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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Bexarotene (Figure 6.106), marketed as TargtretinTM, has a similar structure to tretinoin and alitretinoin, and was approved by the FDA and EMA in 1999 and 2001, respectively, as a treatment for cutaneous T-cell lymphoma (CTCL). It acts as an agonist at the retinoid X receptor which is involved in the regulation of cellular differentiation and proliferation (Figure 6.105).
Non-Melanoma Skin Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Irene De Francesco, Sean Whittaker, Stephen L. Morris
Bexarotene is highly selective for the retinoid X receptor and was the first “rexinoid” to undergo clinical development.255,256 The drug has received EMA approval in Europe for the treatment of skin manifestations in advanced CTCL.257 Although the precise mechanisms are unknown, in vitro studies have shown that bexarotene can inhibit growth in tumor cell lines and cause in vivo tumor regression in animal models: the drug also stimulates apoptosis.258 In Phase II and III studies of 152 patients with CTCL, response rates from 20% to 67% have been reported.257,259 Bexarotene is usually administered at 300 mg/m2/day, and treatment is continued indefinitely in patients who respond.173,260 Bexarotene causes severe central hypothyroidism with high frequency, associated with marked reductions in serum concentrations of thyroid-stimulating hormone and thyroxine. During treatment, patients should be monitored for thyroid function and for hyper-triglyceridemia.172 Most patients will require concomitant treatment with a lipid-lowering agent and thyroxine.173,260 Gemfibrozil is contraindicated in this regard because it increases plasma concentrations of bexarotene, presumably due to inhibition of cytochrome P450 3A4, which in turn, results in a paradoxical elevation of triglycerides.173,260
Beneficial Effects of Omega-3 Fatty Acids on Cardiovascular Disease
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Estela Guerrero De León, Mahabir Prashad Gupta, Juan Antonio Morán-Pinzón
In addition to the LXR, PUFAs bind to the ligand binding domain of several nuclear receptors expressed in the liver, including peroxisome proliferator-activated receptors (PPAR α, β, γ1 y γ2) (Xu et al., 1999), farnesoid X receptor (FXR) (de Urquiza et al., 2000), and hepatic nuclear factor-4α (HNF4α) (Wisely et al., 2002; Yuan et al., 2009). All receptors, except HNF4α, form heterodimers with the nuclear retinoid X receptor (RXR) to regulate gene expression. Fatty acids are hydrophobics, which function as hormones (steroids and thyroid) to control nuclear receptor function (Davidson, 2006).
Emerging drugs for the treatment of acne: a review of phase 2 & 3 trials
Published in Expert Opinion on Emerging Drugs, 2022
Siddharth Bhatt, Rohit Kothari, Durga Madhab Tripathy, Sunmeet Sandhu, Mahsa Babaei, Mohamad Goldust
Retinoids are Vitamin A analogues. These molecules bind to the Retinoic acid receptor (RAR) and Retinoid X receptor (RXR), heterodimerize or homodimerize and then translocate to the nucleus where they bind to the Retinoic acid response element (RARE) bringing about their biological effects. In the skin, retinoids modulate the proliferation and differentiation of the keratinocytes and regulate the activity of the adhesion molecules also. It also down-regulates the expression of TLR 2 receptor which reduces Cutibacterium acnes mediated inflammation. Reduction in the size of sebaceous glands and sebum production is of particular importance in the treatment of acne. Currently, FDA approves the use of Isotretinoin for acne vulgaris. The most dreaded side effect which limits the use of retinoids is teratogenicity. Furthermore, as acne is commoner in adolescents and young adults, the risk of teratogenicity always needs to be weighed while prescribing it. Side effects include dose dependent muco-cutaneous problems like are dryness of mouth, lipid abnormalities which may rarely lead to pancreatitis, hepatitis. Pseudotumor cerebri neuropsychiatric manifestations like depression, sexual dysfunction have also remain a significant concern though these side effects are uncommon [2,5].
Vitamin D in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects
Published in Journal of the American College of Nutrition, 2021
Navya Vyas, Shilia Jacob Kurian, Debasis Bagchi, Mohan K. Manu, Kavitha Saravu, Mazhuvancherry Kesavan Unnikrishnan, Chiranjay Mukhopadhyay, Mahadev Rao, Sonal Sekhar Miraj
Evidence is mounting on vitamin D’s mediatory role in the immune response to infection. The biologically active form of vitamin D modulates innate and adaptive immunity via genes regulated by the vitamin D receptor (VDR), a transcription factor (Figure 2). An in vitro study using human cell lines revealed around 15 genes operating as major mediators of vitamin D’s action in both innate and adaptive immunity (13). Therefore, vitamin D may be considered for combating viral infections in both clinical and preclinical studies (14). Vitamin D acts by binding to the VDR, a nuclear receptor, which dimerizes with an isoform of the retinoid X receptor (RXR), whereupon the VDR-RXR heterodimers bind to vitamin D response elements (VDRE) on the promoter regions of target genes (14). VDRE then promotes the transcription of antimicrobial peptides (AMPs) such as human cathelicidin (human cationic antimicrobial protein; hCAP18) and human β-defensin-2 (hBD-2). AMPs are endogenously synthesized molecules found on mucosal and epithelial layers of multicellular organisms that offer the first-line defense against infections (bacterial and viral). AMPs also possess immunomodulatory functions. Defensins and cathelicidins constitute the two major families of AMPs. Defensins consist of six α- and two β- subclasses. hCAP18/LL-37 is the only type of cathelicidins in humans (15). Additionally, VDR-RXR heterodimers can also displace the nuclear factors of activated T lymphocytes (T cells), thereby suppressing cytokine-related genes in humans (16).
“Structural imprinting” of the cutaneous immune effector function
Published in Tissue Barriers, 2021
Yosuke Ishitsuka, Dennis R. Roop, Tatsuya Ogawa
Although myriad epithelial tissue-derived cytokines that skew immune effector classes toward type 2 immunity, such as interleukin (IL)-33, IL-25, or thymic stromal lymphopoietin,83 have been characterized over the past decades, the important example of the metabolic cues mediated by the lipophilic nutrients vitamin A (VA) and vitamin D (VD).84 It appears that the VA and VD signaling pathways work somewhat antagonistically in the epidermis. The former promotes the hydrolysis of polar lipids and plays a role in the maturation of lipid-based SC permeability (the “mortar”),85,86 whereas the latter promotes the assemblage of the cytoskeletal filament network (the “brick”).87 Persistent activation of epidermal VD receptor signaling through the application of calcipotriol (a low-calcemic calcitriol analog)88 or the genetic ablation of the retinoid X receptor89 results in the production of AD-like phenotypes, whereas systemic retinoid treatment proves useful for the management of chronic hand eczema90 as well as ARCI,91 both conditions that are closely associated with “broken mortar” situations.8,9