Rexinoids for treatment of ocular diseases

Abstract

The present disclosure provides for compounds including retinoid X receptor (RXR) agonists (also known as rexinoids), pharmaceutical compositions including rexinoids, methods of use of the rexinoids and the pharmaceutical compositions, and the like. Compounds and pharmaceutical compositions of the present disclosure can be used in combination with one or more other therapeutic agents for treating different conditions of the eye.

Description

[0001] U23-098 TH 222119-2260 REXINOIDS FOR TREATMENT OF OCULAR DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application entitled “REXINOIDS FOR TREATMENT OF OCULAR DISEASES” and having Serial No. 63 / 517,138, filed August 2, 2023, and this application claims the benefit of U.S. Provisional Application entitled “REXINOIDS FOR TREATMENT OF OCULAR DISEASES” and having Serial No.63 / 592,381, filed October 23, 2023, each of which is herein incorporated by reference in their entireties. STATEMENT ON FUNDING PROVIDED BY THE U.S. GOVERNMENT This invention was made with Government support under contract 1R21DE028349 awarded by the National Institutes of Health. The Government has certain rights in the invention. BACKGROUND The role of retinoid X receptor (RXR) in healthy and diseased retina has not been explored carefully. Thus, there is a need to study RXR and to further develop treatments for treating eye conditions or diseases. SUMMARY Aspects of the present disclosure provide for compounds including retinoid X receptor (RXR) agonists (also known as rexinoids), pharmaceutical compositions including rexinoids, methods of use of the rexinoids and the pharmaceutical compositions, and the like. Compounds and pharmaceutical compositions of the present disclosure can be used in combination with one or more other therapeutic agents for treating different conditions of the eye. In an aspect, the present disclosure provides for a method of treating a condition comprising: administering to a subject in need thereof, a pharmaceutical composition, wherein the pharmaceutical composition includes a therapeutically effective amount of the compound or pharmaceutical composition described below or herein. In an aspect, the condition is a condition related to the eye. For example, condition can be diabetic retinopathy, diabetic retinal dysfunction, inherited retinal dystrophies, age-related macular degeneration, glaucoma, optic neuritis, and the like. In an aspect, the present disclosure provides for a compound having one or more of the following formula: U23-098 TH 222119-2260 each R1is independently alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group; each R2is independently selected from hydrogen, an alkyl group, a haloalkyl, a alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group; each R3is independently selected from hydrogen, an alkyl group, a haloalkyl, a alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group; and at least one of R1, R2, or R3is not hydrogen. In an aspect, the present disclosure provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound to treat a condition in a subject, wherein the compound has the formula: U23-098 TH 222119-2260 each R1is independently alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group; each R2is independently selected from hydrogen, an alkyl group, a haloalkyl, a alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group; and each R3is independently selected from hydrogen, an alkyl group, a haloalkyl, a alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group, optionally wherein at least one of R1, R2, or R3is not hydrogen. BRIEF DESCRIPTION OF THE DRAWINGS Further aspects of the present disclosure will be more readily appreciated upon review of the detailed description of its various embodiments, described below, when taken in conjunction with the accompanying drawings. Figures 1A-1C illustrate expression of RXR in human and mouse diabetic retinas. Figure 1A illustrates immunostaining of human retinas comparing control (left) and diabetic (right) samples reveals reduced RXR expression (in green) in the outer nuclear layer (ONL), U23-098 TH 222119-2260 inner nuclear layer (INL), and retinal ganglion cell layer (RGL) of diabetic retinas. The nuclei are shown in red. Figures 1B and 1C illustrate that immunostaining of db / db mouse retinas, a diabetic mouse model, demonstrates decreased RXR expression in retinal ganglion cells (RGC), inner nuclear layer (INL), outer nuclear layer (ONL), and retinal pigment epithelial cells (RPE) of diabetic mice, consistent with the findings in human diabetic retinas. Figures 2A-E illustrate the oral administration of UAB126 in the diabetic retina. Figure 2A illustrates that LC-MS / MS analysis shows the detection of the RXR agonist, UAB126, in the serum and retinas of mice after systemic delivery. Representative LC-MS / MS peaks are presented. Figure 2B illustrates that diabetic mice treated with UAB126 for 6 weeks display a reduction in blood glucose levels (BGL) compared to diabetic controls (n=3-6). The average of 6-week BGL measurements is shown. Figure 2C illustrates that the decrease in BGL correlates with HbA1C measurements, indicating the beneficial effects of UAB126 treatment on glycemic control at 6 weeks. Figure 2D illustrates that UAB126 treatment does not alter insulin levels, showing that the compound does not affect insulin secretion in diabetic mice. Figure 2E illustrates that the treatment of diabetic mice with UAB126 does not lead to significant body weight loss compared to healthy control mice (n=5). ***p < 0.001, and ****p < 0.0001. Figures 3A-3C illustrate the treatment of diabetic mice with UAB126 prevents retinal function loss. Figure 3A illustrates that electroretinogram (ERG) recordings from diabetic retinas show reduced A-wave amplitudes (photoreceptor response) and B-wave amplitudes (bipolar and Muller cell response) compared to healthy control retinas at 14 weeks after streptozotocin (STZ) injection. Treatment with UAB126 preserves the A-wave amplitude and partially protects the B-wave amplitude decline, indicating protection of retinal function. Figure 3B illustrates representative ERG waveforms from healthy control, diabetic+ vehicle, and diabetic + UAB126-treated mice. Figure 3C illustrates the improvement in retinal function in UAB126-treated diabetic retinas is associated with an increase in AMPK activation (n=5-6). *p < 0.05, **p < 0.01. Figures 4A-4C illustrates the UAB126 treatment normalizes metabolism in bone marrow-derived macrophages. Figure 4A illustrates that glycolytic stress test measures the extracellular acidification rate (ECAR) at each step of glucose, oligomycin, and 2-DG addition (n=3-4). No difference is observed between control and UAB126-treated macrophages. However, significant differences are observed between vehicle-treated diabetic or diabetic + vehicle groups and the control group at all steps of ECAR (*** p<0.001). Results were analyzed by two-way ANOVA. Figure 4B illustrates that UAB126- treated macrophages show a lower rate of 2-DG (2-deoxyglucose) uptake compared to vehicle-treated macrophages, although not reaching the level of healthy untreated control macrophages. Figure 4C illustrates that UAB126-treated macrophages express increased U23-098 TH 222119-2260 levels of Il-10 mRNA, a biomarker of M2 macrophages, while Il-1β mRNA expression remains unchanged (n=3-4). **p < 0.01, ***p < 0.001, and ****p < 0.0001. Figures 5A-5G illustrate the eye drops containing UAB126 were designed for topical application and retinal delivery of rexinoids. Figure 5A illustrates LC-MS / MS analysis that confirms the accumulation of UAB126 in the retinas after topical application of eye drops. LC-MS / MS spectrograms show UAB126-treated retinas compared to untreated controls. Figure 5B illustrates immunostaining of control (left) and diabetic (right) retinas with anti-RXR antibody detects the RXR signal (in green) following topical UAB126 application. Figure 5C illustrates the topical UAB126 application results in an increase in Rxrα, Pparα, and lipid- associated gene expression in db / db retinas, suggesting altered lipid metabolism in treated diabetic retinas (n=3-5). Figure 5D illustrates retinal explants cultured in high glucose medium as compared to control (mannitol) exhibit decreased expression of Rxrα, Pparα, and Lxrβ mRNA. Figure 5E illustrates the treatment with UAB126 in high glucose medium increases the expression of these genes (n=3-4). Figure 5F illustrates the application of other rexinoids (rexinoid 3 and rexinoid 6) to C57BL6 retinal explants exposed to high glucose results in a dramatic increase in all three RXR isoforms (n=3-4). Figure 5G illustrates that in addition to RXR, UAB126 treatment induces an increase in Pparα and Pparγ mRNA expression, suggesting potential interactions and effects on other binding partners for RXR-based therapy (n=4). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. DETAILED DESCRIPTION The present disclosure provides for compounds including retinoid X receptor (RXR) agonists (also known as rexinoids), pharmaceutical compositions including rexinoids, methods of use of the rexinoids and the pharmaceutical compositions, and the like. This disclosure is not limited to particular embodiments described, and as such may, of course, vary. The terminology used herein serves the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. Where a range of values is provided, each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. U23-098 TH 222119-2260 Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the compositions and compounds disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C, and pressure is at or near atmospheric. Standard temperature and pressure are defined as 20 °C and 1 atmosphere. Before the embodiments of the present disclosure are described in detail, it is to be understood that, unless otherwise indicated, the present disclosure is not limited to particular materials, reagents, reaction materials, manufacturing processes, dimensions, frequency ranges, applications, or the like, as such can vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It is also possible in the present disclosure that steps can be executed in different sequence, where this is logically possible. It is also possible that the embodiments of the present disclosure can be applied to additional embodiments involving measurements beyond the examples described herein, which are not intended to be limiting. It is furthermore possible that the embodiments of the present disclosure can be combined or integrated with other measurement techniques beyond the examples described herein, which are not intended to be limiting. It should be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a support” includes a plurality of supports. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent. Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; “application cited documents”), and each of the PCT and foreign applications or patents corresponding to and / or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly incorporated herein by reference. Further, documents or references cited in this text, in a Reference List before the claims, or in the text itself; and each of these documents or references (“herein cited references”), as well as each document or reference cited in each of the herein-cited references (including U23-098 TH 222119-2260 any manufacturer’s specifications, instructions, etc.) are hereby expressly incorporated herein by reference. Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated. Definitions It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It will be understood by those skilled in the art that the moieties substituted can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Cycloalkyls can be substituted in the same manner. The term "acyl" as used herein, alone or in combination, means a carbonyl or thiocarbonyl group bonded to a radical selected from, for example, optionally substituted, hydrido, alkyl (e.g. haloalkyl), alkenyl, alkynyl, alkoxy ("acyloxy" including acetyloxy, butyryloxy, iso-valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy, and substituted acyloxy such as alkoxyalkyl and haloalkoxy), aryl, halo, heterocyclyl, heteroaryl, sulfonyl (e.g. allylsulfinylalkyl), sulfonyl (e.g. alkylsulfonylalkyl), cycloalkyl, cycloalkenyl, thioalkyl, thioaryl, amino (e.g., alkylamino or dialkylamino), and aralkoxy. Illustrative examples of "acyl" radicals are formyl, acetyl, 2-chloroacetyl, 2-bromacetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term "acyl" as used herein refers to a group -C(O)R26, where R26 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl. Examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like. The terms “administering” and “administration” as used herein refer to introducing a composition (e.g., a vaccine, adjuvant, or immunogenic composition) of the present disclosure into a subject. As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, U23-098 TH 222119-2260 intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. A preferred route of administration of the vaccine composition is intravenous. The terms "alkoxyl" or "alkoxyalkyl" as used herein refer to an alkyl-O- group wherein alkyl is as previously described. The term "alkoxyl" as used herein can refer to C1-20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, t-butoxyl, and pentoxyl. The term "alkyl", either alone or within other terms such as "thioalkyl" and "arylalkyl", as used herein, means a monovalent, saturated hydrocarbon radical which may be a straight chain (i.e. linear) or a branched chain. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. An alkyl radical for use in the present disclosure generally comprises from about 1 to 20 carbon atoms, particularly from about 1 to 10, 1 to 8 or 1 to 7, more particularly about 1 to 6 carbon atoms, or 3 to 6. Illustrative alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl, tert-pentyl, n-heptyl, n-actyl, n-nonyl, n-decyl, undecyl, n-dodecyl, n-tetradecyl, pentadecyl, n-hexadecyl, heptadecyl, n-octadecyl, nonadecyl, eicosyl, dosyl, n-tetracosyl, and the like, along with branched variations thereof. In certain aspects of the disclosure an alkyl radical is a C1-C6 lower alkyl comprising or selected from the group consisting of methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, tributyl, sec-butyl, tert-butyl, tert- pentyl, and n-hexyl. An alkyl radical may be optionally substituted with substituents as defined herein at positions that do not significantly interfere with the preparation of compounds of the disclosure and do not significantly reduce the efficacy of the compounds. In certain aspects of the disclosure, an alkyl radical is substituted with one to five substituents including halo, lower alkoxy, lower aliphatic, a substituted lower aliphatic, hydroxy, cyano, nitro, thio, amino, keto, aldehyde, ester, amide, substituted amino, carboxyl, sulfonyl, sulfuryl, sulfenyl, sulfate, sulfoxide, substituted carboxyl, halogenated lower alkyl (e.g. CF3), halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, cycloaliphatic, substituted cycloaliphatic, or aryl (e.g., phenylmethyl benzyl)), heteroaryl (e.g., pyridyl), and heterocyclic (e.g., piperidinyl, morpholinyl). Substituents on an alkyl group may themselves be substituted. The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed U23-098 TH 222119-2260 of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms or 2 to 8 carbon atoms or 2 to 6 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (R1R2)C=C(R3R4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. As used herein, "alkynyl" or “alkynyl group” refers to straight or branched chain hydrocarbon groups having 2 to 40, 2 to 20, 2 to 10, or 2 to 5 carbon atoms and at least one triple carbon to carbon bond, such as ethynyl. Reference to "alkynyl" or “alkynyl group” includes unsubstituted and substituted forms of the hydrocarbon moiety. The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple U23-098 TH 222119-2260 bound. Examples of cycloalkynyl groups include, but are not limited to, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent to a , wherein n is typically an integer. That is, to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), and Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance. The term "carboxyl" as used herein, alone or in combination, refers to -C(O)OR25- or -C(-O)OR25 wherein R25 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, thiol, aryl, heteroaryl, thioalkyl, thioaryl, thioalkoxy, a heteroaryl, or a heterocyclic, which may optionally be substituted. In aspects of the disclosure, the carboxyl groups are in an esterified form and may contain as an esterifying group lower alkyl groups. In particular aspects of the disclosure, -C(O)OR25 provides an ester or an amino acid derivative. An esterified form is also particularly referred to herein as a "carboxylic ester". In aspects of the disclosure a "carboxyl" may be substituted, in particular substituted with allyl which is optionally substituted with one or more of amino, amine, halo, alkylamino, aryl, carboxyl, or a heterocyclic. Examples of carboxyl groups are methoxycarbonyl, butoxycarbonyl, tert.alkoxycarbonyl such as tert-butoxycarbonyl, arylmethyoxycarbonyl having one or two aryl radicals including without limitation phenyl optionally substituted by for example lower alkyl, lower alkoxy, hydroxyl, halo, and / or nitro, such as benzyloxycarbonyl, methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-bromoethoxycarbonyl, 2- U23-098 TH 222119-2260 iodoethoxycarbonyltert.butylcarborlyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxy-carbonyl, benzhydroxycarbonyl, di-(4-methoxyphenyl-methoxycarbonyl, 2-bromoethoxycarbonyl, 2- iodoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 2-triphenylsilylethoxycarbonyl. Additional carboxyl groups in esterified form are silyloxycarbonyl groups including organic silyloxycarbonyl. The silicon substituent in such compounds may be substituted with lower alkyl (e.g. methyl), alkoxy (e.g. methoxy), and / or halo (e.g. chlorine). Examples of silicon substituents include trimethylsilyi and dimethyltert.butylsilyl. In aspects of the disclosure, the carboxyl group may be an alkoxy carbonyl, in particular methoxy carbonyl, ethoxy carbonyl, isopropoxy carbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, sir heptyloxy carbonyl, especially methoxy carbonyl or ethoxy carbonyl. The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such a term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure and a pharmaceutically acceptable carrier. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present disclosure is contemplated. Accordingly, the pharmaceutical compositions of the present disclosure include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, but not intended to be limiting, when a compound of the present disclosure is combined with another agent, the weight ratio of the compound of the present disclosure to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present disclosure and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present disclosure and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). U23-098 TH 222119-2260 A composition of the disclosure can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The compositions can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Various delivery systems are known and can be used to administer a composition of the disclosure, e.g. encapsulation in liposomes, microparticles, microcapsules, and the like. A therapeutic composition of the disclosure may comprise a carrier, such as one or more of a polymer, carbohydrate, peptide or derivative thereof, which may be directly or indirectly covalently attached to the compound. A carrier may be substituted with substituents described herein including without limitation one or more alkyl, amino, nitro, halogen, thiol, thioalkyl, sulfate, sulfonyl, sulfinyl, sulfoxide, hydroxyl groups. In aspects of the disclosure the carrier is an amino acid including alanine, glycine, praline, methionine, serine, threonine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl. A carrier can also include a molecule that targets a compound of the disclosure to a particular tissue or organ. Compounds of the disclosure can be prepared using reactions and methods generally known to the person of ordinary skill in the art, having regard to that knowledge and the disclosure of this application including the Examples. The reactions are performed in solvent appropriate to the reagents and materials used and suitable for the reactions being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the compounds should be consistent with the proposed reaction steps. This will sometimes require modification of the order of the synthetic steps or selection of one particular process scheme over another in order to obtain a desired compound of the disclosure. It will also be recognized that another major consideration in the development of a synthetic route is the selection of the protecting group used for protection of the reactive functional groups present in the compounds described in this disclosure. An authoritative account describing the many alternatives to the skilled artisan is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). A compound of the disclosure may be formulated into a pharmaceutical composition for administration to a subject by appropriate methods known in the art. Pharmaceutical compositions of the present disclosure or fractions thereof comprise suitable pharmaceutically acceptable carriers, excipients, and vehicles selected based on the intended form of administration, and consistent with conventional pharmaceutical practices. Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21.sup.st Edition. 2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company), and in The United States U23-098 TH 222119-2260 Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. By way of example for oral administration in the form of a capsule or tablet, the active components can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like. For oral administration in a liquid form, the chug components may be combined with any oral, non-toxic, pharmaceutically, acceptable inert carrier such as ethanol, glycerol, water, and the like. Suitable binders (e.g., gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes), lubricants (e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride), disintegrating agents (e.g. starch, methyl cellulose, agar, bentonite, and xanthan gum), flavoring agents, and coloring agents may also be combined in the compositions or components thereof. Compositions as described herein can further comprise wetting or emulsifying agents, or pH buffering agents. The terms "subject", "individual", or "patient" as used herein are used interchangeably and refer to an animal preferably a warm-blooded animal such as a mammal. Mammal includes without limitation any members of the Mammalia. A mammal, as a subject or patient in the present disclosure, can be from the family of Primates, Carnivora, Proboscidea, Perissodactyla, Artiodactyla, Rodentia, and Lagomorpha. In a particular embodiment, the mammal is a human. In other embodiments, animals can be treated; the animals can be vertebrates, including both birds and mammals. In aspects of the disclosure, the terms include domestic animals bred for food or as pets, including equines, bovines, sheep, poultry, fish, porcines, canines, felines, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice. The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which a probe of the disclosure is administered and which is approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. When administered to a patient, the probe and pharmaceutically acceptable carriers can be sterile. Water is a useful carrier when the probe is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as glucose, lactose, sucrose, glycerol monostearate, sodium chloride, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain U23-098 TH 222119-2260 minor amounts of wetting or emulsifying agents, or pH buffering agents. The present compositions advantageously may take the form of solutions, emulsion, sustained-release formulations, or any other form suitable for use. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition or prevention of a disease or condition or enhance and / or tune the immune system of the subject to the desirable responses for certain pathogens (e.g., virus). For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms or prevention of a disease or condition and / or tune the immune system of the subject to the desirable responses for certain pathogens, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as infections and consequences thereof and / or tuning the immune system of the subject to the desirable responses for certain pathogens. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term U23-098 TH 222119-2260 "treatment" as used herein can include any treatment of infections in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease or infection but has not yet been diagnosed as having it; (b) inhibiting the disease or infection, i.e., arresting its development; and (c) relieving the disease or infection i.e., mitigating or ameliorating the disease and / or its symptoms or conditions, (d) and / or tune the immune system of the subject to the desirable responses for certain pathogens. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. and / or tuning the immune system of the subject to the desirable responses for certain pathogens. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect and / or tuning the immune system of the subject to the desirable responses for certain pathogens. The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner. The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). U23-098 TH 222119-2260 Discussion The present disclosure provides for compounds including retinoid X receptor (RXR) agonists (also known as rexinoids), pharmaceutical compositions including rexinoids, methods of use of the rexinoids and the pharmaceutical compositions, and the like. Compounds and pharmaceutical compositions of the present disclosure can be used in combination with one or more other therapeutic agents for treating different conditions of the eye. For example, compounds and pharmaceutical compositions of the present disclosure can be used to treat diabetic retinopathy, diabetic retinal dysfunction, inherited retinal dystrophies, age-related macular degeneration, glaucoma, optic neuritis, and the like. The present disclosure provides for methods of treating a condition, including administering to a subject in need thereof a pharmaceutical composition), where the pharmaceutical composition includes a therapeutically effective amount of any of the rexinoids or pharmaceutical composition discussed herein. The condition to be treated can include eye diseases. The conditions to be treated can include diabetic retinopathy, diabetic retinal dysfunction, inherited retinal dystrophies, age-related macular degeneration, glaucoma, optic neuritis, and the like. One aspect of this disclosure provides for rexinoids having one or more of the following the formula as represented by:

[0002] U23-098 TH 222119-2260 or or . Each R1 group, a haloalkyl, an alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group. In other aspects, each R1can be independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group. Each R2can be independently selected from hydrogen, an alkyl group, a haloalkyl, an alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group. In other aspects, each R2can be independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group. Each R3can be independently selected from hydrogen, an alkyl group, a haloalkyl, an alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group. In other aspects, each R3can be independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group. In some aspects, at least one of R1, R2, or R3is not hydrogen (or two are not hydrogen). In an aspect, each of R1, R2, or R3are hydrogen. The rexinoid UAB126 has the following structure: U23-098 TH 222119-2260 UAB126 has demonstrated therapeutic potential to treat obese mice by controlling blood glucose and insulin levels and altering the expression of lipid- and inflammatory response- associated genes. Rexinoid-based therapy can benefit subjects with eye conditions. For example, in subjects with an eye disease such as diabetic retinopathy or diabetic retinal dysfunction. Rexinoid-based therapy can benefit a subject by reducing blood glucose levels, thereby controlling the progression of diabetic retinopathy, and altering local retinal metabolism and the inflammatory response. Other compounds as described above and herein can be used to treat eye conditions as those described for UAB126. The present disclosure also provides for pharmaceutical compositions including a therapeutically effective amount of a compound to treat a condition (e.g., eye disease) in a subject (e.g., animal or human subject), where the compound has one of the formula represented by:

[0003] U23-098 TH 222119-2260 or or Each R1 group, a haloalkyl, an alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group. In other aspects, each R1can be independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group. Each R2can be independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group hydrogen, an alkyl group, a haloalkyl, a alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group. In other aspects, each R2can be independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group. Each R3can be independently selected from hydrogen, an alkyl group, a haloalkyl, a alkenyl group, an alkynyl group, an aryl group, a halogen, a trifluoromethyl group, or a hydroxy group. In other aspects, each R3can be independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group. In some aspects, each one of R1, R2, and R3is hydrogen. In some aspects, at least one of R1, R2, or R3is not hydrogen. The pharmaceutical composition can further comprise a pharmaceutically acceptable carrier. U23-098 TH 222119-2260 Pharmaceutical Formulations and Routes of Administration Embodiments of the present disclosure include the agent (e.g., the rexinoid) as identified herein and can be formulated with one or more pharmaceutically acceptable excipients, diluents, carriers and / or adjuvants. In addition, embodiments of the present disclosure include the agent formulated with one or more pharmaceutically acceptable auxiliary substances. In particular the agent can be formulated with one or more pharmaceutically acceptable excipients, diluents, carriers, and / or adjuvants to provide an embodiment of a composition of the present disclosure. A wide variety of pharmaceutically acceptable excipients are known in the art. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc. The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public. In an embodiment of the present disclosure, the agent can be administered to the subject using any means capable of resulting in the desired effect. Thus, the agent can be incorporated into a variety of formulations for therapeutic administration. For example, the agent can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols. In pharmaceutical dosage forms, the agent may be administered in the form of its pharmaceutically acceptable salts, or a subject active composition may be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting. For oral preparations, the agent can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening U23-098 TH 222119-2260 agents, preservatives and flavoring agents. Embodiments of the agent can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. Embodiments of the agent can be utilized in aerosol formulation to be administered via inhalation. Embodiments of the agent can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like. Furthermore, embodiments of the agent can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water soluble bases. Embodiments of the agent can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature. Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more compositions. Similarly, unit dosage forms for injection or intravenous administration may comprise the agent in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier. Embodiments of the agent can be formulated in an injectable composition in accordance with the disclosure. Typically, injectable compositions are prepared as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation may also be emulsified or the active ingredient (triamino-pyridine derivative and / or the labeled triamino-pyridine derivative) encapsulated in liposome vehicles in accordance with the present disclosure. In an embodiment, the agent can be formulated for delivery by a continuous delivery system. The term “continuous delivery system” is used interchangeably herein with “controlled delivery system” and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art. Mechanical or electromechanical infusion pumps can also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, U.S. Pat. Nos.4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, delivery of the agent can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. In some embodiments, the agent can be in a liquid formulation in a drug-impermeable U23-098 TH 222119-2260 reservoir, and is delivered in a continuous fashion to the individual. In one embodiment, the drug delivery system is an at least partially implantable device. The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to, a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are used in some embodiments because of convenience in implantation and removal of the drug delivery device. Drug release devices suitable for use in the disclosure may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incorporated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc. Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, U.S. Pat. Nos.4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like. In general, a subject treatment method can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time. Osmotic pumps are used in some embodiments due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT published application no. WO 97 / 27840 and U.S. Pat. Nos.5,985,305 and 5,728,396). Exemplary osmotically-driven devices suitable for use in the disclosure include, but are not necessarily limited to, those described in U.S. Pat. Nos.3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like. In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted herein, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites TH 222119-2260 include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. In some embodiments, the agent can be delivered using an implantable drug delivery system, e.g., a system that is programmable to provide for administration of the agent. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U.S. Pat. Nos.4,350,155; 5,443,450; 5,814,019; 5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954. A further exemplary device that can be adapted for the present disclosure is the Synchromed infusion pump (Medtronic). Suitable excipient vehicles for the agent are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. In addition, if desired, the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents. Methods of preparing such dosage forms are known, or will be apparent upon consideration of this disclosure, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 17th edition, 1985. The composition or formulation to be administered will, in any event, contain a quantity of the agent adequate to achieve the desired state in the subject being treated. Compositions of the present disclosure can include those that comprise a sustained- release or controlled release matrix. In addition, embodiments of the present disclosure can be used in conjunction with other treatments that use sustained-release formulations. As used herein, a sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-based hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained- release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxcylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. Illustrative biodegradable matrices include a polylactide matrix, a polyglycolide matrix, and a polylactide co-glycolide (co-polymers of lactic acid and glycolic acid) matrix. In another embodiment, the pharmaceutical composition of the present disclosure (as well as combination compositions) can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one TH 222119-2260 embodiment, a pump may be used (Sefton (1987). CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al. (1980). Surgery 88:507; Saudek et al. (1989). N. Engl. J. Med.321:574). In another embodiment, polymeric materials are used. In yet another embodiment a controlled release system is placed in proximity of the therapeutic target thus requiring only a fraction of the systemic dose. In yet another embodiment, a controlled release system is placed in proximity of the therapeutic target, thus requiring only a fraction of the systemic. Other controlled release systems are discussed in the review by Langer (1990). Science 249:1527- 1533. In another embodiment, the compositions of the present disclosure (as well as combination compositions separately or together) include those formed by impregnation of the agent described herein into absorptive materials, such as sutures, bandages, and gauze, or coated onto the surface of solid phase materials, such as surgical staples, zippers and catheters to deliver the compositions. Other delivery systems of this type will be readily apparent to those skilled in the art in view of the instant disclosure. Dosages Embodiments of the agent (e.g., the rexinoid) can be administered to a subject in one or more doses. Those of skill will readily appreciate that dose levels can vary as a function of the specific the agent administered, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. In an embodiment, multiple doses of the agent are administered. The frequency of administration of the agent can vary depending on any of a variety of factors, e.g., severity of the symptoms, and the like. For example, in an embodiment, the agent can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid). As discussed above, in an embodiment, theagent is administered continuously. The duration of administration of the agent, e.g., the period of time over the agent is administered, can vary, depending on any of a variety of factors, e.g., patient response, etc. For example, the agent in combination or separately, can be administered over a period of time of about one day to one week, about two weeks to four weeks, about one month to two months, about two months to four months, about four months to six months, about six months to eight months, about eight months to 1 year, about 1 year to 2 years, or about 2 years to 4 years, or more. Dosage at concentrations as high as 60 micrograms / kilograms that are non-toxic. U23-098 TH 222119-2260 Also lower concentrations, such as 1-4 micrograms / kilogram, show biological activity in in vivo systems. The concentration in in vitro established at 10-9-10-6 M are active and this concentration is expected to be achieved in the cell environment. (See Slominski AT, Janjetovic Z, Fuller BE, Zmijewski MA, Tuckey RC, et al. (2010) Products of vitamin D3 or 7- dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity. PLoS ONE 5(3): e990; Slominski AT, Kim T-K., Janjetovic Z, Tuckey RC, Bieniek, R, Yue Y, Li W, Chen J, Miller D, Chen T, Holick M (2011) 20- hydroxyvitamin D2 is a non-calcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells. Am J Physiol: Cell Physiol 300:C526-C541; Wang J, Slominski AT, Tuckey RC, Janjetovic Z, Kulkarni A, Chen J, Postlethwaite A, Miller D, Li W (2012) 20-Hydroxylvitamin D3 possesses high efficacy against proliferation of cancer cells while being non-toxic. Anticancer Res 32: 739-746; Slominski A, Janjetovic Z, Tuckey RC, Nguyen MN, Bhattacharya KG, Wang J, Li W, Jiao Y, Gu W, Brown M, Postlethwaite AE (2013) 20-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo. J Clin Endocrinol Metab 98, E298-E30; Chen, J., J. Wang, T. Kim, E. Tieu, E. Tamg, Lin Z, D. Kovacic, D. Miller, A. Postlethwaite, R. Tuckey, A. Slominski and W. Li (2014). Novel Vitamin D Analogs as Potential Therapeutics: The Metabolism, Toxicity Profiling, and Antiproliferative Activity. Anticancer Res 34: 2153-2163.) In an aspect, the dosage for administering to a subject (e.g., a mammal such as a human) having a condition (e.g., COVID-19) of any single agent the present disclosure is about 2 to 60 micrograms / kilogram or a combination of agents, each agent can be about 2 to 60 micrograms / kilogram. Routes of Administration Embodiments of the present disclosure provide methods and compositions for the administration of the agent (e.g., the rexinoid) to a subject (e.g., a human) using any available method and route suitable for drug delivery, including in vivo and ex vivo methods, as well as systemic and localized routes of administration. Routes of administration include intranasal, intramuscular, intratracheal, subcutaneous, intradermal, topical application, intravenous, rectal, nasal, oral, and other enteral and parenteral routes of administration. Routes of administration may be combined, if desired, or adjusted depending upon the agent and / or the desired effect. An agent can be administered in a single dose or in multiple doses. Embodiments of the agent can be administered to a subject using available conventional methods and routes suitable for delivery of conventional drugs, including systemic or localized routes. In general, routes of administration contemplated by the U23-098 TH 222119-2260 disclosure include, but are not limited to, enteral, parenteral, or inhalational routes. Parenteral routes of administration other than inhalation administration include, but are not limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, and intravenous routes, i.e., any route of administration other than through the alimentary canal. Parenteral administration can be conducted to effect systemic or local delivery of the agent. Where systemic delivery is desired, administration typically involves invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations. In an embodiment, the agent can also be delivered to the subject by enteral administration. Enteral routes of administration include, but are not limited to, oral and rectal (e.g., using a suppository) delivery. Methods of administration of the agent through the skin or mucosa include, but are not limited to, topical application of a suitable pharmaceutical preparation, transdermal transmission, injection and epidermal administration. For transdermal transmission, absorption promoters or iontophoresis are suitable methods. Iontophoretic transmission may be accomplished using commercially available "patches" that deliver their product continuously via electric pulses through unbroken skin for periods of several days or more. While embodiments of the present disclosure are described in connection with the Examples and the corresponding text and figures, there is no intent to limit the disclosure to the embodiments in these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure. While embodiments of the present disclosure are described in connection with the Examples and the corresponding text and figures, there is no intent to limit the disclosure to the embodiments in these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure. EXAMPLE 1 Introduction Functioning as a nuclear receptor (NR), the retinoid X receptor (RXR) is a transcriptional factor that binds to the promoter region of genes either as a dimer with itself (homodimer) or with another NR to form a heterodimer. Although RXR can activate transcription as a homodimer, this receptor also serves as an obligatory common dimerization partner for numerous other NRs.1, 2A response element (RE) consisting of two six-base pairs sequences separated from each other is the DNA binding sequence for RXR.3These regions are known for RXR-NR heterodimer binding. U23-098 TH 222119-2260 In general, the molecular structure of RXR is like that of other NRs; RXR proteins contain an A / B region located at the N-terminal, a DNA-binding domain (DBD), and a ligand- binding domain (LBD) positioned at the C-terminal. The role of the A / B domain is still under investigation, although it has been proposed that the structure responds to the interaction of RXR with specific binding partners and determines either the activation or repression of transcriptional complexes.4Moreover, a few nuclear localization sequences are present within the DBD domain of RXR proteins,5and in the absence of ligands, RXR could be found both in the cytoplasm and in the nucleus.6RXR occupies a central position in the NR family because forming heterodimers with many other family members and is therefore involved in controlling a myriad of physiologic processes. RXR heterodimers can be classified into two main groups: permissive and non- permissive binding partners. Permissive heterodimers are dimers, whose activation can be triggered by the binding of RXR agonists, binding of the agonists of the NR partner, or binding of the agonist to both NRs.7Examples of this type of heterodimerization include the RXR / Liver X receptor (LXR), the RXR / Peroxisome proliferator-activated receptor (PPAR), and the RXR / Farnesoid X receptor (FXR) heterodimers.8Along with this, the binding of ligands to both partners could provide an additive or synergistic biological response. Non- permissive heterodimers require that the agonist binds to a heterodimerization partner while RXR acts as a silent partner. Examples of this heterodimerization include RXR / RAR (retinoid A receptor), RXR / VDR (vitamin D receptor) and RXR / TR (Thyroid hormone receptor). Overall, three different isoforms of RXR, RXRα, RXRβ, and RXRγ exist. RXRα and RXRβ mRNAs are widely expressed, whereas RXRγ mRNA is restricted to only a few tissues.9One of them is the retina, which expresses all three RXRs.10, 11RXRα is a predominant isoform that has been identified in the nucleus, cytoplasm, and mitochondria.12Localized on chromosome 6p21.32, RXRβ is abundantly expressed in endothelial cells and cancer cell lines and is largely conserved across species.13RXRγ is a 14 kB long isoform containing 9 introns widely ranged in size. High RXRγ expression is found in the brain, which perhaps explain the importance of this isoform for the development of memory deficit and depression-like behavior upon its ablation.14Mounting evidence indicates that abnormal RXR signaling is involved in neuronal stress and neuroinflammatory response in several neuropathological conditions. The RXR protective effects mediated through pharmacological activation have been established in various cell and animal models, including Alzheimer’s, Parkinson’s, glaucoma, multiple sclerosis, and stroke.13For example, it has been proposed that RXRα controls the innate inflammatory responses through upregulating chemokine expression, such as Ccl6 and Ccl9 in macrophages; the treatment with RXR agonists (also known as rexinoids), LG268, and LG754 resulted in an increase in their mRNA expression ranging from 2- to 4 folds, which U23-098 TH 222119-2260 suggests that these chemokines are transcriptionally regulated by RXRα.15Moreover, decreased RXR activity leading to decreased CCL6 and CCL9 chemokines dramatically impairs leukocyte recruitment in myeloid. In addition, RXRs also control the clearance of apoptotic cells and β-amyloid protein in macrophages; the lack of RXRα impairs the transcription of genes associated with phagocytosis-related events, including Cd36, Fcgr1, Mertk, Axl, C1qa, C1qb, C1qc, and Tgm2, suggesting that RXRs are important constituents for apoptotic cell uptake and anti-inflammatory macrophage activation.16Another study using an experimental model of colitis based on the adaptive transfer of CD4+CD45RBhighcells demonstrates that the RXR agonist NEt-3IB reduced CD45+cells, inhibits the differentiation and proliferation of Th1 cells, and ameliorates colitis in mice.17The other RXR agonist, NEt-4IB, was proposed to reduce CXCL5, IFN-γ, IL-17, and VEGF and attenuate pulmonary emphysema in an experimental mouse model.18The study also highlighted that as compared to the known RXR selective agonist bexarotene, NEt-4IB did not cause hyperglyceridemia in mice suggesting Net-4IB as a potential therapeutic strategy.18The latter rexinoid, bexarotene, is a FDA-approved drug known to inhibit inflammatory conditions in a cellular model of human rheumatoid arthritis.19The exposure of primary human fibroblast-like synoviocytes to this rexinoid significantly reduced expression of cytokines, IL-6, IL-8, and TNF-α. This effect was mediated through inhibition of p38 pathway and phosphorylation of NF-kB.19Cumulatively, previous research suggests that RXR agonists have an anti-inflammatory role. Another physiological role of RXR is regulation of lipid metabolism. Thus, bexarotene improved cholesterol homeostasis and inhibited atherosclerosis progression in a mouse model of dyslipidemia.20The level of hepatic gene expression—such as Scd1 (stearoyl- Co enzyme A desaturase 1), Fas (fatty acid synthase), Angptl3 (angiopoietin-like 3), Abaca1 (ATP-binding cassette subfamily a member 1), and ApoA-1 (apolipoprotein A1) mRNAs— was significantly increased in these mice, suggesting improved cholesterol efflux. Despite this fact, the adverse effect from the treatment included increase in plasma triglycerides. The authors of the mentioned above study concluded that these data provide evidence of the favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, which is likely due to its beneficial action on intestinal absorption and macrophage efflux.20Recently, a rexinoid-like molecule UAB126 has been developed by modifying the previously known rexinoid UAB30 and studied by Ren at al.21, 22Thus, in a study of obese mice, the oral administration of UAB126 reduced obesity, insulin resistance, and dyslipidemia without changes in thyroid hormones.22Treatment of mice with UAB126 significantly increased expression of the genes responsible for lipid metabolism, such as U23-098 TH 222119-2260 Ucp1, Cytb, Cpt1a, Cpt1b, Elovl3, Acox, and Prdm16 in brown adipose tissue. Moreover, a decrease in the inflammatory gene expression of F4 / 80, Il-1β, Il-6, Tnfα, Mcp1, Cd68, and Cd45 was found in white adipose tissue. Interestingly, Not only did UAB126 treatment not raise serum triglyceride levels, but it also improved insulin signaling via a decrease in overnight blood glucose and insulin levels.22Ren et al. suggest that the role of UAB126 should be carefully examined in mice in order to modulate other human metabolic disorders, for example, diabetes. Overall, the role of RXR in healthy and diseased retina has not been explored carefully, with the exception of the study with rd1 mice that manifested inherited retinal degeneration, or retinitis pigmentosa.10The rd1 mice retinas manifested lower levels of RXRα as compared to the C57BL6 mice. Moreover, the RXR agonist PA024 decreased photoreceptor cell death in a neuro-glial culture isolated from rd1 mice and delayed the onset of photoreceptor apoptosis. The author proposed that the mechanism of therapeutic effect provided by PA024 is linked to a decrease in Bax mRNA expression and the transcription of the anti-inflammatory cytokine IL-10, thus introducing the RXR agonist as a pharmacological tool for treating retinal degenerative diseases.10Given that RXR could be a therapeutic target for degenerating retina, that UAB126 controls lipid metabolism and inflammatory response in obese mice, and that dyslipidemia and inflammation are two critical components of diabetic retinal pathogenesis, we decided to test UAB126 in mice with diabetic retinopathy (DR). We systemically delivered UAB126 to type 1 diabetic (T1D) mice and monitored the development of DR. Our study demonstrates the therapeutic potential of UAB126 to treat diabetic retinal dysfunction and delay the onset of DR in mice. To our knowledge, this is the first study validating RXR as a therapeutic target for DR. Materials and Methods Animals: Male C57BL / 6J (Strain#: 000664) mice, and db / dbb (BKS.Cg-Dock7m + / + Leprdb / J; Strain#: 000642) mice were obtained from The Jackson Laboratory and housed in the University of Alabama at Birmingham (UAB) animal facility, adhering to the guidelines set by the institutional animal care and use committee (UAB-IACUC protocol no.22104) and the Association for Research in Vision and Ophthalmology guidelines. The mice were kept in a 12-hour light-dark cycle with ad libitum access to food and water. Diabetes Induction: After an 8-week acclimation period, diabetes was induced by administering five consecutive intraperitoneal injections of 50 mg / kg streptozotocin (STZ) or vehicle (10 mM sodium citrate buffer, ice-cold, pH 4.5). Prior to each STZ injection, the mice underwent a 6-hour food deprivation. Animals were considered suitable for the study when their blood glucose concentrations consistently exceeded 250 mg / dL after 6 hours of fasting TH 222119-2260 for four consecutive weeks. Blood glucose levels were monitored weekly, and HbA1C levels were measured during the final week of the experiment. UAB126 synthesis. The synthesis of UAB126 has been performed as previously described,22, which is incorporated herein by reference and also described in WO 2016 / 004066, which is incorporated herein by reference. Preparation of UAB126 Eye Drops: The nanoemulsion development was carried out using the phase inversion temperature method, as described in the references by Singh et al.23and Fernandes et al.24In this process, a surfactant mixture comprising Polysorbate- 80 (200 mg) and Pluronic-127 (62.5 mg) was heated to a temperature above 70°C and mixed using a magnetic stirrer at 250 rpm for 10 minutes. Once a clear jelly-like liquid was obtained, the active pharmaceutical ingredient UAB-126 (150 mg) was added, and mixing continued until a clear and transparent jelly was formed. Simultaneously, in a separate beaker, 25 ml of water was heated to 70°C, and beta-cyclodextrin (125 mg) and EDTA (6.25 mg) were dissolved in it. This solution was then used for solubilizing the UAB-126 surfactant mixture. Finally, the pH of the solution was adjusted to 7.4 using either 4M sodium hydroxide or diluted hydrochloric acid, as required. UAB126 Administration: UAB126 was administered orally in 10% DMSO mixed with corn oil at a dosage of 100 mg / kg, starting a month after the STZ injection, and continued daily for 6 weeks. Topical administration of 2.5% UAB126 was performed using ophthalmic demulcent solution (the contralateral eye was treated with the vehicle). A total of 40 μL of UAB126 was administered over 2 hours (10 μL every 30 minutes). After the final administration, both eyes were washed five times with PBS. UAB126 topical application: Ten week old dB / dB animals were used in this experiment. One eye was treated with 10 µl UAB 126 eye drops and fellow eye received same amount of PBS as a Control. Eye drops were applied every day for 2 weeks. After 2 weeks retinas from animals were collected for LC-MS / MS study to detect UAB 126 after the treatment and for RNA isolation following qRT-PCR analysis and Immunohistochemistry. Retinal explants. The eyes from C57BL6J animals at postnatal day 8 were enucleated and retina was gently isolated from eyecap and placed in Neurobasal Serum free medium (Neurobasal-A, 10888022; Invitrogen) containing 2%B27 (0080085-SA; Invitrogen, Carlsbad, CA, USA), 1%N2 (17502-048; Invitrogen)2 mM GlutaMAX (35050038; Invitrogen), 100 units / mL penicillin–100 lg / mL streptomycin (P4333; Sigma-Aldrich Corp., St. Louis, MO, USA). Retinal explants were maintained at 37°C and 5% CO2 condition.19mM Mannitol (Control) (Sigma, M4125) and 34mM D-glucose (High glucose) (Sigma, G5767) were dissolved in growth medium. Rexinoid 3, Rexinoid 6 and UAB126 were prepared in sterile water and added to treatment groups with final concentration 100µM. Explants were cultured for 24 hr and analyzed by using qRT-PCR. TH 222119-2260 Tissue homogenization and extraction for mass spectrometry. Kidney, retina, and brain tissues were weighed and homogenized at a density of 140 mg of dry tissue per milliliter in ethyl acetate / isopropanol (4:1) using a Bead Mill 4 homogenizer (Thermo Fisher Scientific, Waltham MA) and 2-mL pre-filled polypropylene microtubes (2.8 mm ceramic beads, 3 x 20 sec cycles, speed 5). Insoluble debris was removed by centrifugation (10,000 x g, 30 min, 5 °C). Fixed aliquots of the supernatants (225 μL) were transferred to clean Eppendorf tubes and evaporated under a gentle stream of nitrogen gas. The residues were reconstituted in 75 μL of methanol / water (4:1), centrifuged (18,000 x g, 30 min, 5 °C), and transferred to 2-mL autosampler vials equipped with low-volume polypropylene inserts and Teflon-lined rubber septa for analysis. Mass Spectrometry. The LC-MS / MS analysis was performed using a Thermo Quantum Ultra triple quadrupole mass spectrometer interfaced to a Waters Acquity UPLC system (Waters Corp, Milford MA). The mass spectrometer was operated in negative ion mode with the following optimized APCI source parameters: corona discharge current 22 μA; ion transfer tube temperature 300°C; vaporizer temperature 290 °C; N2 sheath gas 40; N2 auxiliary gas 5; in-source CID 14. Quantitation was based on MRM detection (UAB- 126: m / z 273 → 229, collision energy 15, tube lens 90; Ar collision gas 1.5 mTorr; scan time 100 ms; Q3 scan width 1.0 m / z; Q1 / Q3 peak widths at half-maximum 0.7 m / z.). Data acquisition and quantitative spectral analysis were done using Thermo Xcalibur version 2.0.7 SP1 and Thermo LCQuan version 2.7, respectively. Calibration curves were constructed by plotting peak areas against analyte concentrations for a series of nine calibration standards, ranging from 0.375 to 3,750 nmol total analyte. A weighting factor of 1 / C2 was applied in the linear least-squares regression analysis to maintain homogeneity of variance across the concentration range. A kinetic XB-C18 reverse phase analytical column (2.1 x 100 mm, 2.6 μm, Phenomenex, Torrance, CA) was used for all chromatographic separations. Mobile phases were made up of 15 mM ammonium acetate and 0.2 % acetic acid in (A) water / acetonitrile (9:1) and in (B) acetonitrile / methanol / water (90:5:5). Gradient conditions were as follows: 0–1.0 min, B = 40 %; 1–5 min, B = 40–100 %; 5–5.5 min, B = 100 %; 5.5–6 min, B = 100–40 %; 6–10 min, B = 40 %. The flow rate was maintained at 300 μL / min, and the total chromatographic run time was 10 min. A software-controlled divert valve was used to transfer the LC eluent from 0 to 1.5 min of each chromatographic cycle to waste. Mouse Bone Marrow-Derived Macrophages (BMDM) Generation: The following protocol was employed for BMDM generation: bone marrow cells were isolated by centrifuging bones at >10,000 x g in a microcentrifuge tube for 15 seconds, as previously described.25Briefly, we isolated bone-marrow-derived stem cells from the diabetic UAB126 treated animals, grown them in complete DMEM medium with 10% FBS and 1 IU / mL Pen- Strep and then differentiated them in macrophages by supplementing with M-CSF (20 U23-098 TH 222119-2260 ng / mL, Peprotech, Rocky Hill, NJ). We then performed the Seahorse stress test with the macrophages to compare their metabolic glycolytic activity after 7 days of differentiation. BMDM activation and pro-inflammatory assessment. On the 7th day of culturing, bone marrow-derived macrophages were detached using 15mM EDTA in PBS for 10 minutes on ice. The macrophage population was then evaluated by flow cytometry, specifically by examining the expression of CD45 / CD11b (double positive) and F4 / 80 markers, which yielded a percentage of >96%. Subsequently, the detached cells were seeded in 12-well plates and cultured in DMEM supplemented with 10% FBS and 1 IU / mL pen-strep. The following day, any non-adherent cells were washed away with PBS, leaving the activated macrophages behind. The activation process involved adding 200 ng / uL of LPS to the culture media. After 24 hours of conditioning, the media was collected for further analysis. It was tested for pro-inflammatory cytokines using the V-PLEX Proinflammatory Panel 1 Mouse Kit by Meso Scale Diagnostics (Rockville, MD, USA). Glucose Uptake Assay: One day before the assay, BMDM cells were seeded in a 24-well plate at a density of 3x104cells / well. The assay was conducted using both flow cytometry and fluorescent microscopy. Positive control cells were treated with Phloretin for 1 hour before the assay. The assay involved exposing the cells to fluorescent 2-deoxy-2-[(7- nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose (2-NBDG) for 30 minutes, following the manufacturer's recommendations (ab287845, Abcam, Waltham, MA, USA). For the flow cytometry analysis, cells were washed, trypsinized, and resuspended in 400 µL of assay buffer. The glucose uptake was measured using an LSR Fortezza flow cytometer at the UAB Comprehensive Flow Cytometry Core. For fluorescence microscopy, a technical repeat plate was centrifuged at 400 x g for 5 minutes. The cells were washed with 500 μL of ice- cold 1X Analysis Buffer and then replaced with fresh 200 μL of 1X Analysis Buffer. Confocal microscopy was utilized, and fluorescent signal quantification in the confocal microscopy images was performed using ImageJ software. Metabolic Stress test (Seahorse Assay): Resuspended cells were plated in the XF96 tissue culture microplate (Agilent Technologies, Seahorse Bioscience) at a concentration of 3 x 10^5 cells per well in 180 μL of growth media (DMEM with 5.56 mM glucose, 1.0 mM pyruvate, 4 mM L-glutamine, 10% FBS, 1% pen-strep). On the day of the assay, the growth media was removed, and the cells were washed once and replaced with either Glycolytic Stress Test media (phenol-red-free DMEM, with 4 mM glutamine, pH 7.4 at 37°C) or Mito Stress Test media (phenol-red-free DMEM, with 5.56 mM glucose, 1 mM pyruvate, 4 mM glutamine, pH 7.4 at 37°C) to achieve a final volume of 180 μL per well for their respective tests. The cells were then incubated at 37°C in a non-CO2 incubator for 1 hour and subsequently loaded into the Seahorse XFe96 Analyzer (Agilent Technologies, Seahorse Bioscience) when prompted. The Seahorse XF96 sensor cartridge (Agilent U23-098 TH 222119-2260 Technologies, Seahorse Bioscience) was hydrated in sterile water in a non-CO237°C incubator overnight, and then in pre-warmed calibrant in a non-CO237°C incubator 1 hour before the assay run. All effectors were prepared to 10x desired concentrations and loaded into the appropriate ports of the sensor cartridge at 20, 22, and 25 µL in ports A, B, and C, respectively, for the Glycolytic Stress Test assay (port A: 100 mM glucose, port B: 15 mM oligomycin, port C: 500 mM 2-DG), and the Mito Stress Test assay (port A: 15 µM oligomycin, port B: 10 μM FCCP, port C: 5 µM each rotenone and antimycin A). The cartridge was then loaded into the Seahorse XFe96 Analyzer, and the protocol was run as follows: calibrate (15 min), equilibrate (15 min), 3 x basal reads (Mix: 3 min, Wait: 0 min, Measure: 3 min), followed by a port injection (A, B, C), each followed by 3 x reads. The extracellular acidification rate (ECAR) were obtained at baseline and in response to each effector injection. Electroretinography (ERG): To perform electroretinography (ERG) recordings, we utilized the LKC BigShot ERG instrument from Gaithersburg, MD, USA. The protocol consisted of consecutive scotopic and photopic ERGs. For scotopic ERG, the mice were dark-adapted for 12 hours, and all subsequent procedures were conducted in a dark room. Anesthesia was induced with an intraperitoneal injection of ketamine / xylazine based on the mice's weight. We applied topical 2.5% phenylephrine (Paragon BioTeck, Inc., 42702–102- 15, Portland, OR, USA) and Gonak (2.5% sterile hypromellose ophthalmic demulcent solution, AKORN, Lake Forest, IL, USA) to the corneal surfaces. Next, a monopolar contact loop was positioned on the cornea to record the retinal a- and b-wave ERG amplitudes. For scotopic ERG, the mice were exposed to 25 flashes of white LED light with an intensity of 3.14E-05 cds / m2, with 1.5-second intervals between flashes. Subsequently, a series of 5 flashes was applied at various intensities: 0.025 cds / m2, 2.5 cds / m2, 7.91 cds / m2, and 25 cds / m2, with 45-second intervals between flashes. Following the scotopic protocol, each mouse was light-adapted for 10 minutes under a dome background light of 25 cd / mm. The photopic protocol involved a series of 15 flashes with 1-second intervals between each flash, at intensities of 2.5 cds / m2, 7.91 cds / m2, 25 cds / m2, and 79 cds / m2. The resulting a- and b- waveforms were analyzed using the LKC EM software from Gaithersburg, MD, USA. Immunoblotting: For immunoblotting, mouse retinas were isolated and homogenized using RIPA buffer supplemented with 1% Halt Protease Inhibitor and a phosphatase inhibitor cocktail (Thermo Fisher Scientific, Waltham, MA, USA). The Western blot techniques described in a previous study were employed for further analysis.26Protein samples (40–60 μg) were separated by SDS-PAGE and transferred to a PVDF membrane. The anti-phosphorylated AMPK (Cell signaling #2535T, dilution 1:1000) and anti-AMPK (Cell signaling, #5832S, dilution 1:1000) antibodies were used for target protein detection. U23-098 TH 222119-2260 Immunohistochemistry: To perform immunohistochemistry (IHC), the eyes were fixed with 4% paraformaldehyde for 4 hours and subsequently preserved in a series of sucrose solutions (15% and 30% sucrose). After preservation, the eyes were washed in 1x PBS and embedded in Tissue-Tek O.C.T. compound (Sakura Fintek USA, Torrance, CA, USA). The embedded eyes were then frozen in 2-methylbutane at -43°C. IHC analysis was carried out on 12 μm thick retinal sections. The primary anti-RXR antibody (Invitrogen, 433900, dilution 1:200) was used to detect RXR in the human and mouse retinas. Fluorescent confocal microscopy with a Nikon AX-R was performed to take images of retinal sections. Results RXR is reduced in the diabetic retinas of humans and mice. Knowing that degenerating retina has a reduced RXRα level,10we became interested in whether the diabetic retina shows the same trend. We performed immunohistochemical analysis for both human and mouse T2D diabetic retinas. Figs.1A-1C depict the reduced RXR staining in both diabetic retinas as compared to age matched controls (human non-DM and db / m mice). Interestingly, the retinal pigment epithelial (RPE), ganglion (RGC), photoreceptor (Rh) cells were those that showed a marked reduction of RXR. The data suggest that development of DR is associated with RXR reduction and serve as rationale to investigate the role of RXR in DR. As a result, we next generated diabetic mice by STZ injection and systemically delivered the RXR agonist UAB126 to evaluate its potential to treat diabetic retina. UAB126 treatment reduces blood glucose level in diabetic mice. The therapeutic effect of UAB126 on obese mice, though associated with a reduced BGL and insulin signaling, was not linked to UAB126 detection in the serum.22In this study, Ren et al. analyzed the UAB-126-treated serum by HPLC and learned that 1h after the treatment, the serum of treated animals showed a shifted profile as compared to the standard, with the major peak at 3.24 min instead of 3.96 min. This result suggests that UAB126 is metabolized in vivo and acts as a pro-drug. UAB126 utilization is proposed to be due to metabolic degradation by active intestinal or hepatic enzymes giving rise to an active pro-drug compound. Therefore, we next analyzed UAB126 in the serum and retinas of the LC- MMs / MS–treated mice, which were collected 2h later (Fig.2A). Thus, the LC-MS / MS study demonstrates that both the serum and retinal samples had peaks corresponding to a UAB126-loaded standard while the samples from the vehicle-treated mice showed no compatible peaks. These data demonstrate that UAB126 can stay non-metabolized in diabetic mice for at least 2 h and reach the retina upon systemic treatment. This result raised the question of whether the systemic treatment, overall, benefits diabetic retina. U23-098 TH 222119-2260 We conducted the measurements of blood glucose (BGL) levels every week for 6 weeks. Moreover, at the end of the treatment, we measured HbA1c. Figs.2B and C highlight the summarized data on BGL and glucose-coated hemoglobin. While significant elevation of both measurements was found in hyperglycemic mice as compared to the healthy control, the treatment of diabetic mice with UAB126 significantly reduced these parameters, although it did not reverse their levels back to normal ones. Interestingly, in contrast to the diminished BGL level, the blood insulin level measured did not change in treated diabetic mice. This result suggests that the treatment primarily controls insulin receptor levels, resulting in enhanced glucose uptake (Fig.2D). Both UAB126 treated and untreated diabetic mice demonstrated no differences as compared to health controlled analyzed by two-way Anova (Fig.2E). UAB126 treatment improves the diminished retinal function and alters cellular signaling in diabetic retina. At the end of the treatment, the mice were analyzed by scotopic ERG analysis. Figs.3A and 3B demonstrate that while vehicle-treated diabetic mice showed a reduction in ERG amplitudes, treatment with rexinoid markedly prevents the declines of A- and B-waves. It is also worth noting that although the B-waves were significantly higher in UAB126-treated vs untreated groups, the recording did not reach the level of those found in the healthy control group, suggesting that UAB126 treatment delays the progression of vision loss in diabetes. We next sacrificed animals, collected the retinal tissues, and performed western blot and RNAseq analyses in diabetic treated vs untreated mice. We became interested in AMPK because this molecular is a hub of metabolic control in cells and its stimulation prevents diabetes-induced photoreceptor cell degeneration.27Thus, we found that UAB126-traeted mice show a significantly higher level of p-AMPK as compared to vehicle-treated ones. Overall, these data suggest that the systemic delivery of UAB126 may modify metabolism and cellular sinking in the retina. UAB126 regulates metabolism-relative biological pathways in diabetic retinas. During DR progression, the diabetic retina experiences monocyte infiltration, which is critical for overall innate immune response and inflammation. Therefore, we next assessed the properties of the monocytes isolated from the bone marrow of UAB126-traeted mice. We cultured the isolated monocytes, differentiated them into macrophages, and performed the glycolysis stress test, measuring the extracellular acidification rate (ECAR) using the Seahorse approach. Fig.4A demonstrates that while the diabetic macrophages isolated from vehicle-treated mice showed an increase in the acidification rate after the addition of glycose, oligomycin, and 2-DG as compared to the healthy control group; UAB126 treatment dramatically reduced the measured ECAR in diabetic macrophages, making them indistinguishable from healthy macrophages. These data demonstrate that glycolysis in U23-098 TH 222119-2260 vehicle-treated diabetic macrophages may be enhanced, leading to increase in lactate efflux. Therefore, we next asked ourselves whether an ECAR increase could be associated with an increase in glucose uptake by macrophages. Indeed, a significant (over 2-fold) increase in the uptake of 2-DG labeled with Alexa Flour 488 was detected in the diabetic macrophages isolated from vehicle-treated mice (Fig. 4B). Interestingly, treatment with UAB126 markedly reduced the 2-DG uptake in macrophages, suggesting that the insulin signaling tends to be normalized in these macrophages. We then analyzed the pro- and anti-inflammatory cytokines in treated macrophages and found that UAB126 treatments led to an increase in IL-10 cytokine while Il-1β was not different between the UAB216- and vehicle-treated macrophages. This result suggests that not only metabolic status but also inflammatory response could be altered because of rexinoid treatment (Fig.3C). Overall, the results of the study indicate that UAB216 treatment balanced glucose metabolism in monocytes as compared to untreated diabetic cells, suggesting that systemic delivery of UABV126 not only reduced BGL and normalized metabolism but also increased the anti-inflammatory program in diabetic macrophages, leading to improved retinal electrophysiology. Evaluating the systemic effect of UAB126 treatment on diabetic mice, we wondered whether topically applying eye drops containing rexinoid may be an effective drug delivery approach. Ocular application of UAB126 drops on the corneal surface of db / db mice was carried out daily for two weeks. At the end of the treatment, the mice were sacrificed, and their retinas were harvested to conduct the gene expression study and detect UAB126 after the corneal drug application. The LC-MS / MS results demonstrate that the control (untreated) retinas did not contain UAB126-associated puck and that a strong signal was detected in the retina treated with UAB126 drops (Fig 5A). Moreover, RXR staining of the treated retina with anti-RXR antibody demonstrated strong immunoreactivity as compared to buffer-treated retinas (Fig. 5B). The increase in the RXRα mRNA expression level was also detected in the treated eyes, which was much higher than the from untreated diabetic and healthy control group eyes (C57BL6) (Fig.5C). Interestingly, like RXR, PPAR was also reduced in diabetic retinas, and UAB126 treatment also increased its expression level. In addition to the altered expression of two NRs, RXR and PPAR, the expression of genes responsible for lipid metabolism—such as Elovl4, Acly, Fasn, Scd1, and Acc1—was reduced in untreated diabetic retinas and increased upon UAB126 treatment (p<0.05), with the exceptions of Scd1 and Acc1 genes. Noticing that the treatment with UAB126 drops increased not only RXR but PPAR as well, we next decided to assess the ability of other rexinoids to increase PPAR and LXR expression in ex vivo experiment. Fig.5D shows that the retinal explants cultured in the U23-098 TH 222119-2260 media with high glucose to model diabetic retinas and supplemented with rexinoid 3 and rexinoid 6—the previously studied rexinoids28— demonstrated significant upregulations of Rxrα, Rxrβ, and Rxrγ mRNAs at 24h. We next examined the expression of Pparα and Pparγ genes, and we found significant increases in their expression as well. Overall, the data presented in Fig.5 suggest that RXR-based therapy may require PPAR as a binding partner to provide optimal therapeutic benefits in diabetic retinas. Discussion NR RXR as a therapeutic target has recently attracted a great deal of attention from the scientific community, perhaps explaining the growing number of clinical trials associated with RXR-based therapy (NCT#05550766,NCT#04245982, NCT#04220146). Despite the convincing data linking RXR-controlled lipid metabolism and inflammatory response, two major critical components of diabetic retinal complications, to RXR-regulated genome expression29, 30and the therapeutic potential needed to treat neurodegenerative disorders such as Alzheimer’s31and Parkinson’s32, the RXR agonists have never been validated to treat DR. Therefore, for the first time, in this study, we demonstrate that RXR is a promising candidate to slow DR. The previous study conducted with obese mice did not detect the drug in the serum of the animals, suggesting that UAB126 is a pro-drug with quick metabolic degradation.22We found that systemic delivery of UAB126 to diabetic mice resulted in accumulation of UAB126 in both serum and retinas. Perhaps, the methods identifying the drug used in our and the above-mentioned study, LC-MS / MS and HPLC, respectively, explain the different results. Nevertheless, although it has not been detected in serum, in the above-mentioned study, UAB126 treatment significantly diminished BGL in obese mice.22Our study with T1D confirmed the capability of UAB126 to control glucose levels; both glucose and HbA1C levels were reduced. These data imply that UAB126 could be beneficial to diabetic patients not only by maintaining the blood glucose, and therefore managing the progression of diabetes, but also by altering the biological processes in diabetic retina. UAB126 treatment reprograms cellular metabolism and macrophages with modified glycolysis, and glucose consumption rates are the example of cell types affected by the treatment. The UAB126 treated macrophages responded to all steps of metabolic stress like the cells isolated from the untreated healthy mice. Overall, the published data on glucose uptake and the rate of glycolysis in diabetic and high glucose-treated macrophages seem to be controversial in the literature. For example, the study conducted by Zeng et al. proposed that glycolysis is upregulated in C57BL6 bone marrow–derived macrophages under high glucose conditions.33In line with this research, other studies have demonstrated enhanced ECAR in the adipose tissue macrophages derived from obese mice.34, 35Meanwhile, the U23-098 TH 222119-2260 peritoneal macrophages isolated from STZ-induced diabetic Ldr- / -mice manifest suppression of glucose uptake and glycolysis.36Moreover, Pavlou et al. proposed that long-term exposure of C57BL6 bone marrow–derived macrophages in the medium supplemented with high glucose suppresses the ECAR rate.37Despite the above-mentioned controversy, which is perhaps explained by the difference in the mouse strains—the sources of isolated macrophage and the conditions of its treatment, in vitro vs. in vivo—the importance of the metabolic shift in diabetic macrophage’s health is widely recognized. Thus, it has been proposed that M1 macrophages rely mainly on glycolysis and that their aberrant TCA cycle leads to the accumulation of succinate, which in turn induces HIF1a stabilization and activates the transcription of glycolytic genes with sustained glycolytic metabolism.38In contrast, M2 macrophages depend on oxidative phosphorylation, and that their TCA cycle is intact. Together, these data suggest that the metabolic state of macrophages could determine their polarization. Aligning with these data, the LPS-treated macrophages from UAB126-fed animals manifested increased concentration of anti-inflammatory IL-10 cytokine, which in general is known to be a M2 marker.39This result also implies that populations of either retinal residential macrophages or infiltrated monocytes during the course of diabetes may have a good chance to be pro-M2-type immune cells in the treated diabetic retina as compared to the untreated. In line with the upregulated ECAR rate, in diabetic macrophages, we also observed reduced glucose consumption. Interestingly, the reduction in glucose level was not accompanied by changes in the insulin level in treated mice. Partially, this could be explained by the toxicity of STZ for pancreas β cells in the T1D mouse model. Most likely, the β cell damage cannot be overcome by RXR-based treatment. Meanwhile, the RXR agonist-induced decrease in BGL suggests an improved insulin receptor sensitivity in varied diabetic tissues; treated diabetic retinas could be among them. These findings also suggest that the UAB126 RXR agonist could help to treat T2D, in which the insulin receptors are desensitized; to balance glucose uptake by retinal cells and their activation, it might be helpful to improve insulin-controlled rhodopsin signaling to restore diminished retinal function and vascular disfunction.40Overall, UAB126 treatment normalizes glucose uptake, suggesting that the retinal glucose flux and metabolism might be corrected in diabetic retinas as well. In support of this hypothesis, we found that the 6-week treatment of diabetic mice prevents the decline of retinal function. These data suggest that the vision deficit in treated diabetic mice is slowed down. Moreover, the increase in the p-AMP level in treated diabetic retinas indicate a metabolic shift towards homeostasis. It has been demonstrated that diabetes-induced inflammation strongly correlates with a reduced AMPK pathway, the downregulation of which leads to diminished SIRT1 and NF-kB activation.41AMPK stimulation is known to prevent photoreceptor cell degeneration in T1D mice.27Therefore, an U23-098 TH 222119-2260 increase in AMPK activity may indicate the reduced inflammatory response and diminished photoreceptor functional loss. This data correlate with the observed reduction in decline of A- wave scotopic amplitudes in UAB126-treated diabetic mice vs untreated ones. Given that BGL is reduced, insulin is not changed, glucose uptake is normalized, and AMPK activity is increased in UAB126-treated animal tissues, it is possible that RXR-based therapy provides effects like metformin in T2D patients. We next prepared the UAB126 eye drops and treated the animals. The clinical importance of the eye drops containing effective drugs to correct DR is difficult to overestimate. The way of delivering bioactive compounds on an everyday basis would significantly improve the quality of life of diabetic patients losing their vision. The topical application of UAB126 delivered the drug to the retina and increased the expression of genes responsible for lipid metabolism. This suggests that UAB126 application could normalize local lipid synthesis. Thus, the reduced expression of Elovl2 and Elovl4, elongases required for the biosynthesis of long-chain polyunsaturated fatty acids, occurs in diabetic retinas.42, 43It worth mentioning that their increases would help to slow down retinal pathogenesis by producing complex lipids known to be diminished in diabetic retinas overall44; an increase would also balance lipid composition by normalizing the cholesterol influx / efflux ratio. A small UAB126 compound could be useful in this matter as well. In conclusion, we validated a new UAB126 agonist with a therapeutic potential to treat DR. In sum, our data indicate that RXR-based therapy could benefit diabetic patients not only by reducing the BGL, and therefore controlling DR progression, but also by altering local retinal metabolism and the inflammatory response. References for Example 1 1. Zhang XK, Lehmann J, Hoffmann B, et al. Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature 1992;358:587-591. 2. Osz J, Brelivet Y, Peluso-Iltis C, et al. Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors. Proc Natl Acad Sci U S A 2012;109:E588-594. 3. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996;10:940-954. 4. Huang P, Chandra V, Rastinejad F. Retinoic acid actions through mammalian nuclear receptors. Chem Rev 2014;114:233-254. 5. Gocek E, Baurska H, Marchwicka A, Marcinkowska E. Regulation of Leukemic Cell Differentiation through the Vitamin D Receptor at the Levels of Intracellular Signal Transduction, Gene Transcription, and Protein Trafficking and Stability. Leuk Res Treatment 2012;2012:713243. U23-098 TH 222119-2260 6. Yasmin R, Williams RM, Xu M, Noy N. Nuclear import of the retinoid X receptor, the vitamin D receptor, and their mutual heterodimer. J Biol Chem 2005;280:40152-40160. 7. Szeles L, Poliska S, Nagy G, et al. Research resource: transcriptome profiling of genes regulated by RXR and its permissive and nonpermissive partners in differentiating monocyte-derived dendritic cells. Mol Endocrinol 2010;24:2218-2231. 8. Kubickova B, Martinkova S, Bohaciakova D, et al. Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology 2023;487:153461. 9. Sugawara A, Yen PM, Qi Y, Lechan RM, Chin WW. Isoform-specific retinoid-X receptor (RXR) antibodies detect differential expression of RXR proteins in the pituitary gland. Endocrinology 1995;136:1766-1774. 10. Volonte YA, Ayala-Pena VB, Vallese-Maurizi H, et al. Retinoid X receptor activation promotes photoreceptor survival and modulates the inflammatory response in a mouse model of retinitis pigmentosa. Biochim Biophys Acta Mol Cell Res 2021;1868:119098. 11. Roberts MR, Hendrickson A, McGuire CR, Reh TA. Retinoid X receptor (gamma) is necessary to establish the S-opsin gradient in cone photoreceptors of the developing mouse retina. Invest Ophthalmol Vis Sci 2005;46:2897-2904. 12. UniProt C. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res 2021;49:D480-D489. 13. Sharma S, Shen T, Chitranshi N, et al. Correction to: Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement. Mol Neurobiol 2022;59:2051. 14. Wietrzych-Schindler M, Szyszka-Niagolov M, Ohta K, et al. Retinoid x receptor gamma is implicated in docosahexaenoic acid modulation of despair behaviors and working memory in mice. Biol Psychiatry 2011;69:788-794. 15. Nunez V, Alameda D, Rico D, et al. Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression. Proc Natl Acad Sci U S A 2010;107:10626-10631. 16. Roszer T, Menendez-Gutierrez MP, Cedenilla M, Ricote M. Retinoid X receptors in macrophage biology. Trends Endocrinol Metab 2013;24:460-468. 17. Matsumoto R, Takahashi D, Watanabe M, et al. A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice. Front Pharmacol 2021;12:715752. 18. Morichika D, Miyahara N, Fujii U, et al. A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation. Respir Res 2019;20:2. 19. Li Y, Xing Q, Wei Y, et al. Activation of RXR by bexarotene inhibits inflammatory conditions in human rheumatoid arthritis fibroblast-like synoviocytes. Int J Mol Med 2019;44:1963-1970. U23-098 TH 222119-2260 20. Lalloyer F, Fievet C, Lestavel S, et al. The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia. Arterioscler Thromb Vasc Biol 2006;26:2731-2737. 21. Grubbs CJ, Hill DL, Bland KI, et al.9cUAB30, an RXR specific retinoid, and / or tamoxifen in the prevention of methylnitrosourea-induced mammary cancers. Cancer Lett 2003;201:17-24. 22. Ren G, Kim T, Kim HS, et al. A Small Molecule, UAB126, Reverses Diet-Induced Obesity and its Associated Metabolic Disorders. Diabetes 2020;69:2003-2016. 23. Singh Y, Meher JG, Raval K, et al. Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release 2017;252:28-49. 24. Fernandes AR, Sanchez-Lopez E, Santos TD, Garcia ML, Silva AM, Souto EB. Development and Characterization of Nanoemulsions for Ophthalmic Applications: Role of Cationic Surfactants. Materials (Basel) 2021;14. 25. Amend SR, Valkenburg KC, Pienta KJ. Murine Hind Limb Long Bone Dissection and Bone Marrow Isolation. J Vis Exp 2016. 26. Saltykova IV, Elahi A, Pitale PM, Gorbatyuk OS, Athar M, Gorbatyuk MS. Tribbles homolog 3-mediated targeting the AKT / mTOR axis in mice with retinal degeneration. Cell Death Dis 2021;12:664. 27. Song S, Bao S, Zhang C, et al. Stimulation of AMPK Prevents Diabetes-Induced Photoreceptor Cell Degeneration. Oxid Med Cell Longev 2021;2021:5587340. 28. Atigadda VR, Kashyap MP, Yang Z, et al. Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers. J Med Chem 2022;65:14409- 14423. 29. Kiss M, Czimmerer Z, Nagy L. The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology. J Allergy Clin Immunol 2013;132:264-286. 30. Reich LA, Leal AS, Ellsworth E, Liby KT. The Novel RXR Agonist MSU-42011 Differentially Regulates Gene Expression in Mammary Tumors of MMTV-Neu Mice. Int J Mol Sci 2023;24. 31. Nam KN, Mounier A, Fitz NF, et al. RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Abeta oligomers. Sci Rep 2016;6:24048. 32. Spathis AD, Asvos X, Ziavra D, et al. Nurr1:RXRalpha heterodimer activation as monotherapy for Parkinson's disease. Proc Natl Acad Sci U S A 2017;114:3999-4004. 33. Zeng H, Qi X, Xu X, Wu Y. TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy. Inflamm Res 2020;69:1215-1234. U23-098 TH 222119-2260 34. Sharma M, Boytard L, Hadi T, et al. Enhanced glycolysis and HIF-1alpha activation in adipose tissue macrophages sustains local and systemic interleukin-1beta production in obesity. Sci Rep 2020;10:5555. 35. Serbulea V, Upchurch CM, Schappe MS, et al. Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proc Natl Acad Sci U S A 2018;115:E6254-E6263. 36. Matsuura Y, Shimizu-Albergine M, Barnhart S, et al. Diabetes Suppresses Glucose Uptake and Glycolysis in Macrophages. Circ Res 2022;130:779-781. 37. Pavlou S, Lindsay J, Ingram R, Xu H, Chen M. Sustained high glucose exposure sensitizes macrophage responses to cytokine stimuli but reduces their phagocytic activity. BMC Immunol 2018;19:24. 38. Viola A, Munari F, Sanchez-Rodriguez R, Scolaro T, Castegna A. The Metabolic Signature of Macrophage Responses. Front Immunol 2019;10:1462. 39. Cantero-Navarro E, Rayego-Mateos S, Orejudo M, et al. Role of Macrophages and Related Cytokines in Kidney Disease. Front Med (Lausanne) 2021;8:688060. 40. Rajala A, Teel K, Bhat MA, et al. Insulin-like growth factor 1 receptor mediates photoreceptor neuroprotection. Cell Death Dis 2022;13:613. 41. Kubota S, Ozawa Y, Kurihara T, et al. Roles of AMP-activated protein kinase in diabetes-induced retinal inflammation. Invest Ophthalmol Vis Sci 2011;52:9142-9148. 42. Wang Q, Tikhonenko M, Bozack SN, et al. Changes in the daily rhythm of lipid metabolism in the diabetic retina. PLoS One 2014;9:e95028. 43. Tikhonenko M, Lydic TA, Wang Y, et al. Remodeling of retinal Fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4. Diabetes 2010;59:219-227. 44. Fort PE, Rajendiran TM, Soni T, et al. Diminished retinal complex lipid synthesis and impaired fatty acid beta-oxidation associated with human diabetic retinopathy. JCI Insight 2021;6. 45. Yuan T, Dong L, Pearsall EA, Zhou K, Cheng R, Ma JX. The Protective Role of Microglial PPARalpha in Diabetic Retinal Neurodegeneration and Neurovascular Dysfunction. Cells 2022;11. It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a concentration range U23-098 TH 222119-2260 of “about 0.1 percent to about 5 percent” should be interpreted to include not only the explicitly recited concentration of about 0.1 weight percent to about 5 weight percent but also include individual concentrations (e.g., 1 percent, 2 percent, 3 percent, and 4 percent) and the sub-ranges (e.g., 0.5 percent, 1.1 percent, 2.2 percent, 3.3 percent, and 4.4 percent) within the indicated range. The term “about” can include traditional rounding according to significant figures of the numerical value. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”. Many variations and modifications may be made to the above-described aspects. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

U23-098 TH 222119-2260 CLAIMS What is claimed:

1. A method of treating a condition comprising: administering to a subject in need thereof, a pharmaceutical composition, wherein the condition to be treated is an eye disease, wherein the pharmaceutical composition includes a therapeutically effective amount of the compound or pharmaceutical composition including the compound or salts thereof, wherein the compound has one of the following formula: orwherein: each R1is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group; each R2is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group;U23-098 TH 222119-2260 each R3is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group; and at least one of R1, R2, or R3is not hydrogen.

2. The method of claim 1, wherein the condition to be treated is diabetic retinopathy, diabetic retinal dysfunction inherited retinal dystrophies, age-related macular degeneration, glaucoma, or optic neuritis.

3. The method of claim 2, wherein the condition to be treated is diabetic retinopathy.

4. The method of claim 2, wherein the condition to be treated is diabetic retinal dysfunction.

5. The method of claim 1, wherein each R1is independently selected from hydrogen, a C1- C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

6. The method of claim 1, wherein each R2is independently selected from hydrogen, a C1- C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

7. The method of claim 1, wherein each R3is independently selected from hydrogen, a C1- C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

8. The method of claim 1, wherein each R1, R2, and R3is hydrogen.

9. The method of claim 1, wherein at least one of R1, R2, or R3is not hydrogen.

10. A compound having the formula:U23-098 TH 222119-2260 orwherein: each R1is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group; each R2is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group; each R3is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group; and at least one of R1, R2, or R3is not hydrogen.

11. The compound of claim 1, wherein each R1is independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

12. The compound of claim 1, wherein each R2is independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.U23-098 TH 222119-2260 13. The compound of claim 1, wherein each R3is independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound to treat a condition in a subject, wherein the compound has the formula: oreach R1is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group; each R2is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group; and each R3is independently selected from hydrogen, an alkyl group, a halogen, a trifluoromethyl group, or a hydroxy group.U23-098 TH 222119-2260 15. The pharmaceutical composition of claim 14, wherein each R1is independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

16. The pharmaceutical composition of claim 14, wherein each R2is independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

17. The pharmaceutical composition of claim 14, wherein each R3is independently selected from hydrogen, a C1-C6 alkyl group, fluorine, a trifluoromethyl group, or a hydroxy group.

18. The pharmaceutical composition of claim 14, wherein each R1, R2, and R3is hydrogen.

19. The pharmaceutical composition of claim 14, wherein at least one of R1, R2, or R3is not hydrogen.

20. The pharmaceutical composition of any one of claims 14-10, wherein the composition further comprises a pharmaceutically acceptable carrier.

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