AbstractRetinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.
AbstractRexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.
Nuclear receptors (NRs) are a superfamily of transcription factors induced by ligands and also function as integrators of hormonal and nutritional signals. Among NRs, the liver X receptors (LXRs) and farnesoid X receptor (FXR) have been of significance as targets for the treatment of metabolic syndrome-related diseases. In recent years, natural products targeting LXRs and FXR have received remarkable interests as a valuable source of novel ligands encompassing diverse chemical structures and bioactive properties. This review aims to survey natural products, originating from terrestrial plants and microorganisms, marine organisms, and marine-derived microorganisms, which could influence LXRs and FXR. In the recent two decades (2000–2020), 261 natural products were discovered from natural resources such as LXRs/FXR modulators, 109 agonists and 38 antagonists targeting LXRs, and 72 agonists and 55 antagonists targeting FXR. The docking evaluation of desired natural products targeted LXRs/FXR is finally discussed. This comprehensive overview will provide a reference for future study of novel LXRs and FXR agonists and antagonists to target human diseases, and attract an increasing number of professional scholars majoring in pharmacy and biology with more in-depth discussion.
Transcriptome analyses performed in both human and zebrafish indicate strong expression of Apoe and Apoc1 by microglia. Apoe expression by microglia is well appreciated, but Apoc1 expression has not been well-examined. PPAR/RXR and LXR/RXR receptors appear to regulate expression of the apolipoprotein gene cluster in macrophages, but a similar role in microglia in vivo has not been studied. Here, we characterized microglial expression of apoc1 in the zebrafish central nervous system (CNS) in situ and demonstrate that in the CNS, apoc1 expression is unique to microglia. We then examined the effects of PPAR/RXR and LXR/RXR modulation on microglial expression of apoc1 and apoeb during early CNS development using a pharmacological approach. Changes in apoc1 and apoeb transcripts in response to pharmacological modulation were quantified by RT-qPCR in whole heads, and in individual microglia using hybridization chain reaction (HCR) in situ hybridization. We found that expression of apoc1 and apoeb by microglia were differentially regulated by LXR/RXR and PPAR/RXR modulating compounds, respectively, during development. Our results also suggest RXR receptors could be involved in endogenous induction of apoc1 expression by microglia. Collectively, our work supports the use of zebrafish to better understand regulation and function of these apolipoproteins in the CNS.
Cholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation and haematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors (LXRs), affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials in acute myeloid leukemia (AML) to test the combination of chemotherapy with drugs interfering with cholesterol synthesis, i.e. statins. We review the role of cholesterol homeostasis in hematopoietic malignancies, as well as in cells of the tumor microenvironment, and discuss the potential use of lipid modulators for therapeutic purposes.
Chronic high-fat diet consumption induces hypercholesterolemia. The effect of Tessaria absinthioides (Hook. & Arn.) DC. (Asteraceae) was studied on the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), and triglycerides, and on the expression of liver X receptors (LXRs) in a hypercholesterolemic model. Adult male rats received a normal diet (ND) or a high-fat diet (HFD; normal diet + bovine fat + cholesterol). After 14 days, rats received water (W) or a decoction of the aerial parts of T. absinthioides (Ta; 10% w/v) for 2, 4, or 6 weeks. Four and six weeks of Ta improved the levels of TC and HDL-c in HFD. After 6 weeks of Ta, the expression of LXRs in HFD was the same as that in ND in both tissues. The Ta chemical profile was studied with an ultrahigh resolution liquid chromatography Orbitrap MS analysis (UHPLC–PDA–OT-MS/MS). Fifty-one compounds were identified, of which twelve are reported for the first time. Among these compounds, caffeoylquinic acid and its derivatives could modify the lipid profile and the expression of LXRs. This is the first in vivo report of T. absinthioides, which may be a potential candidate against hypercholesterolemia.