Small molecule steroid receptor coactivator stimulators for use in repairing tissue

Abstract

Provided herein are methods of modulating cellular stress pathways using small molecule steroid receptor coactivators (SRC) stimulators. A method of repairing tissue in a subject comprises administering to the subject an effective amount of a pharmaceutical composition comprising a compound as described herein. Methods of protecting tissue adjacent to an injury site or reducing tissue loss in a subject, preserving insulin production and preventing diabetes in a subject, and / or inhibiting kidney fibrosis in a subject are further provided herein.

Description

[0001] SMALL MOLECULE STEROID RECEPTOR COACTIVATOR STIMULATORS FOR USE IN REPAIRING TISSUE

[0002] CROSS-REFERENCE TO PRIORITY APPLICATION

[0003] This application claims the benefit of and the priority to U.S. Provisional Application No. 63 / 648,775, filed May 17, 2024, which is hereby incorporated by reference in its entirety for all purposes.

[0004] BACKGROUND

[0005] A key determinant connected to the inability of the body to resolve injury involves inadequate or counterproductive responses, such as reactive oxygen species (ROS) generation and inflammation. This is intricately connected to how injured and distressed tissues respond to and resolve these stresses through proper sequential modulation of inflammation responses, immune system engagement with stressed tissues, and fibrosis. As a part of this process, a major hurdle to the healthy resolution of tissue injury in multiple organs is related to insufficient activation of cellular stress response pathways that react to ROS and proteostasis disruption, including those driven by NF-E2-related factor 2 (Nrf2). Also closely coupled with injured tissue recovery is localized inflammation that sets in motion an immune Ml to M2 transition that promotes the repair and restoration of healthy function in injured and stressed tissues.

[0006] SUMMARY

[0007] Described herein are methods of modulating cellular stress pathways using small molecule steroid receptor coactivators (SRC) stimulators. A method of repairing tissue in a subject comprises administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula: or a pharmaceutically acceptable salt or prodrug thereof. In these compounds, A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6 alkyl; and X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl. Optionally, the method further comprises selecting a subject experiencing tissue injury. The administering step can be performed within a period of time after tissue injury (e.g., within 24 hours of issue injury, within 48 hours of tissue injury, within 7 days of tissue injury, within 1 month of tissue injury, or within 6 months of tissue injury). The administering can increase the ratio of M2 macrophages to M1 macrophages. In some cases, the administering promotes macrophage transition to an M2-like state. The administering can optionally inhibit inflammation. In some cases, the subject has suffered traumatic brain injury or kidney injury. In some cases, the subject has Alzheimer’s disease or diabetes (e.g., Type 1 diabetes). Optionally, the compound has the following formula: or a pharmaceutically acceptable salt or prodrug thereof. Optionally, the compound has the following formula: , or a pharmaceutically acceptable salt or prodrug thereof, wherein m and n are each independently 1, 2, 3, 4, or 5. In some cases, the compound is: . In some cases, the compound has the following formula: or a pharmaceutically acceptable salt or prodrug thereof. In some cases, the compound has the following formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein m and n are each independently 1, 2, 3, 4, or 5. Optionally, the compound is . Also provided herein is a method of protecting tissue adjacent to an injury site or reducing tissue loss in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula: or a pharmaceutically acceptable salt or prodrug thereof. In these compounds, A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6alkyl; and X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl. Optionally, the method further comprises selecting a subject that has suffered traumatic brain injury or kidney injury. Optionally, the method comprises selecting a subject that has Alzheimer’s disease or diabetes (e.g., Type 1 diabetes). Further described herein is a method of preserving insulin production and preventing diabetes in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula: or a pharmaceutically acceptable salt or prodrug thereof. In these compounds, A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6alkyl; and X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl. Also described herein is a method of inhibiting kidney fibrosis in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula: or a pharmaceutically acceptable salt or prodrug thereof. In these compounds, A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6alkyl; and X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl. Optionally, the method further comprises selecting a subject that has suffered kidney injury. The details of one or more embodiments are set forth in the drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. DESCRIPTION OF DRAWINGS Fig.1A-C shows that SRC activation decreases cytokines and matricellular proteins associated with fibrotic remodeling in cardiac fibroblasts. Fig.1A shows the analysis of secreted cytokine factors in conditioned media from control or MCB-61310-1–treated cardiac fibroblasts (6 μM for 24 hours) using R&D Systems Proteome ProfilerTM Antibody Array. Fig.1B shows the array quantification. Fig.1C includes graphs showing the validation of mRNA expression by RT-PCR of cultured cells for Ccl2,Opg and matricellular genesThbs2 and Ccn3. Representative values from 3 experiments. Values shown are mean ± SEM; Student’s t-test n = 3 control and n = 310-1. Fig.2A-E shows that 10-1 inhibits cardiac fibroblast activation. Fig.2A shows gels from CFs cultured in a collagen I gel and treated with TGF-β or 10-1. Gel size was measured using ImageJ. Representative images of 6 experiments with 6 wells per experiment. Fig.2B shows representative images of cells growing in collagen I gels treated with TGF-β or pre- treated with 10-1 then stained with phalloidin and imaged. Fig.2C shows the results of cell migration as measured using a scratch assay. Images were taken at different time points. Quantification of the percent closure of the scratch area. Representative images from 3 experiments. Values shown are mean ± SEM; Student’s t-test n = 6 control and n = 610-1 from one experiment. Fig.2D shows CF cell viability as measured at 24h. Values shown are mean ± SEM; Student’s t-test n = 4 from one of three experiments. Mean cell counts were measured every hour for 17 hours. Representative of two experiments. Fig.2E shows SRC-1, 2 and 3 protein expression in cultured cardiac fibroblasts 4 and 24 hours after 10-1 treatment. Representative images from 3 experiments. Fig.3 shows the results from cleaved caspase-3 staining performed in CFs treated with vehicle control or MCB-613-10-1 for 24 hours. Representative images from 3 experiments plated in replicates of 6. Fig.4 depicts a volcano plot showing up- and down-regulated differentially regulated genes 4 and 24 hours after 10-1 treatment in cardiac fibroblasts compared to vehicle control. Fig.5 shows gene lists for DAVID Annotation Cluster Extracellular Matrix. Fig.6 contains gene lists for WIKI Pathway: Transcriptional activation by Nfe2l2 and WIKI NRF2 Pathway at Msig DB. Fig.7 contains gene lists for Reactome KEAP1-NFE2l2 pathway. Fig.8 contains gene lists for Reactome Nuclear events mediated by NFE2l2. Fig.9A-B shows results from the analysis of the SRC activation gene signature in CFs shows the cardioprotective transcriptional response is dominated by the NRF2 transcriptional network. Fig.9A contains the gene ontology analysis of functional annotation clusters and molecular pathways of differentially regulated genes 4 hours after 10-1 treatment in cardiac fibroblasts compared to vehicle control. Fig.9B contains the gene ontology analysis of functional annotation clusters and molecular pathways of differentially regulated genes 4 hours after 10-1 treatment in cardiac fibroblasts compared to vehicle control. Fig.10 shows that SRC activation stimulates antioxidant and cytoprotective genes in the NRF2 pathway. The figure shows differentially expressed genes in NRF2 pathway at 4 and 24 hours following 10-1 treatment. Fig.11A-E shows that 10-1 stimulates the NRF2 oxidative stress cellular defense pathway and improves mitochondrial function. RT-PCR and Western Blot validation of RNAseq 4 and 24-hours following treatment for (Fig.11A) RT-PCR for NRF2 antioxidant response genes at 4- and 24-hours control or 10-1 treatment. Values shown are mean ± SEM; Student’s t-test n = 3 control and n = 310-1. Representative of 3 experiments. (Fig.11B) Western Blots for NRF2 antioxidant response proteins at 4- and 24-hours control or 10-1 treatment. (Fig.11C) NRF2 and HMOX1 immunostaining. Representative images of 3 experiments. Quantification of HMOX1 in 5 images per condition. (Fig.11D) Western Blot of NRF2 in cytoplasmic and nuclear fractions in WT CF lysates. (Fig.11E) Seahorse analysis of cellular oxygen consumption rate (OCR) in CFs treated with 10-1 compared to control. Data are representative of 3 independent experiments. N= 4 measurements per treatment group. Fig.12 contains a volcano plot showing up- and down-regulated differentially regulated proteins 24 hours after 10-1 treatment in cardiac fibroblasts compared to vehicle control. Fig.13 contains gene lists for WIKI Pathway: Transcriptional activation by Nfe2l2 and WIKI NRF2 Pathway at Msig DB. Fig.14 shows the top enrichment NRF2-Pathway from proteomics profiling of CFs treated with 10-1 for 24 hours compared to vehicle control. Fig.15 shows the top 5 DAVID WIKI pathway enrichments for 248 shared proteins and DEGs in 10-1-treated CFs compared to control for 24 hours. Fig.16A-D shows that MCB-613-10-1 prevents production of intracellular ROS and promotes resistance to H2O2-induced loss of cell numbers and cellular and mitochondrial dysfunction. Fig.16A shows CFs were treated with 600 μM H2O2in the presence or absence of MCB-613-10-1 for 24 hours. Intracellular ROS was detected using the CellRox assay. Representative images from 3 experiments n=6 control and n=6 MCB-613-10-1. Quantification of 4 fields of view for percent ROS positive cells (right panel). Fig.16B shows cell viability as measured 24 hours following addition of 600 μM H2O2with 30-minute 10-1 (6μM) pre-treatment, 24-hour 10-1 pre-treatment or 6 hours H2O2pre-treatment followed by 24 hours 10-1. Values shown are mean ± SEM; Student’s t-test. n = 6 for each condition representative of three experiments. Fig.16C shows cell painting that was performed on CFs that were pre-treated with MCB-613-10-1 for 24 hours followed by 900 μM H2O2or no H2O2. Representative images from 3 experiments. Quantification of two experiments n=4 for each experiment. Values shown are mean ± SEM; Student’s t-test for H2O2compared to H2O2plus MCB-613-10-1. Fig.16D shows a cell painting analysis of cellular and mitochondrial features. Quantification of two experiments, n=4 replicates for each experiment. Values shown are mean ± SEM; Student’s t-test for H2O2compared to H2O2plus MCB-613-10-1. Fig.17A-D shows that NRF2 is required for 10-1-induced improved mitochondrial function and resistance to oxidative stress. Fig.17A shows a seahorse analysis of cellular oxygen consumption rate (OCR) in NRF2KO CFs treated with vehicle control compared to MCB-613-10-1 for 24 hours. Representative data of three replicate experiments. Fig.17B shows CFs from NRF2 K.O mice were treated with vehicle control or 10-1 for 24 hours. Values shown are mean ± SEM; Student’s t-test. n = 3 for each condition from one of three experiments. Fig.17C shows cell viability measured 24 hours following addition of 600 μM H2O2with 30-minute or 24-hour 10-1 (6μM) pre-treatment or co-treatment of H2O2and 10-1. Values shown are mean ± SEM; Student’s t-test. n = 4 for each condition from one of two experiments. Fig.17D shows NRF2KO CFs treated with 600 μM H2O2in the presence or absence of MCB-613-10-1 for 24 hours. Intracellular ROS was detected using the CellRox assay. Representative images from 3 experiments n=3 control and n=3 MCB-613-10-1. Quantification of %ROS fluorescence compared to DAPI from 4 images per condition. Fig.18 shows SRC expression by Western blot in NRF2 KO CFs. Fig.19 shows HMOX1 and GSTA3 protein expression in NRF2KO CFs 24 hours after treatment with control or MCB-613-10-1. Fig.20A-B shows SRCs-1,2,3 and NRF2 bind to ARE enhancer regions in mouse cardiac fibroblasts. Fig.20A shows the results from analysis of potential ARE regions in mouse HMOX1 enhancer and promoter regions using Cistrome.org database. Fig.20B shows results from quantifying ARE region E2 and E3 by qPCR in cardiac fibroblasts following IP using IgG, SRC-1,2,3 and NRF2 antibodies. Values shown are mean ± SEM; Student’s t-test. n = 4 for each condition from one of three experiments. Fig.21 shows potential ARE regions in the 5’upstream region of the mouse HMOX1 gene sequence derived from NRF2 ChIP sites in the mouse genome. Cistrome Data Browser database. Fig.22 presents photographs and graphs showing that MCB-613-10-1 attenuates the extent of injury post-stroke in a rat middle cerebral artery occlusion (MCAO) model. Fig.23A-H presents photographs and graphs showing that the extent of surgically- induced traumatic brain injury is reduced in MCB-613-10-1 treated mice. Fig.24A-B presents photographs and graphs showing that long-term treatment with MCB-613-10-1 reduces phosphorylated tau accumulation and astrogliosis in ps19 Alzheimer’s disease model mice. Fig.25 contains graphs showing that treatment of nonobese diabetic (NOD) mice with MCB-613-10-1 strongly reduces the formation of type 1 diabetes. Fig.26 contains images and a graph showing that surgically induced kidney injury that induces kidney fibrosis can be attenuated by treatment with MCB-613. DETAILED DESCRIPTION Described herein are methods of modulating cellular stress pathways using small molecule steroid receptor coactivator (SRC) stimulators. Optionally, the small molecule SRC stimulators are SRC-3 (AIB1 / RAC3 / ACTR / pCIP) stimulators, SRC-1 stimulators, or SRC-2 simulators. The SRC stimulators are administered in a manner (such as, for example, the timing for administration post- or pre-stress) such that the compounds are useful for repairing tissue in a subject. Also described herein are methods of using the compounds to protect tissue adjacent to an injury site or reduce tissue loss in a subject, preserve insulin production and / or prevent diabetes in a subject, and / or inhibit kidney fibrosis in a subject. I. Compounds A class of SRC stimulators described herein is represented by Formula I: and pharmaceutically acceptable salts or prodrugs thereof. In Formula I, A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N. Each R1group present in Formula I is independently selected from hydrogen, halogen, alkoxy, cyano, trifluoromethyl, and substituted or unsubstituted C1-6alkyl. Also, in Formula I, X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl. As used herein, the terms alkyl, alkenyl, and alkynyl include straight- and branched- chain monovalent substituents. Examples include methyl, ethyl, isobutyl, 3-butynyl, and the like. Ranges of these groups useful with the compounds and methods described herein include C1-C20alkyl, C2-C20alkenyl, and C2-C20alkynyl. Additional ranges of these groups useful with the compounds and methods described herein include C1-C12alkyl, C2-C12 alkenyl, C2-C12alkynyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl. Heteroalkyl, heteroalkenyl, and heteroalkynyl are defined similarly as alkyl, alkenyl, and alkynyl, but can contain O, S, or N heteroatoms or combinations thereof within the backbone. Ranges of these groups useful with the compounds and methods described herein include C1-C20heteroalkyl, C2-C20heteroalkenyl, and C2-C20heteroalkynyl. Additional ranges of these groups useful with the compounds and methods described herein include C1- C12heteroalkyl, C2-C12heteroalkenyl, C2-C12heteroalkynyl, C1-C6heteroalkyl, C2-C6heteroalkenyl, C2-C6heteroalkynyl, C1-C4heteroalkyl, C2-C4heteroalkenyl, and C2-C4heteroalkynyl. The terms cycloalkyl, cycloalkenyl, and cycloalkynyl include cyclic alkyl groups having a single cyclic ring or multiple condensed rings. Examples include cyclohexyl, cyclopentylethyl, and adamantanyl. Ranges of these groups useful with the compounds and methods described herein include C3-C20cycloalkyl, C3-C20cycloalkenyl, and C3-C20cycloalkynyl. Additional ranges of these groups useful with the compounds and methods described herein include C5-C12cycloalkyl, C5-C12cycloalkenyl, C5-C12cycloalkynyl, C5-C6cycloalkyl, C5-C6cycloalkenyl, and C5-C6cycloalkynyl. The terms heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl are defined similarly as cycloalkyl, cycloalkenyl, and cycloalkynyl, but can contain O, S, or N heteroatoms or combinations thereof within the cyclic backbone. Ranges of these groups useful with the compounds and methods described herein include C3-C20heterocycloalkyl, C3-C20heterocycloalkenyl, and C3-C20heterocycloalkynyl. Additional ranges of these groups useful with the compounds and methods described herein include C5-C12heterocycloalkyl, C5-C12heterocycloalkenyl, C5-C12heterocycloalkynyl, C5-C6heterocycloalkyl, C5-C6heterocycloalkenyl, and C5-C6heterocycloalkynyl. Aryl molecules include, for example, cyclic hydrocarbons that incorporate one or more planar sets of, typically, six carbon atoms that are connected by delocalized electrons numbering the same as if they consisted of alternating single and double covalent bonds. An example of an aryl molecule is benzene. Heteroaryl molecules include substitutions along their main cyclic chain of atoms such as O, N, or S. When heteroatoms are introduced, a set of five atoms, e.g., four carbon and a heteroatom, can create an aromatic system. Examples of heteroaryl molecules include furan, pyrrole, thiophene, imadazole, oxazole, pyridine, and pyrazine. Aryl and heteroaryl molecules can also include additional fused rings, for example, benzofuran, indole, benzothiophene, naphthalene, anthracene, and quinoline. The aryl and heteroaryl molecules can be attached at any position on the ring, unless otherwise noted. The term alkoxy as used herein is an alkyl group bound through a single, terminal ether linkage. Likewise, the term aryloxy as used herein is an aryl group bound through a single, terminal ether linkage. The term hydroxyl as used herein is represented by the formula —OH. The terms amine or amino as used herein are represented by the formula —NZ1Z2, where Z1and Z2can each be a substitution group as described herein, such as hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. The alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl molecules used herein can be substituted or unsubstituted. As used herein, the term substituted includes the addition of an alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl group to a position attached to the main chain of the alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl, e.g., the replacement of a hydrogen by one of these molecules. Examples of substitution groups include, but are not limited to, hydroxyl, halogen (e.g., F, Br, Cl, or I), and carboxyl groups. Conversely, as used herein, the term unsubstituted indicates the alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl has a full complement of hydrogens, i.e., commensurate with its saturation level, with no substitutions, e.g., linear decane (–(CH2)9–CH3). In some examples, Formula I is represented by Structure I-A: Structure I-A In Structure I-A, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, and R2are as defined above for Formula I. In some examples of Structure I-A, each of A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are CR1, where each R1is independently selected from a group as defined above for Formula I. For example, the compound of Structure I-A can be represented by Structure I-A1: Structure I-A1 In Structure I-A1, m and n are each independently 1, 2, 3, 4, or 5. In other words, the phenyl rings of the molecule can include from one to five R1groups. Each of the R1groups can be independently selected from a group as defined above for Formula I. In some examples of Structure I-A, one or more of A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10can be N. For example, the compound of Structure I-A can be represented by Structure I-A2, Structure I-A3, or Structure I-A4: Structure I-A4 In Structure I-A2, Structure I-A3, and Structure I-A4, m and n are each independently 1, 2, 3, or 4. In other words, the phenyl rings of the molecule can include from one to four R1groups. Each of the R1groups can be independently selected from a group as defined above for Formula I. Optionally, in Structure I-A1, Structure I-A2, Structure I-A3, and / or Structure I- A4, R2is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. In some examples, R2is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some examples, Formula I is represented by Structure I-B: Structure I-B In Structure I-B, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, R3, and R4are as defined above for Formula I. In some examples of Structure I-B, each of A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are CR1, where each R1is independently selected from a group as defined above for Formula I. For example, the compound of Structure I-B can be represented by Structure I-B1: Structure I-B1 In Structure I-B1, m and n are each independently 1, 2, 3, 4, or 5. In other words, the phenyl rings of the molecule can each independently include from one to five R1groups. Each of the R1groups can be independently selected from a group as defined above for Formula I. In some examples of Structure I-B, one or more of A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10can be N. For example, the compound of Structure I-B can be represented by Structure I-B2, Structure I-B3, or Structure I-B4: Structure I-B4 In Structure I-B2, Structure I-B3, and Structure I-B4, m and n are each independently 1, 2, 3, or 4. In other words, the phenyl rings of the molecule can each independently include from one to four R1groups. Each of the R1groups can be independently selected from a group as defined above for Formula I. In some examples, Formula I is represented by Structure I-C: Structure I-C In Structure I-C, A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are as defined above for Formula I. In some examples of Structure I-C, each of A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are CR1, where each R1is independently selected from a group as defined above for Formula I. For example, the compound of Structure I-C can be represented by Structure I- C1: Structure I-C1 In Structure I-C1, m and n are each independently 1, 2, 3, or 4. In other words, the phenyl rings of the molecule can each independently include from one to four R1groups. Each of the R1groups can be independently selected from a group as defined above for Formula I. In some examples of Structure I-C, one or more of A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10can be N. For example, the compound of Structure I-C can be represented by Structure I-C2, Structure I-C3, or Structure I-C4: Structure I-C4 In Structure I-C2, Structure I-C3, and Structure I-C4, m and n are each independently 1, 2, 3, or 4. In other words, the phenyl rings of the molecule can each independently include from one to four R1groups. Each of the R1groups can be independently selected from a group as defined above for Formula I. Examples of Formula I include the following compounds: SYC-940 (Compound 2-4) SYC-941 (Compound 2-5) SYC-944 (Compound 2-8) (or MCB-613) SYC-908 (Compound 2-9) SYC-952 (Compound 3-9) SYC-849 (Compound 4-1) SYC-912 (Compound 5-5) SYC-959 (Compound 5-6) SYC-960 (Compound 5-7) SYC-928 (Compound 5-8) SYC-962 (Compound 6-2) SYC-963 (Compound 6-3) SYC-967 (Compound 7-1) SYC-968 (Compound 7-2) SYC-975 (Compound 8-6) SYC-976 (Compound 8-7) Compound S2 Compound S3 SYC-923 (Compound 1-8-2) SYC-925 (Compound 4-8-2) SYC-918 (Compound 7-19) Compound 9-2 Compound 10-2 In some embodiments, the compound is SYC-944 (Compound 2-8) (also referred to herein as MCB-613). In some embodiments, the compound is Compound 10-1 (also referred to herein as MCB-613-10-1). II. Methods of Making the Compounds The compounds described herein can be prepared in a variety of ways. The compounds can be synthesized using various synthetic methods. At least some of these methods are known in the art of synthetic organic chemistry. The compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Variations on the compounds described herein include the addition, subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, all possible chiral variants are included. Additionally, compound synthesis can involve the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts, Greene’s Protective Groups in Organic Synthesis, 5th. Ed., Wiley & Sons, 2014, which is incorporated herein by reference in its entirety. Reactions to produce the compounds described herein can be carried out in solvents, which can be selected by one of skill in the art of organic synthesis. Solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products under the conditions at which the reactions are carried out, i.e., temperature and pressure. Reactions can be carried out in one solvent or a mixture of more than one solvent. Product or intermediate formation can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography. The compounds described herein can be synthesized according to methods as described in U.S. Patent Nos.10, 875,841 and 11,312,676, which are incorporated herein by reference in their entireties. III. Pharmaceutical Formulations The compounds described herein or derivatives thereof can be provided in a pharmaceutical composition. Depending on the intended mode of administration, the pharmaceutical composition can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, or suspensions, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include a therapeutically effective amount of the compound described herein or derivatives thereof in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, or diluents. By pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, which can be administered to an individual along with the selected compound without causing unacceptable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained. As used herein, the term carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington: The Science and Practice of Pharmacy, 22d Edition, Loyd et al. eds., Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences (2012). Examples of physiologically acceptable carriers include buffers, such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt- forming counterions, such as sodium; and / or nonionic surfactants, such as TWEEN® (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICSTM(BASF; Florham Park, NJ). Compositions containing the compound described herein or derivatives thereof suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants, such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be promoted by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like may also be included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Solid dosage forms for oral administration of the compounds described herein or derivatives thereof include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art. They may contain opacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration of the compounds described herein or derivatives thereof include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents. Suspensions, in addition to the active compounds, may contain additional agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. Compositions of the compounds described herein or derivatives thereof for rectal administrations are optionally suppositories, which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers, such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of the compounds described herein or derivatives thereof include ointments, powders, sprays, inhalants, and skin patches. The compounds described herein or derivatives thereof are admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, ointments, powders, and solutions are also contemplated as being within the scope of the compositions. Optionally, the compounds described herein can be contained in a drug depot. A drug depot comprises a physical structure to facilitate implantation and retention in a desired site (e.g., a synovial joint, a disc space, a spinal canal, abdominal area, a tissue of the patient, etc.). The drug depot can provide an optimal concentration gradient of the compound at a distance of up to about 0.1 cm to about 5 cm from the implant site. A depot, as used herein, includes but is not limited to capsules, microspheres, microparticles, microcapsules, microfibers particles, nanospheres, nanoparticles, coating, matrices, wafers, pills, pellets, emulsions, liposomes, micelles, gels, antibody-compound conjugates, protein-compound conjugates, or other pharmaceutical delivery compositions. Suitable materials for the depot include pharmaceutically acceptable biodegradable materials that are preferably FDA approved or GRAS materials. These materials can be polymeric or non-polymeric, as well as synthetic or naturally occurring, or a combination thereof. The depot can optionally include a drug pump. The compositions can include one or more of the compounds described herein and a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable salt refers to those salts of the compound described herein or derivatives thereof that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein. The term salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds described herein. These salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See S.M. Barge et al., J. Pharm. Sci. (1977) 66, 1, which is incorporated herein by reference in its entirety, at least, for compositions taught therein.) Administration of the compounds and compositions described herein or pharmaceutically acceptable salts thereof can be carried out using therapeutically effective amounts of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein for periods of time effective to treat a disorder. The effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein may be determined by one of ordinary skill in the art and includes exemplary dosage amounts for a mammal of from about 0.0001 to about 200 mg / kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. Alternatively, the dosage amount can be from about 0.01 to about 150 mg / kg of body weight of active compound per day, about 0.1 to 100 mg / kg of body weight of active compound per day, about 0.5 to about 75 mg / kg of body weight of active compound per day, about 0.5 to about 50 mg / kg of body weight of active compound per day, about 0.01 to about 50 mg / kg of body weight of active compound per day, about 0.05 to about 25 mg / kg of body weight of active compound per day, about 0.1 to about 25 mg / kg of body weight of active compound per day, about 0.5 to about 25 mg / kg of body weight of active compound per day, about 1 to about 20 mg / kg of body weight of active compound per day, about 1 to about 10 mg / kg of body weight of active compound per day, about 20 mg / kg of body weight of active compound per day, about 10 mg / kg of body weight of active compound per day, about 5 mg / kg of body weight of active compound per day, about 2.5 mg / kg of body weight of active compound per day, about 1.0 mg / kg of body weight of active compound per day, or about 0.5 mg / kg of body weight of active compound per day, or any range derivable therein. Optionally, the dosage amounts are from about 0.01 mg / kg to about 10 mg / kg of body weight of active compound per day. Optionally, the dosage amount is from about 0.01 mg / kg to about 5 mg / kg. Optionally, the dosage amount is from about 0.01 mg / kg to about 2.5 mg / kg. Those of skill in the art will understand that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Further, depending on the route of administration, one of skill in the art would know how to determine doses that result in a plasma concentration for a desired level of response in the cells, tissues and / or organs of a subject. IV. Methods of Use Provided herein are methods of repairing tissue in a subject. The methods include administering to a subject an effective amount of a pharmaceutical composition as described herein. Effective amount, when used to describe an amount of compound in a method, refers to the amount of a compound that achieves the desired pharmacological effect or other biological effect. The methods can further include selecting a subject experiencing tissue injury. In some cases, the subject has suffered traumatic brain injury or kidney injury. Optionally, the subject has Alzheimer’s disease. Optionally, the subject has diabetes (e.g., Type 1 diabetes). In the methods described herein, the timing of the administering, prior to or post tissue injury, can impact tissue repair in the subject. Optionally, the administering is performed within a period of time after tissue injury, within hours of tissue injury (e.g., up to 48 hours of tissue injury), within days of tissue injury (e.g., within 7 days of tissue injury), or within months of tissue injury (e.g., within 6 months of tissue injury). In some cases, the administering is performed within 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, or 72 hours of tissue injury. Optionally, the administering is performed within 4 days of tissue injury, within 5 days of tissue injury, within 6 days of tissue injury, or within 7 days of tissue injury. In some cases, the administering is performed within 1 month of tissue injury, within 2 months of tissue injury, within 3 months of tissue injury, within 4 months of tissue injury, within 5 months of tissue injury, or within 6 months of tissue injury. In some cases, the administering increases the ration of M2 macrophages to M1 macrophages. The administering as described herein promotes macrophage transition to an M2-like state. Optionally, the administering inhibits inflammation. Also contemplated is a method that includes administering to the subject an amount of one or more compounds described herein such that an in vivo concentration at a target cell in the subject corresponding to the concentration administered in vitro is achieved. Further described herein are methods of protecting tissue adjacent to an injury site or reducing tissue loss in a subject. The methods include administering to the subject an effective amount of a pharmaceutical composition as described herein. Optionally, the methods can include selecting a subject that has suffered traumatic brain injury. In other cases, the methods can include selecting a subject that has suffered kidney injury. The methods can optionally include selecting a subject that has Alzheimer’s disease or a subject having diabetes (e.g., Type 1 diabetes). Methods of preserving insulin production and preventing diabetes in a subject are also described herein. The methods include administering to the subject an effective amount of a pharmaceutical composition as described herein. Further described herein are methods of inhibiting kidney fibrosis in a subject. The methods include administering to the subject an effective amount of a pharmaceutical composition as described herein. Optionally, the method can further include selecting a subject that has suffered kidney injury. The methods for repairing tissue, protecting tissue adjacent to an injury site, reducing tissue loss, preserving insulin production, preventing diabetes, and / or inhibiting kidney fibrosis in a subject can further comprise administering to the subject one or more additional agents. The one or more additional agents and the pharmaceutical composition described herein can be administered in any order, including concomitant, simultaneous, or sequential administration. Sequential administration can be administration in a temporally spaced order of up to several days apart. The methods can also include more than a single administration of the one or more additional agents and / or the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof. The administration of the one or more additional agents and the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof can be by the same or different routes and concurrently or sequentially. Additional therapeutic agents include, but are not limited to, anti-inflammatory agents, anti-convulsant agents, diuretics, sedatives, cholinesterase inhibitors, and insulin. Therapeutic agents also include insulin and agents (e.g., glyburide, exenatide, pramlinitide, and metformin) used to control blood sugar in subjects with diabetes. Any of the aforementioned therapeutic agents can be used in any combination with the compositions described herein. Combinations are administered either concomitantly (e.g., as an admixture), separately but simultaneously (e.g., via separate intravenous lines into the same subject), or sequentially (e.g., one of the compounds or agents is given first followed by the second). Thus, the term combination is used to refer to concomitant, simultaneous, or sequential administration of two or more agents. Optionally, a compound or therapeutic agent as described herein may be administered in combination with a surgery (e.g., a blood clot removal surgery). The methods and compounds as described herein are useful for both prophylactic and therapeutic treatment. For prophylactic use, a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein are administered to a subject prior to onset (e.g., before obvious signs of tissue injury), during early onset (e.g., upon initial signs and symptoms of tissue injury), or after the occurrence of a tissue injury. Prophylactic administration can occur for several days to years prior to the manifestation of symptoms of a myocardial infarction. Therapeutic treatment involves administering to a subject a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein after the occurrence of a myocardial infarction. The methods herein for prophylactic and therapeutic treatment optionally comprise selecting a subject who has suffered or is at an elevated risk of suffering a tissue injury. A skilled artisan can make such a determination using, for example, a variety of prognostic and diagnostic methods, including, for example, a personal or family history of the disease or condition, clinical tests (e.g., genetic tests), and the like. Optionally, the methods herein can be used for preventing a subject who has suffered tissue injury from suffering tissue injury to adjacent tissue. The pharmaceutical compositions described herein are useful for repairing tissue, protecting tissue adjacent to an injury site, reducing tissue loss, preserving insulin production, preventing diabetes, and / or inhibiting kidney fibrosis in humans, including, without limitation, pediatric and geriatric populations, and in animals, e.g., veterinary applications. V. Kits Also provided herein are kits for repairing tissue, protecting tissue adjacent to an injury site, reducing tissue loss, preserving insulin production, preventing diabetes, and / or inhibiting kidney fibrosis in a subject. A kit can include any of the compounds or compositions described herein. For example, a kit can include one or more compounds of Formula I. A kit can further include one or more additional agents, such as anti- inflammatory agents, anti-convulsant agents, diuretics, sedatives, cholinesterase inhibitors, insulin, and combinations of these. A kit can include an oral formulation of any of the compounds or compositions described herein. A kit can include an intravenous or intraperitoneal formulation of any of the compounds or compositions described herein. A kit can additionally include directions for use of the kit (e.g., instructions for treating a subject), a container, a means for administering the compounds or compositions (e.g., a syringe), and / or a carrier. As used herein the terms treatment, treat, or treating refer to a method of reducing one or more symptoms of a disease or condition. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of one or more symptoms of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms or signs (e.g., size of the tumor or rate of tumor growth) of the disease in a subject as compared to a control. As used herein, control refers to the untreated condition (e.g., the tumor cells not treated with the compounds and compositions described herein). Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. As used herein, the terms prevent, preventing, and prevention of a disease or disorder refer to an action, for example, administration of a composition or therapeutic agent, that occurs before or at about the same time a subject begins to show one or more symptoms of the disease or disorder, which inhibits or delays onset or severity of one or more symptoms of the disease or disorder. As used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level. Such terms can include, but do not necessarily include, complete elimination. As used herein, subject means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; horses; sheep; rats; mice; pigs; and goats. Non-mammals include, for example, fish and birds. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application. The examples below are intended to further illustrate certain aspects of the methods and compositions described herein, and are not intended to limit the scope of the claims. EXAMPLES Example 1: Steroid Receptor Coactivation of NRF2 Signaling in Cardiac Fibroblasts Promotes Resistance to Oxidative Stress Methods and Materials Animal procedures: Animal procedures were performed using guidelines for the proper use of animals developed by the National Institutes of Health. Cardiac fibroblasts were isolated from female C57BL / 6 wild type mice or B6.129X1-Nfe2l2tm1Ywk / J aged 8-10 weeks. Cardiac Fibroblast isolation: Cardiac fibroblasts (CFs) were isolated following the protocol by Melzer, M et al., J Vis Exp, 2020 (157). Cells were allowed to expand, trypsinized, counted and plated for experiments on day 4. All experiments were conducted using passage 1 CFs. Cytokine assays: Cytokines in conditioned media from isolated CFs were detected using the Proteome Profiler Mouse XL Cytokine Array (R&D Systems; Minneapolis, MN). CF Gel contraction assays: A 1:1 dilution of 150 µl of Type 1 rat collagen (Corning Cat. # 354236) with 150 µl culture media containing 75,000 CF cells were incubated in a 24- well culture plate. Gels were incubated at 37 °C in a cell culture hood for 25 minutes. Gels were then dislodged from wells using a 30-gauge needle. 600 µl of media containing growth factors was added for 24 hours. TGF-β (R&D Systems Cat. # 7666-MB-005) was used at 1 ng / ml as a positive control. Gel sizes were measured using ImageJ. Phalloidin staining of collagen gels: Gels were fixed for 15 minutes in 4% paraformaldehyde (PFA) in PBS and stored in 0.16% PFA in PBS. Gels were cut into small pieces followed by blocking and permeabilization with 3% bovine serum albumin (BSA) in 0.2% Triton X- 100 in phosphate buffered saline (PBS) for 30 minutes. Gels were then washed 3 times for 7 minutes with 0.5% bovine serum albumin (BSA) and 0.03% Triton X- 100 in PBS. Gels were then incubated with 1:400 Phalloidin antibody (ThermoFisher Cat. # A12379) and 1 µg / ml DAPI (Invitrogen; Carlsbad, CA; Cat. # D1306) in 3% BSA and 0.2% Triton X-100 in PBS for 1 hour. Gels were washed 3 times for 7 minutes and mounted on slides with 90% glycerol and sealed with fingernail polish. Cell viability assay: The WST-1 cell proliferation assay measures the number of viable cells based on measurement of light absorbance resulting from mitochondrial succinate reductase's conversion of WST-1 (i.e., (4-[3-(4-iodophenyl)-2-(4-nitro-phenyl)-2H-5-tetrazolio]- 1,3-benzene sulfonate)) to formazane. Cells were plated at 15,000 cells / well in a 96-well plate.CFswere treated with 600 µM hydrogen peroxide (H2O2) with and without MCB-613-10-1or vehiclecontrol as indicated. After 24 hours of treatment, cell viability / mitochondrialmetabolic activity was measured by WST-1 assay (Roche; Basel, Switze Cat. # 501594401). Viability was reported as a percentage of cell viability compared to vehicle control. Cell counts assay: Cells were plated in 24-well plates at 100,000 cells per well. CFs were treated with MCB-613-10-1 or vehicle control as indicated. Plates were imaged on a Sartorius Incucyte S3 imager for 17 hours. Images were taken every hour. Apoptosis assay: Cells were plated in 96-well plates (n=6 wells per condition). CFs were treated with MCB-613-10-1 or vehicle control as indicated. Cells were stained using the Cleaved Caspase-3 Staining Kit (FITC) (Abcam Cat# ab65613; Cambridge, United Kingdom). ROS detection assay: Cells were plated in 96-well plates at 15,000 cells per well (n=6percondition). CFs were treated with 600 µM H2O2in the presence or absence of MCB-613-10-1 for24 hours. ROS was detected using the CellRox assay kit (Invitrogen Cat# C10422;Carlsbad, CA). Cell Painting assay: Cells were plated in 96-well plates (PerkinElmer PhenoPlate; Waltham, MA) at 7,500 cells per well. After overnight incubation, cells were treated withvehicle control or MCB-613-10-1 for 24 hours. The following day, 900 µM H2O2was addedfor 24 hours. Cells were then stainedlive with MitoTracker Deep RED FM and Wheat GermAgglutinin (Alexa Fluor 555) for 20 min at 37 °C. The stains were removed, and cells were then fixed with 4% paraformaldehyde at room temperature for 20 minutes. Following fixation, cells were washed 3 times in PBS at room temperature for 3 minutes each. Finally, cells were stained with DAPI, Concavalin A (Alexa Fluor 488), SYTO 14, and Phalloidin (Alexa Fluor 568) in a PBS solution containing 1% BSA and 0.1% TX-100 for 20 minutes. Cells were then washed 3 times with PBS at room temperature for 3 minutes each. Cells were left in PBS to image and imaged on a Yokogawa CV8000 spinning disk high throughput confocal with max projections intensity images collected for each channel. Nine fields were collected per well. Images were analyzed using CellProfiler with DAPI used to segment the nucleus, and SYTO14 to segment the cytoplasm. Channel quantification occurred within these two regions. The number of nuclei (based on DAPI with a size threshold remove dead cells) per well were normalized to the average numbers of nuclei in the vehicle control wells to normalize differences in cell number between plates. Nuclear eccentricity was calculated as the distance between foci of the ellipse and its major axis length. The higher the eccentricity, the more elliptical the shape. DAPI variance / mitochondrial variance is a measure of the variation of image intensity values. Uniform intensity (an object with the same pixel intensity across) would be 0. The higher the number, the higher range of pixel intensities. In H2O2, the DAPI and mitochondria signals have a wider range of intensities than the other treatments, commonly observed in stressed / dying cells. Mitochondrial contrast is determined as a measure of local variation in an image, including how much the pixel intensities change in a small area. In H2O2, mitochondria intensity changes highly within small area, commonly observed in mitochondrial dysfunction. Measurements were calculated according to the CellProfilers method. Cell migration assays: Isolated CFs (passage 1) were plated at 150,000 cells per well in 24-well plates and incubated overnight. Wells were scratched with a 200 µl yellow pipette tip down the middle of each well. Cells were then washed with media with or without additional factors. Plates were imaged on a Sartorius Incucyte S3 imager for 46 hours. Images were taken every 2 hours. RT-PCR: Cells were plated at 300,000 cells / well in a 6-well plate and cultured overnight. Cells were treated with vehicle control or 6 µM MCB-613-10-1 for 4 or 24 hours. RNA was isolated using the RNAeasy MiniKit (Qiagen Cat# 74106; Hilden, Germany). For CF mRNA expression analysis, first-strand synthesis was performed using the SuperScript VILO MasterMix cDNA synthesis kit (ThermoFisher; Waltham, MA). Quantitative gene expression was performed using SYBR Green and gene-specific primers. Melt curves were performed for each primer set. Data were graphed relative to 18S ribosomal RNA internal standard using the ΔΔCt method. Western blots: Primary C57BL6 / J CFs or HeLa cells were seeded in 6-well plates at ~3.0X105cells / well and allowed to settle overnight at 37 °C, 5% CO2. The cells were treated with either 6 µM of MCB-613-10-1, 10 µM of MCB-613-10-1 or ethanol as vehicle control for 4 or 24 hours. After treatment, the cells were rinsed with ice cold 1X PBS and scraped into a 1.5 ml centrifuge tube using 200 µl of RIPA buffer (Sigma Aldrich, Cat#: R0278; St. Louis, MO) with protease / phosphatase inhibitor cocktail (100X) (Cell signaling, cat#: 5872S) at a 1:100 dilution. Cell lysates were incubated at 4 °C on a rocker for 45 minutes. The cell lysates were then spun down at 8,000 g for 10 minutes at 4 °C and the supernatant was placed into clean tubes. Protein concentrations were measured using a BCA assay (Thermo Fisher, cat# 23225).20-30 µg of the protein sample were mixed with 4X laemmli buffer (Biorad, cat# 1610747; Hercules, CA) at a 1:3 dilution and heated for 5 minutes at 90 °C. Samples were loaded onto a 4- 20% Tris-glycine gel (Biorad, cat# 5671094) and run at 130 mV on a vertical electrophoresis cell (Biorad, cat# 1656001) until the loading dye left the gel. The gel was transferred using a polyvinylidene fluoride (PDVF) transfer kit (Biorad, cat# 1704157) and the transblot turbo transfer system. Gels were transferred for 7 minutes, and the membranes blocked with 5% non-fat dry milk tris-buffered saline and polysorbate 20 (TBST) blotto (Biorad, cat# 1706404). Membranes were then incubated with 3% non-fat dry milk TBST blotto and mixed with either anti-hmox-1 (Abcam, cat# 12343), anti-sqstm1 (Abcam, cat# ab91526), anti-keap1 (Cell signaling, cat# 8047S), anti-Src-1 (Cell signaling, cat# 2191S), anti-Src-2 (Cell signaling, cat# 96687S), anti-Src-3 (Cell signaling, cat# 2126S), or β-actin (Sigma, cat# A3854) and incubated overnight at 4°C on a rocker overnight. The antibodies were all diluted at 1:1000 except for β- actin which was diluted at 1:50,000. After primary incubation, the membranes were washed with 1X TBST twice at 10- minute intervals and twice at 5-minute intervals. Secondary antibody was added to 3% non- fat dry milk TBST blotto at a 1:2000 dilution for 4 hours at room temperature. The membranes were washed again with 1X TBST twice at 10-minute intervals and twice at 5- minute intervals. The membranes were developed using Prosignal™ Femto (Prometheus, cat# 20- 302; San Diego, CA) for 2 minutes and images were taken using the Biorad Chemidoc™ MP imaging system. RNA-Seq: RNA sequencing used Illumina platforms located in Durham, NC. Total RNA extracted from mouse primary CFs (provided in triplicates) were incubated with poly-T oligo-attached magnetic beads to isolate mRNA. cDNA synthesis was carried out using random hexamer primers for reverse transcription and dTTP for the second strand cDNA synthesis. Library construction included cDNA end repair, A-tailing, adapter ligation, size selection, amplification, and purification, followed by Qubit fluorometric quantification, real- time PCR for quantification and bioanalyzer analysis for size distribution detection. Sequencing raw data controls were performed, paired-end clean reads were aligned to the mouse reference genome mm39 using Hisat2 v2.0.5; statistics of sequencing quality and mapping for all samples were: error rate 0.02, Q Phred value Q20 >97.6, Q30 >93.7, total reads >65 million, proper mapping >88.5%, Distribution: >95% exonic, <5% intronic, <3% intragenic feature. Counts v1.5.0-p3 was used to count the reads numbers mapped to each gene, and FPKM of each gene was calculated based on read count mapped to the gene and the length of the gene. DESeq2 was used for calculating differential expression values; the resulting P-values were adjusted using Benjamini and Hochberg's approach for controlling the false discovery rate. Genes with an adjusted P-value <=0.05 found by DESeq2 and thresholded 1.5x (4hr samples) and 2x (24 hr samples) fold change in absolute expression were assigned as differentially expressed genes (DEGs). Gene ontogeny overrepresentation analyses were done using the public on-line resources PANTHER knowledgebase v17.0, DAVID Knowledgebase v2023q2, and GSEA / MSigDBusing individual data resources such as GO, KEGG and Reactome, independently. Proteome Profiling: Protein extraction, digestion and peptide fractionation was carried out. Cells were lysed in 8M urea buffer, reduced / alkylated and digested using LysC and Trypsin proteases. Samples (100µg peptide per sample) were labeled with TMT10 plex isobaric label reagent (Thermo Fisher Scientific). The high-pH offline fractionation was carried to generate 24 peptide pools and acidified with final concentration of 0.1% formic acid (FA). The deep-fractionated peptide samples were separated on Vanquish Neo UHPLC (Thermo Fisher Scientific, San Jose, CA) system coupled to Orbitrap Eclipse (Thermo Fisher Scientific, San Jose, CA). The samples were loaded on Pepmap Neo trap (5μm x 300μm x 5mm, C18) switched in-line with an in-housed 20cm x 75µmI.D. column (Reprosil- Pur Basic C18, 1.9 µm, Dr.Maisch GmbH, Germany). The peptide elution was done using a 110 min discontinuous gradient of 80% acetonitrile buffer (B) in 0.1% formic acid at 250 nl / min (2- 35% B: 87 min, 35-60% B: 10 min, 60-95% B: 7min, 95-50% B: 6 min). The heated column was maintained at 60oC. The eluted peptides were directly electro-sprayed into mass spectrometer operated in the data-dependent acquisition mode acquiring HCD fragmentation spectra for 2 second cycle time. The MS1 was done in Orbitrap (120000 resolution, scan range 375-1500 m / z, 50ms Injection time) followed by MS2 in Orbitrap at 30000 resolution (HCD 38%) with TurboTMT algorithm. Dynamic exclusion was set to 20 seconds, and the isolation width was set to 0.7 m / z. The data search was conducted using the mouse protein database downloaded from GENCODE (release 32). ChIP-qPCR assays: Primary female C57BL6 / J CFs were plated in 10-cm dishes at~1.5 x106 cells / plate and allowed to settle overnight at 37 °C, 5% CO2. The cells were thentreated witheither 6 µM MCB-613-10-1 or ethanol vehicle control for four hours. Aftertreatment, the cells were fixed, and nuclei were prepped for sonication using a Covaris shearing kit (Covaris, Cat# 520154; Woburn, MA). The cell suspension was sonicated using a Covaris Ultrasonicator LE220 for 17 minutes with settings recommended by the Covaris shearing kit protocol. After sonication, chromatin fragment size was verified by agarose gel electrophoresis and was found to be around 200bp-500bp. Immunoprecipitation of the crosslinked protein / DNA was done using the EZ ChIP kit (Millipore, Cat # 17-371). The samples were mixed with either IgG control, anti-NRF2 (Cell Signaling Cat # D1Z9C), anti- SRC-1 (Cell Signaling, Cat# 128E7), anti-SRC-2 (Cell Signaling, Cat# D2X4M), or anti- SRC-3 (Cell Signaling, Cat # 2126S) and incubated at 4 °C on a rocker overnight. The antibodies were added according to the dilution protocol for ChIP assays by the manufacturer. After the protein / DNA complexes were pulled, washed, and reverse cross- linked according to the EZ ChIP protocol, the DNA was purified using the QIAquick PCR purification kit (Qiagen, Cat #28104). The DNA samples were eluted with 50 µl of water (Invitrogen). Real- time PCR was performed using the following primers within the Hmox15’ upstream region: E1: 5’ GGG CAG TCT TAA GCA ATC CA -3’ (SEQ ID NO: 1), and 5’ CCA TGA CTC AGC GAA AAC AG-3’ (SEQ ID NO: 2), E2: 5’ CCT AGT GCA GAA GGC TTT GG-3’ (SEQ ID NO: 3), and 5’ TCA GGG GAA GAA CAA AGG AA-3’ (SEQ ID NO: 4), P1: 5’ GCT GGA ATG CTG AGT TGT GA-3’ (SEQ ID NO: 5) and 5’ TGA GGG AAC AGA GGG TGA CT- 3’ (SEQ ID NO: 6), E3: 5’ GCT GGA ATG CTG AGT TGT GA-3’ (SEQ ID NO: 7), and 5’ TGA GGG AAC AGA GGG TGA CT -3’ (SEQ ID NO: 8). For qPCR, samples were diluted 1:2 and inputs were diluted 1:20 with water (Invitrogen) and 2µl of the diluted material was used for PCR reactions. Statistics: Results are reported below as the mean + / - SEM. The statistical significance of the difference between means was assessed using Prism Software using the paired 2-tailed Student’s t-test. P values of less than 0.05 were considered significant. Data Availability: Data are available in the Gene Expression Omnibus (GEO) under accession number GSE157542. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier “PXD050373." Results MCB-613-10-1 suppresses secretion of proteins associated with fibrotic remodeling in CFs. To identify cytokines associated with an improved response to injury, cytokines were measured in conditioned media from isolated CFs treated with MCB-613- 10-1 compared to control. CFs treated with MCB-613-10-1 present a unique CF secretory signature (Fig.1A and Fig.1B). Of the ones examined, no secreted proteins were increased in response to MCB- 613-10-1 treatment. In contrast, Insulin-like growth factor-binding protein 2 (IGFBP2), Osteoprotegerin (OPG), C–C motif chemokine ligand 2 (CCL2), Cystatin C, Transferrin (TF), WNT1-inducible-signaling pathway protein 1 (WISP1), chemokine ligand (CXCL)16, and CXCL12 were decreased in CFs treated with MCB-613-10-1, as were the mRNA levels of Wisp1, Ccl2, Opg, matricellular proteins thrombospondin 2 (Thbs2) and cellular communication network 3 (Ccn3) (Fig.1C). These results indicate that SRC activation impacts cardiac fibroblast expression of cytokines and chemokines. These findings also demonstrate that SRC activation controls expression of nonstructural ECM-associated signaling proteins that may govern protective cardiac fibrotic remodeling. MCB-613-10-1 inhibits CF activation. To determine whether MCB-613-10-1 alters activated CF functions, gel contraction, migration and proliferation were measured in CFs isolated from mice. Functional studies show that MCB-613- 10-1 blocks basal and TGF-β-induced fibroblast collagen I gel contraction (Fig.2A). The effects of MCB-613-10-1 on F-actin skeleton morphology were determined by performing phalloidin staining (Fig. 2C). The results show that SRCs prevent actin polymerization and actin cytoskeleton remodeling, which can be associated with the promotion of focal adhesion turnover and cell migration. Furthermore, after treatment with transforming growth factor TGF-β, filamentous F-actin was significantly enhanced, and this effect was inhibited by pretreatment with MCB-613- 10-1 (Fig.2B). This result further illustrates that F-actin polymerization depends on MCB-613-10- 1 treatment. Cell migration was assessed as another stress-related function of CFs. Cell migration was suppressed 22 hours after MCB-613-10-1 treatment indicating that MCB-613-10-1 inhibits CF migration (Fig.2C). Next, it was determined whether MCB-613-10-1 limits cell viability, cell numbers or apoptosis which may affect gel contraction and cell migration. The WST-1 assay is based on the cleavage of tetrazolium salt to formazan by cellular mitochondrial dehydrogenase. In addition to measuring cell viability, the WST-1 assay can be used as a measure of mitochondrial metabolic function. Cell viability was slightly increased in CFs following 6 µM MCB-613- 10-1 treatment and further increased with 10 µM indicating that MCB-613-10-1 does not decrease cell viability (Fig.2D). These findings show that MCB-613-10-1 stimulates an increase in mitochondrial metabolism. In contrast, cell numbers were decreased (Fig.2D) but apoptosis was not increased (Fig.3). These findings indicate that MCB-613 inhibits CF proliferation while enhancing cell viability without inducing CF apoptosis. SRC protein expression, in response to MCB-613-10-1 in CFs, was then measured to determine if there is an association between SRC protein expression and CF activation. It was found that treatment with MCB-613-10- 1 did not result in a change in SRC expression, indicating that CF activation correlates with SRC activation and function, but not abundance (Fig.2E). SRC activation stimulates the NRF2 transcriptional network in cardiac fibroblasts and improves mitochondrial function. RNA-seq was performed to identify SRC transcriptional regulatory mechanisms involved in the cardioprotective response to MCB-613-10-1. To focus on early transcriptional targets compared to later phenotype-related gene expression, RNA was isolated from primary CFs following treatment with MCB-613-10-1 or control at 4 and 24 hours, respectively. Differentially expressed genes (DEGs) were then analyzed. At 4 hours, 191 genes were differentially up-regulated and 230 genes down-regulated in MCB-613-10-1 treated CFs compared to vehicle control (Fig.4). Unbiased gene ontology and gene network analyses revealed the top over-represented GO terms included cell cycle, mitosis, chaperone, protein folding, and cellular response to fibroblast growth factor stimulus (Fig.9A). Bioinformatics pathways analysis of differentially expressed genes at 4 hours revealed that MCB-613-10-1 modulation of the fibroblast transcriptional response was dominated by the NRF2 pathway and nuclear receptors meta- pathway followed by cell cycle, VEGFA- VEGFR2 signaling, and MAPK signaling pathway (Fig.9A, bottom graph). Upregulation of NRF2 signaling pathway genes and NRF2 target genes at 4 hours (Fig.9A, right graph) indicates MCB-613-10-1 induces the NRF2 transcriptional network. Bioinformatics analysis of at least two-fold differentially expressed genes were then performed at 24 hours. At 24 hours, 1084 genes were differentially up-regulated and 1167 genes down-regulated in MCB-613-10-1 treated CFs compared to vehicle control (Fig.4), indicating that MCB-613-10-1 triggers more transcriptional changes at 24 hours compared to 4 hours. The top GO terms associated with the 24-hour transcriptional response included cell cycle, proteosome, extracellular matrix, endoplasmic reticulum, and DNA repair (Fig.9B). Genes associated with the GO term extracellular matrix were predominantly down-regulated (Fig.5). In addition to SRC activation leading to downregulation of matricellular genes shown in Fig.1A-C, the cardiac ECM remodeling-Lysyl oxidase (Lox) and 3 lox-like isoenzymes (Lox1, Lox2 and Lox3) were highly down-regulated in response to MCB-613-10- 1 in CFs at 24 hours (Fig.4), indicating that MCB-613-10-1 regulates secreted non-structural ECM signaling proteins. Top signaling pathways associated with the 24-hour upregulated transcriptional response genes included cellular responses to stimuli, cell cycle-related signaling and KEAP1-NRF2 pathway and nuclear events mediated by NFE2L2 (Fig.9B, bottom graph). Consistent with 4-hour transcriptome data, Keap1-Nrf2 signaling pathway genes also were predominantly upregulated at 24 hours (Fig.9B, right graph), indicating that SRC activation stimulates the NRF2 transcriptome by liberating NRF2 from being hedged in the cytoplasm. Given that the NRF2 pathway was the top and 4thoverrepresented pathway at 4 and 24 hours respectively, a comparative evaluation was performed of all DEGs in the NRF2 pathway at 4 and 24 hours (Fig.10 and Figs.6-8). DEGs at 4 hours predominantly encode antioxidant proteins and the category of “other” consisting of key NRF2 target genes Heme oxygenase 1 (Hmox1) and Sequestosome 1 (Sqstm1) compared to phase 2 proteins and transport proteins suggesting that MCB-613-10-1 stimulates antioxidant genes in the NRF2 transcriptional network compared to transport proteins. Interestingly, almost fifty percent of the NRF2 growth factor targets were downregulated at 24 hours indicating decreased cellular growth factor signaling. In contrast to HSPA1A which is only upregulated at 4 hours, genes upregulated at 4 hours were also upregulated at 24 hours. Nineteen NRF2 pathway genes were exclusively up regulated in response to MCB-613-10-1 at 24 hours, in line with a more robust transcriptional response at 24 hours. Next, to validate MCB-613-10-1-induced gene expression, the transcriptional response was measured for NRF2-related signaling pathway genes in control and MCB-613- 10- 1-treated CFs. Like the RNA-seq analysis, RT-qPCR data show that the NRF2-target genes Hmox1, Sqstm1 and Gsta3 were up-regulated at both 4 and 24 hours after MCB-613- 10-1 treatment (Fig. 11A). In contrast, MCB-613-10-1 increased gene expression of Prdx1, Nqo1 at both 4 hours in addition to 24 hours. Protein expression of NRF2 target gene HMOX1, SQSTM1 and the NRF2 negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in cell lysates from CFs treated with vehicle control compared to MCB-613-10-1 for 4 and 24 hours were then measured. KEAP1 protein was decreased and HMOX1 and SQSTM1 proteins were increased in response to MCB-613-10-1 at both 4 and 24 hours (Fig. 11B). To directly confirm the activation of NRF2, quantification of NRF2 nuclear proteins was measured in cytoplasmic compared to nuclear cellular protein fractions and by immunofluorescence. MCB-613-10-1 promoted increased NRF2 expression and nuclear localization (Fig.11C). HMOX1 expression by evaluated by immunostaining. HMOX1 staining was more abundant in response to MCB-613-10-1. (Fig.11C). Cell fractionation showing nuclear accumulation of NRF2 following 24 hours MCB-613-10-1 treatment (Fig. 11D) further indicates NRF2 activation. Given the role NRF2 in respiration, the effect of MCB-613 on oxygen consumption was evaluated in intact CFs. Compared to control, oxygen consumption in drug-treated CFs was increased (Fig.11E) demonstrating MCB-613 improves mitochondrial function by enhancing energy metabolism. Given the robust changes in NRF2 pathway proteins, quantitative proteomics was performed. Protein was isolated from primary CFs following treatment with MCB-613-10-1 or control at 24 hours. Tandem mass tag (TMT) proteomics profiling of CFs treated with MCB-613- 10-1 and analyzed against mock-treated CFs for differential iBAQ (peptide area- based quantification) largely reproduced the differential expression profile obtained by RNA- seq.410 proteins satisfied thresholding at 1.5 x-fold change presence and Padj <0.05 significance (Fig.12).248 of these proteins agreed with differentially expressed genes called at 1.5 x-fold change, 204 (82%) of which also agreed with the direction of expression change. Statistical overrepresentation tests carried out with the differential proteins alone or with their intersection with the 1.5x-Fc DEGs reproduced the NRF2-related enrichments (Figs.13-14) – along with the differential protein expression for the top enrichment (Fig.15), including the DAVID WIKI overrepresentation analysis generated with the 248 shared proteins and DEGs. These results establish that the NRF2 pathway is the dominant pathway stimulated by MCB- 613-10-1 in cardiac fibroblasts. MCB-613-10-1 promotes cell survival and preserves cellular and mitochondrialmorphology and function following H2O2exposure.The effect of MCB-613-10-1 on ROS production was evaluated. To ascertain ifMCB-613-10-1 influences H2O2-mediated oxidative stress in cardiac fibroblasts, CFs wereexposed to H2O2to induce the generation of intracellular ROS. MCB-613-10-1 alone did notlead toaccumulation of ROS by itself. Intracellular ROS was robustly inhibited in thepresence of MCB-613-10-1 in response to H2O2treatment (Fig. 16A). Elevated levels ofH2O2leads to mitochondrialdysfunction and loss of cell viability in cultured cells. Toexamine whether MCB-613-10-1treatment affects cell viability in CFs exposed to oxidativestress, CFs were exposed to H2O2to induce ROS. Cell viability was decreased by 50%following exposure to 600 µM H2O2(Fig. 16B).Pre-treatment of CFs with MCB-613-10-1for either 30 minutes or 24-hours prevented thedecrease in cell viability after H2O2exposure(Fig. 16B), indicating that SRC activation promotesresistance to oxidative stress.Interestingly, MCB-613-10-1 pre-treatment for 24-hours increasedcell viability in response toH2O2, indicating that MCB-613-10-1 enhances a cell adaptive response to oxidative stress. Incontrast, MCB-613-10-1 did not inhibit the loss of cell viability followingH2O2pre-treatmentfor 6 hours, indicating that MCB-613-10-1 promotes cell survival by controllingtheaccumulation of intracellular ROS, likely by preserving mitochondrial function. H2O2exposure can lead to cell death along with mitochondrial fragmentation and mitochondrial dysfunction. Cell painting was used to obtain an unbiased assessment of cellular and mitochondrial morphology in response to H2O2and MCB-613-10-1. Cells were stained with fluorescent dyes to detect nuclei (DAPI), nucleoli and cytoplasmic RNA (SYTO-14), F-actin (phalloidin) and mitochondria (MitoTracker) (Fig.16C). Cell numbers,based on nucleicount, were decreased by 70% following exposure to 900 µM H2O2(Fig.16C). Pre-treatment of CFs with MCB-613-10-1 for 24-hours prevented cell death induced by H2O2exposure (Fig.16C), indicating that SRC activation promotes resistance to oxidativestress. H2O2altered nucleareccentricity and actin intensity (Fig. 16C). MCB-613-10-1reversed the change in nucleareccentricity indicating that it guards against nuclearabnormalities brought on by H2O2(Fig.16C). MCB-613-10-1 also rescued the effects ofH2O2on nuclear morphology and actin intensity. Next,given that ROS can causemitochondrial dysfunction and cell death,textural characteristics of mitochondria, measuredby grey scale correlation matrixes, were studied. H2O2 robustly changed mitochondrialvariance and contrast, indicating the presence of unhealthy mitochondria (Fig.16D),including promoting mitochondrial network fragmentation. MCB-613-10-1reversed H2O2-induced changes in mitochondrial variance and contrast (Fig. 16D), indicatingthat MCB-613-10-1 acts as a mitochondrial protectant against oxidative stress-induced mitochondrial damage. NRF2 is required for SRC activation mediated cell survival. To determine if NRF2 is required for improved mitochondrial function in response to MCB-613-10-1, OCR was measured in CFs isolated from NRF2 knock-out (NRF2KO) mice. Unlike WT CFs (Fig.11E), MCB-613-10-1 did not increase oxygen consumption in NRF2KO CFs (Fig.17A), indicating NRF2 is required for improved mitochondrial function. To determine if the NRF2 / antioxidant response element (ARE) signaling pathway was involved in the survival of CFs exposed to MCB-613-10-1, NRF2-target gene expression was measured in NRF2KO CFs. SRC expression was not changed in WT CFs compared to NRF2KO CFs indicating that NRF2 is not required for SRC expression (Fig.18). NRF2 was required for transcription of Hmox1, Nqo1, Sqstm1 and Prdx1 antioxidant genes compared to Gsta3 (Fig.17B and Fig.19), indicating that the NRF2 transcriptional network is an MCB- 613-10-1 therapeutic target in CFs. In support of the transcriptional response, NRF2 was required for HMOX1 protein expression compared to GSTA3 in NRF2KO CFs (Fig.19). To determine if NRF2 is required for MCB-613-10-1 promotion of CF cell survival,CFsisolated from NRF2KO mice were exposed to H2O2to induce generation of intracellularROS. As expected, H2O2decreased CF cell survival by 50% 24 hours after exposure (Fig.17C). MCB-613-10-1 did not prevent cell death of NRF2KO CFs when administered as apre- or post-treatment indicating that NRF2 is required for MCB-613-10-1 mediated protection against oxidative stress. To ascertain if NRF2 is required for MCB-613-10-1inhibition of ROS production, NRF2KO CFswere exposed to H2O2to induce the generation ofintracellular ROS.ROS production is elevated in NRF2KO cells compared to WT CFs.MCB-613-10-1 did notinhibit the accumulation of intracellular ROS in response to H2O2treatment (Fig. 17D) indicatingNRF2 is required for MCB-613-10-1 inhibition of ROSproduction. SRC activation enhances antioxidant signaling through interaction with the Hmox15’ region. It was then determined whether SRCs can directly regulate NRF2 signaling in CFs by binding to Nrf2 ARE sequences in the mouse Hmox1 gene regulatory region. To identify potential ARE regions in the 5’ of mouse Hmox1, NRF2-occupied sites in the mouse genome were surveyed using the publicly available Cistrome Data Browser database. Results indicate the presence of several potential AREs upstream of mouse Hmox1 (Fig.21 and Fig.20A). SRC and NRF2 recruitment to four of these regions, namely potential enhancers E1, E2 and E3, and the promoter P, was tested by qPCR of chromatin immunoprecipitated DNA using anti-SRC-1, 2, 3 or anti-NRF2 antibodies (Fig.20A). Regions E1, E2 or P1 were not amplified following NRF2 ChIP, whereas the E3 ARE sequence was amplified following SRC-1, 2, 3, and NRF2 IP (Fig.20B) in the absence of MCB-613-10-1, indicating basal enrichment. Enrichment of both SRC-1 and NRF2 over E3 was enhanced upon MCB-613-10-1 treatment. These chromatin immunoprecipitation experiments show that SRCs and NRF2 are part of the gene-regulatory network of mouse Hmox1 in CF, and together with gene expression data, show that SRC activation stimulates the NRF2 transcriptional network to control cardiac fibroblast antioxidant and cytoprotective signaling. These findings demonstrate the existence of dynamic transcriptional gene regulation of oxidative metabolism by SRCs. Example 2: MCB-613-10-1 attenuates the extent of injury post-stroke in a rat middle cerebral artery occlusion (MCAO) model Materials and Methods Animal procedures were approved under Institutional Animal Care and Use Committee and conducted under National Institutes of Health guidelines for the Care and Use of Laboratory Animals. All experimental methods were standardized and performed by specified investigators to minimize potential confounders. All investigators were blinded throughout the experiment. Using computer-based randomization, rodents were assigned to the treatment groups prior to the initial procedure. Forty male Sprague Dawley rats (Charles River Laboratories), age 7-9 weeks and weighing 225-250 grams, were divided into two experiments: 24-hour (n=20) and 4-day survival (n=20). Due to their bigger size, only male mice were employed in this study in order to rule out the influence of gender and treatment response on stroke recovery. Subjects received equal volume intraperitoneal (IP) injections of either 10-1 (20 mg / kg) or saline control 30 minutes after reperfusion or sham surgery then injected daily, if they survived for more than 24 hours. For the 24-hour survival experiment, 10 rodents were randomly assigned to 10-1 and 10 rats assigned to the control groups. In the 4-day experiment, 10 rodents were randomly assigned to the 10-1 and 10 to the control groups. Surgical Preparation Atropine sulfate (0.5 mg / kg IP), buprenorphine SR (1 mg / kg SQ) and meloxicam SR (2 mg / kg SQ) were injected one hour before anesthesia. General anesthesia was induced using 5% isoflurane in 100% oxygen, by placing the rats in an induction chamber for approximately 3-5 minutes. The animals were then intubated with a 16-gauge angiocatheter and mechanically ventilated using a Harvard Apparatus VentElite ventilator. A surgical plane of anesthesia was maintained throughout the procedure with 2% isoflurane at 100% medical air. Rectal temperature, respirations, pulse oximetry were monitored via automated monitoring system (HPMS Model# 75-1501, Harvard Apparatus). Body temperature was continuously monitored and maintained between 36.5 and 37 °C throughout the procedure. The scalp was shaved and cleaned using an iodine-based solution. The surgical field was draped with sterile linens. With the animal placed in a prone position, a 2 to 2.5 cm midline sagittal incision was performed and the scalp with periosteum were reflected to expose the left parietal bone. A laser doppler flowmetry (LDF) probe and holder was affixed to the left parietal bone using cyanoacrylate adhesive. The animal was then placed in supine position for the remainder of the procedure. Middle Cerebral Artery Occlusion Under microscopy, blunt dissection was performed through the carotid triangle to expose the left common carotid artery (CCA) and bifurcation of the external carotid artery (ECA) and internal carotid artery (ICA). The superior thyroid artery (STA) of the ECA was then isolated and coagulated, followed by the occipital artery. The ICA was carefully isolated from the adjacent vagus nerve. Next, two 3-0 silk sutures were placed around the ECA with one ligated distal to the STA. Cerebral blood flow (CBF) was monitored and recorded for baseline readings with the LDF system (moorVMS-LDF2, Moor Instruments) for 5 minutes. Two micro-vascular clips were placed on the CCA and ICA to prevent any bleeding, and the ECA was partially severed with microscissors. A 4-0 monofilament nylon suture with an occlusive diameter of 0.41 mm was inserted through the proximal ECA into the ICA, and the remaining ECA was severed. The micro-vascular clip on the ICA was removed and the filament was advanced until the LDF showed a 70% decrease from baseline CBF. The silk suture around the ECA stump was tightened around the intraluminal nylon suture to prevent bleeding. Occlusion time was set for 90 min then the filament was removed to allow for reperfusion. Exclusion Criteria and Stroke-Related Deaths Criteria for exclusion consisted of excessive bleeding occurred during surgery, operation time exceeded 120 min, anesthesia recovery time exceeded 30 min, animals died prior to scheduled euthanasia date or if subarachnoid hemorrhage was found during postmortem examination. Stroke-related deaths were defined as post-operative deaths due to neurologic devastation not associated with the above exclusion criteria. One animal was excluded in the 24-hour cohort and 6 animals (four 10-1 and 2 control) were excluded in the 4-day cohort due to stroke-related death. No data was collected from these animals and there was no statistical difference due to stroke-related death. Neurologic Assessment A modified Bederson test was used to assess for neurologic impairments beginning on post-operative day 1. The scoring was as follows: (1) Forearm Flexion was graded 0 to 1, (2) Resistance to Lateral Push was graded 0 to 2, (3) Circling Behavior was graded 0 to 3. The sum of these assessments determined the final score of 0 (normal) to 6 (severe) each day. Infarct volume measurements Brains were sliced coronally into 2 mm slices and incubated at 37 °C for 20 minutes in 2,3,5-triphenyltetrazolium chloride (TTC). Brains were then fixed in formalin and then paraffin embedded. Brain slices were photographed and infarct volume was measured using Image J (NIH.gov). Infarct area was calculated by tracing unstained regions in each section (both sides) and multiplied by slice thickness to calculate infarct volume. For measurements of cortical and subcortical infarction sizes, hematoxylin and eosin (H&E) slides were made from paraffin imbedded brain sections. Cortical and subcortical structures were consistently identified using the Rat Brain Atlas as reference. Consistent with data shown herein, treatment with MCB-613-10-1 can protect vulnerable brain tissue surrounding the area of surgically induced ischemia. Normally after stroke, vulnerable brain tissue adjacent to necrotic tissue dies due to ROS stress and inflammation. SRC stimulation with MCB-613-10-1 inhibits inflammation and activates the Nrf2 pathway to counteract ROS and inflammation, resulting in a smaller area of brain injury (Fig.22, left panel) and improved neurological function (Fig.22, right panel). Example 3: Extent of surgically-induced traumatic brain injury is reduced in MCB- 613-10-1 treated mice Methods and Materials Subjects and experimental design. Male Long Evans rats, 275-300 gm, were obtained from Envigo. Two series of experiments were performed on rats post-TBI, with 12 rats in series 1 and 17 rats in series 2. In both series, rats underwent TBI, were randomly assigned to receive vehicle or MCB10-1 once daily for 7 days, and motor function was tested on day (D) 1, D3 and D7. In series 1, cognitive function was tested on D7, following which rats were euthanized. In series 2, drug administration was stopped after D7 and cognitive function was tested on D10, following which rats were euthanized. One rat randomized to vehicle in series 2 died 1-day following surgery, leaving 7 vehicle-treated rats in this series. Data on motor function from the two series were pooled (13 vs.15 rats administered vehicle vs. MCB10-1). Data on cognitive function from the two series were not pooled (6 vs.6 rats in series 1; 7 vs. 9 rats in series 2). A separate series of 11 rats were uninjured and used as controls for normal cognitive function. Model of traumatic brain injury (TBI). TBI was induced by a controlled cortical impact (CCI). Rats were anesthetized (isoflurane, 3% and 1.2% with 100% O2for induction and maintenance, respectively; SomnoSuite Small Animal Anesthesia System; Kent Scientific Corp., Torrington, CT). Core temperature was maintained at 37 °C with an isothermal pad (Deltaphase; Braintree Scientific, Braintree, MA). Oxygen saturation and heart rate were monitored using a pulse oximeter (Mouse Ox™; STARR Life Sciences Corp., Oakmont, PA). Surgical incision sites were prepared using iodine and alcohol, and a sterile environment was maintained throughout the procedure. Rats were mounted in a stereotactic apparatus (Stoelting Co., Wood Dale, IL, USA). Lidocaine solution (2%) was injected prior to making an incision. A midline scalp incision was made to expose the skull. A circular bone incision positioned 2 mm anterior to lambda and 1 mm lateral to midline was made using a high-speed drill with a 1 mm diamond burr (Dremel, model 732), to create a 6-mm diameter craniotomy in the left parietal region. After removing the bone flap, contusion-TBI was induced using a controlled cortical impact device (Impact One impactor system; 39463920; Leica Biosystems, Buffalo Grove, IL) with the following parameter settings: 5 mm diameter impactor, angled 20° from vertical, 4.5 mm tissue displacement from the dural surface, 1 m / sec velocity, 200 msec dwell time. The bone flap was then repositioned and cemented in place using a cyanoacrylate adhesive (Loctite® 454 Prism Instant Adhesive Gel plus Insta- Set accelerator). Buprenorphine (0.05 mg / kg) 15 min before surgery then every 12 hours for 24 hours was used for analgesia. MCB-613-10-1 administration. A stock solution of MCB10-1 was prepared in ETOH (20 mg / mL); 300 μL of stock solution was added to 1.4 mL normal saline (NS) and injected IP once daily (formulation with ETOH). For a 300-gm rat, this dose is equivalent to 20 mg / kg, as used in a previous report. Immunohistochemistry. Following transcardial perfusion of rats with saline followed by 4% paraformaldehyde (PFA), brains were collected and postfixed in PFA for 6 hours. Brains were later cryoprotected in 30% sucrose and were embedded in OCT compound.12 μm coronal cryosections were collected on slides. Sections were blocked in 2% donkey serum with 0.2% Triton X-100 in phosphate buffered saline (PBS) for 1 hour, then incubated overnight at 4 °C with primary antibodies (Table 1). Table 1. Primary Antibodies Sections were washed 3x in PBS for 10 minutes each, then incubated in the dark with the appropriate fluorescent-labeled secondary antibodies (1:500; Invitrogen, Molecular Probes, Eugene, OR) at room temperature. After 1 hour, the slides were washed and cover- slipped with Prolong Antifade reagent with DAPI (Molecular Probes, Invitrogen, Carlsbad, CA). Control experiments involved omission of the primary antibody. Sections were examined using epifluorescence microscopy and images were captured with NIS-Elements software (Nikon Instruments, Melville, NY). Image analysis was performed in which the treatment groups were blinded. Images were captured at 10x and 20x magnification with consistent settings for gain and exposure. For the quantification of GFAP immunolabeling, 3 regions of interest (ROI) were selected: (i) ipsilateral hemisphere (outlined medially by the interhemispheric sulcus and inferiorly by the rhinal fissure), (ii) ipsilateral thalamus, and (iii) contralateral hippocampus. The threshold was set to 3x the background for each individual section and all labeling was performed as a single batch. Percent signal of GFAP for each specific area was compared for statistical analysis. For cleaved caspase-3 staining, the same ROI’s were selected and the total number of caspase-3 positive cells were quantified. Data analyses were performed using GraphPad Prism. Similar to that seen in Fig.22, the pathological impact of surgically induced traumatic brain injury (TBI) can be attenuated with MCB-613-10-1. Tissue loss as measured by GFAP staining is markedly improved in MCB-613-10-1 TBI mice (compare Fig.23A and Fig. 23B). Quantitation of tissue sparing (Fig.23C) and GFAP staining in the thalamus (Fig. 23D) entorhinal cortex (Fig.23E), and hippocampus (Figs.23F, 23G and 23H) indicates reduced brain inflammation in multiple areas in the brain. Example 4: Long-term treatment with MCB-613-10-1 reduces phosphorylated tau accumulation and astrogliosis in ps19 Alzheimer’s disease model mice. Material and Method: Animal model and experimental design. The ps19 mouse model, known for overexpressing the 0N4R P301S mutant form of human tau, served as the primary model organism for this study. ps19 mice (male and female) were divided into two experimental groups: one group was treated with MCB-613 (20mg / kg body weight, 5 times in a week) while the other group received an equivalent volume of saline (administered 5 times a week) via intraperitoneal injection. A control group comprised wild-type mice without any intervention. Treatment initiation occurred when the mice reached 4 months of age, with a subsequent 5-month duration of drug administration. Upon completion of the treatment period, mice from both the experimental and the control group were sacrificed at 9 months of age for further analysis. Tissue processing and sectioning Whole intact brain was carefully extracted from the sacrificed mice and sagittal sections were cut which were immediately fixed in 4% paraformaldehyde (PFA) solution for 24 hours. Following fixation, the brains were transferred to 70% ethanol for additional preservation. Subsequently, they were dehydrated and embedded in paraffin and finally sliced into sections at a thickness of 6 μm and an area of -1.4, ensuring consistent and standardized sectioning across all samples. Immunofluorescence analysis Immunofluorescence staining was performed to assess the expression levels and distribution patterns of key proteins within the brain cortex region. Primary antibodies targeting glial fibrillary acidic protein (GFAP, Millipore Sigma, 1:1000) and phosphorylated tau (pTau, ThermoFisher, 1:1000) were used. To detect the primary antibodies, fluorescent- conjugated secondary antibodies were employed: anti-rabbit (488) for GFAP and anti-mouse (594) for pTau. Secondary antibodies were diluted in phosphate-buffered saline (PBS) at a concentration of 1:1,000. Image acquisition and analysis Fluorescent images of brain cortex sections were acquired using a confocal microscope (Nikon A1) to assess the distribution and intensity of GFAP and pTau staining. Images were captured at 20x magnification. Signal intensity analysis was conducted using ImageJ software. For quantification, regions of interest (ROIs) were defined, and mean fluorescence intensity was measured within these regions. The acquired data were then analyzed statistically by using GraphPad to determine any significant differences between experimental groups. Fig.24A shows the immunofluorescence analysis of phosphorylated (pTau) and Fig. 24B shows astrogliosis in the cortex region of aged ps19 and age-matched wild-type mice showing MCB 613-10-1 treatment significantly decreases pTau expression (Fig.24A) and astrocyte activation (GFAP staining) (Fig.24B). Representative immunofluorescence images of cortex regions are taken at 20X magnification using Nikon A1 confocal microscopy. The image scale bar represents 100 μm. Data are expressed as the means ± SEM. Statistical analysis was calculated by using Tukey’s multiple comparison test using graph pad. Graph bars represent means ± SEM. *p < 0.05. **p < 0.01; ***p < 0.001. Example 5: Treatment of nonobese diabetic (NOD) mice with MCB-613-10-1 strongly reduces the formation of type 1 diabetes. Materials and Methods Subject and Treatment groups: 5 cohorts of NOD / ShiLtJ or C57BL / 6 mice at 3 or 8 weeks of age were injected with MCB-613-10-1 or vehicle control (Table 2). Table 2 Mice in Groups 2 and 3 began treatment with vehicle or test article according to the table above starting at 4 weeks of age. Mice in Group 4 began treatment with test article according to the table above starting at 10 weeks of age. Mice in Group 5 began treatment with test article according to the table above when two weekly successive hyperglycemic readings are measured. Body weight and fasting blood glucose using a glucometer were recorded weekly. Mice in Groups 2 – 4 were euthanized and a necropsy performed when two weekly successive hyperglycemic readings were measured. Mice in Group 5 were euthanized, and a necropsy performed once they reach pre-defined IACUC endpoint criteria. Blinding. All technicians injecting and phenotyping animals were blinded to treatment. Each group and animal were assigned a non-descript number at study initiation (i.e., Animals will be assigned sequential numbers as unique id, 1,2, 3, 4, 5, etc.). MCB-613-10-1 administration. A stock solution of MCB-613-10-1 was prepared in ETOH (20 mg / ml). Stock MCB-613-10-1 was diluted 1:10 in sterile saline and administered intraperitoneally at 20 mgs / kg three times weekly for the duration of the study. As shown in Fig.25, NOD mice can spontaneously develop diabetes due to immune system attack of β cells in pancreas, similar to that seen in type 1 diabetes in humans. In a model of early prevention (green line - top) and late prevention (purple line – bottom), MCB- 613-10-1 can preserve insulin production in NOD mice better than control mice (red line – top). In a model of NOD reversal where β cells have already been destroyed by the immune system (orange line – bottom), MCB-613-10-1 is unable to reserve established type 1 diabetes in NOD mice. Example 6: Surgically induced kidney injury that induces kidney fibrosis can be attenuated by treatment with MCB-613 Materials and methods Seven-week-old male C57BL / 6 mice were purchased from Jackson Laboratories. The animals were housed on a 12-h day / night cycle and were allowed free access to food and water. To investigate the involvement of MCB-613 in the development of contralateral renal fibrosis, male SD mice (n= 9) were divided into three groups: the Sham group, the Unilateral Ureteral Obstruction (UUO group), and UUO + MCB-613 group (each group = 3). In the establishment of UUO model, an incision was made in the midline of the abdomen, and the left proximal ureter was exposed by ligation of the left ureter at the ureteropelvic junction using 3-0 silk. In the MCB-613 group, mice subjected to UUO were administered 20 mg / kg MCB-613 for seven days. In the Sham group, the left ureter was only exposed without ligation. Kidney samples were harvested at the end of day seven. After the mice were decapitated under isoflurane anesthesia, the right kidney was removed; sections of the kidney were fixed in 10% formalin and embedded in paraffin for histological evaluation. Histological examination and immunohistochemical analysis kidney sections were histologically evaluated with HE staining. HE staining was performed using standard procedures, and semiquantitative grading was also performed. Picrosirius red staining was also performed on these histological sections to visualize the extent of kidney fibrosis with quantification performed using ImageJ software (NIH.gov). The data are presented in Fig.26. In a unilateral ureteral obstruction model where the urine duct of one kidney is surgically blocked, kidney fibrosis occurs due to urine blockage. However, in mice receiving MCB-613, the extent of kidney fibrosis as measured by picrosirius red staining is reduced (compare Fig.26, bottom three images with the five image panels above). Quantitation of picrosirius red staining is indicated in the histogram on the right. The compounds and methods of the appended claims are not limited in scope by the specific compounds and methods described herein, which are intended as illustrations of a few aspects of the claims and any compounds and methods that are functionally equivalent are within the scope of this disclosure. Various modifications of the compounds and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compounds, methods, and aspects of these compounds and methods are specifically described, other compounds and methods are intended to fall within the scope of the appended claims. Thus, a combination of steps, elements, components, or constituents can be explicitly mentioned herein; however, all other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

WHAT IS CLAIMED IS:

1. A method of repairing tissue in a subject, comprising: administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula:or a pharmaceutically acceptable salt or prodrug thereof, wherein: A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6alkyl; and X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

2. The method of claim 1, further comprising selecting a subject experiencing tissue injury.

3. The method of claim 1 or 2, wherein the administering step is performed within a period of time after tissue injury.

4. The method of claim 3, wherein the administering step is performed within 6 months of tissue injury.

5. The method of claim 4, wherein the administering step is performed within 24 hours of tissue injury.

6. The method of any one of claims 1-5, wherein the administering increases the ratio of M2 macrophages to M1 macrophages.

7. The method of any one of claims 1-6, wherein the administering promotes macrophage transition to an M2-like state.

8. The method of any one of claims 1-7, wherein the administering inhibits inflammation.

9. The method of any one of claims 1-8, wherein the subject has suffered traumatic brain injury.

10. The method of any one of claims 1-9, wherein the subject has suffered kidney injury.

11. The method of any one of claims 1-10, wherein the subject has Alzheimer’s disease.

12. The method of any one of claims 1-11, wherein the subject has diabetes.

13. The method of claim 12, wherein the diabetes is Type 1 diabetes.

14. The method of any one of claims 1-13, wherein the compound has the following formula:or a pharmaceutically acceptable salt or prodrug thereof.

15. The method of claim 14, wherein the compound has the following formula:, or a pharmaceutically acceptable salt or prodrug thereof, wherein: m and n are each independently 1, 2, 3, 4, or 5.

16. The method of claim 14 or 15, wherein the compound is:.

17. The method of any one of claims 1-13, wherein the compound has the following formula:or a pharmaceutically acceptable salt or prodrug thereof.

18. The method of claim 17, wherein the compound has the following formula:or a pharmaceutically acceptable salt or prodrug thereof, wherein: m and n are each independently 1, 2, 3, 4, or 5.

19. The method of claim 17 or 18, wherein the compound is:.

20. A method of protecting tissue adjacent to an injury site or reducing tissue loss in a subject, comprising: administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula:or a pharmaceutically acceptable salt or prodrug thereof, wherein:A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6alkyl; and X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

21. The method of claim 20, further comprising selecting a subject that has suffered traumatic brain injury.

22. The method of claim 20, further comprising selecting a subject that has suffered kidney injury.

23. The method of claim 20, further comprising selecting a subject that has Alzheimer’s disease.

24. The method of claim 20, further comprising selecting a subject having diabetes.

25. The method of claim 20, wherein the diabetes is Type 1 diabetes.

26. A method of preserving insulin production and preventing diabetes in a subject, comprising: administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula:or a pharmaceutically acceptable salt or prodrug thereof, wherein: A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6alkyl; andX is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

27. A method of inhibiting kidney fibrosis in a subject, comprising: administering to the subject an effective amount of a pharmaceutical composition comprising a compound of the following formula:or a pharmaceutically acceptable salt or prodrug thereof, wherein: A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10are each independently selected from CR1and N, wherein each R1is hydrogen, halogen, alkoxy, cyano, trifluoromethyl, or substituted or unsubstituted C1-6alkyl; and X is NR2, CR3R4, or O, wherein R2, R3, and R4are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

28. The method of claim 27, further comprising selecting a subject that has suffered kidney injury.

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