDA for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Bexarotene treatment induces apoptosis of CTCL cells with down-regulation of its receptors and of survivin, an inhibitor of apoptosis. Identification of new receptor subtype-selective retinoids, combination of various receptor-selective retinoids or other agents, and a new drug delivery system may improve the clinical efficacy of retinoids in the future.
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8.
Indinavir-induced retinoid-like effects: incidence, clinical features and management.
García-Silva, J, Almagro, M, Peña-Penabad, C, Fonseca, E
Drug safety. 2002;(14):993-1003
Abstract
Since 1998, many cases of antiretroviral therapy-related paronychia of the toes or fingers and ingrown toenails have been reported. Most of them were related to indinavir. Other indinavir-induced mucocutaneous disorders resembling the adverse effects of systemic retinoid therapy have also been reported. Although there is some uncertainty in the literature regarding a cause-effect relationship, results of several epidemiological and in vitro studies, together with cumulated clinical experience leave no doubt that indinavir causes a retinoid-like effect and nail alterations. Indeed, indinavir is the only antiretroviral drug that produces these disorders, although ritonavir may enhance indinavir-induced retinoid-like effects through pharmacokinetic interactions leading to increased plasma indinavir concentrations. Approximately 30% of patients receiving indinavir show two or more retinoid-like manifestations and 4-9% develop paronychia. These adverse effects are not related to other epidemiological variables such as the patient's sex, age or other risk factors or immune status. They seem to be exposure dependent and, therefore, largely dose-dependent. Chronic paronychia is considered generally to be caused by contact irritants and candidal infection. Nevertheless, indinavir is currently the most frequent cause of chronic or recurrent paronychia in HIV-infected patients. In addition, retinoid-like manifestations such as cutaneous xerosis and cheilitis are frequent mucocutaneous adverse effects related to indinavir. The exact mechanism of indinavir-induced retinoid-like effects is unclear. Hypotheses for pathogenesis include interference with retinoid metabolism by enhancing the retinoic acid signalling pathway, or by increasing retinoic acid synthesis, or by reducing cytochrome p450-mediated retinoic acid oxidative metabolism. Replacement of therapy by an antiretroviral regimen not containing indinavir, while retaining other protease inhibitors and lamivudine, resolves retinoid-like manifestations without recurrences.
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9.
Cutaneous T-cell lymphoma. New immunomodulators.
Apisarnthanarax, N, Duvic, M
Dermatologic clinics. 2001;(4):737-48
Abstract
During the most recent decades, much knowledge has been gained concerning the immunologic and pathologic mechanisms of CTCL. The development of immunomodulators aimed at correcting aberrations in immunology and cellular growth and differentiation reflects this increased understanding. This review of the currently available immune-response modifying drugs shows that recombinant forms of natural cytokines and retinoids can be developed with tolerable toxicity profiles and substantial efficacy. Although milestone drugs such as bexarotene have been approved by the FDA- for treatment of CTCL, other agents such as IL-12 may also have a place in treatment of the disease. Even though unapproved, IFN-alpha may be the most active single immunomodulating agent against CTCL. It seems that further delineation of CTCL cytokine profile changes and immunologic aberrations are key in developing effective immunomodulators that are able to reverse these alterations.
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10.
Historical perspective on the use of retinoids in cutaneous T-cell lymphoma (CTCL).
Burg, G, Dummer, R
Clinical lymphoma. 2000;:S41-4
Abstract
Vitamin A and its analogues influence differentiation and proliferation and may also alter immune responses. Limited clinical efficacy of these compounds given alone or as part of a combination therapy has been shown in various types of cutaneous T-cell lymphoma (CTCL), including mycosis fungoides, Sézary syndrome, and prelymphomatous disorders such as parapsoriasis en plaques. Compounds used mostly in small, nonrandomized trials are isotretinoin (13-cis-retinoic acid), etretinate, acitretin, and all-trans-retinoic acid. Clinical responses have been found despite persistent residual disease with atypical lymphocytes in various compartments. The exact mechanism of action of retinoids in CTCL is unclear and depends on the presence of retinoid receptors on the tumor cells, which is variable in different forms of CTCL. Therapies combining retinoids with psoralen-ultraviolet A or with interferons may have a synergistic effect, which deserves confirmation through randomized trials in the future.