Intraindividual Correlation and Comparison of Maximal Aerobic Capacity and Maximum Power in Hand-Crank and Bicycle Spiroergometry.

BACKGROUND: Spiroergometry is important for modern performance diagnostics, and reference values have been evaluated for bicycle and treadmill ergometers. The aim of this study is to assess the comparability of bicycle and hand-crank spiroergometry and its associated parameters, as hand-crank spiroergometry can be used during rehabilitation in patients with definitive or temporally impairment of the lower extremity. METHODS: Thirty-seven healthy volunteers completed 2 exhausting performance diagnostics on hand-crank and bicycle spiroergometry. Participants' anthropometric characteristics, maximum power, multiple exertion criteria, maximum aerobic capacity, and maximum heart rate were detected, and ventilatory and metabolic thresholds were determined. RESULTS: The maximum power, maximum heart rate, maximum aerobic capacity, and ventilatory thresholds were significant higher on the bicycle ergometer (P < .001). The metabolic thresholds occurred on higher lactate values on the hand-crank ergometer. Equations for calculating maximum aerobic capacity from the maximum power measured in either hand-crank or bicycle ergometer could be found through regression analysis. CONCLUSIONS: Although there are problems in interpreting results of different ergometries due to severe physiology differences, the equations can be used for patients who are temporally unable to complete the established ergometry due to a deficit in the lower extremity. This could improve training recommendations for patients and para-athletes in particular.

An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene.

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.

Endogenous and combination retinoids are active in myelomonocytic leukemias.

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB).

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.

Aspartate ß-hydroxylase modulates cellular senescence through glycogen synthase kinase 3ß in hepatocellular carcinoma.

UNLABELLED: Aspartate ß-hydroxylase (ASPH) is an enzyme overexpressed in human hepatocellular carcinoma (HCC) tumors that participates in the malignant transformation process. We determined if ASPH was a therapeutic target by exerting effects on cellular senescence to retard HCC progression. ASPH knockdown or knockout was achieved by short hairpin RNAs or the CRISPR/Cas9 system, respectively, whereas enzymatic inhibition was rendered by a potent second-generation small molecule inhibitor of ASPH. Alterations of cell proliferation, colony formation, and cellular senescence were evaluated in human HCC cell lines. The potential mechanisms for activating cellular senescence were explored using murine subcutaneous and orthotopic xenograft models. Inhibition of ASPH expression and enzymatic activity significantly reduced cell proliferation and colony formation but induced tumor cell senescence. Following inhibition of ASPH activity, phosphorylation of glycogen synthase kinase 3ß and p16 expression were increased to promote senescence, whereas cyclin D1 and proliferating cell nuclear antigen were decreased to reduce cell proliferation. The mechanisms involved demonstrate that ASPH binds to glycogen synthase kinase 3ß and inhibits its subsequent interactions with protein kinase B and p38 upstream kinases as shown by coimmunoprecipitation. In vivo experiments demonstrated that small molecule inhibitor treatment of HCC bearing mice resulted in significant dose-dependent reduced tumor growth, induced phosphorylation of glycogen synthase kinase 3ß, enhanced p16 expression in tumor cells, and promoted cellular senescence. CONCLUSIONS: We have identified a new mechanism that promotes HCC growth and progression by modulating senescence of tumor cells; these findings suggest that ASPH enzymatic activity is a novel therapeutic target for HCC.

Distinct functional modes of SUMOylation for retinoid X receptor alpha.

The present study investigated human retinoid X receptor alpha (hRXRα) as a substrate for modification with small ubiquitin like modifier (SUMO) and how members of the protein inhibitor of activated STAT (PIAS) family may impact upon this process. In agreement with a previous study, we validate Ubc9 to facilitate SUMOylation of hRXRα at lysine 108 but note this modification to occur for all isoforms rather than specifically with SUMO1 and to preferentially occur with the unliganded form of hRXRα. SUMOylation of hRXRα is significantly enhanced through PIAS4-mediated activity with lysine 245 identified as a specific SUMO2 acceptor site modified in a PIAS4-dependent fashion. While individual mutations at lysine 108 or 245 modestly increase receptor activity, the combined loss of SUMOylation at both sites significantly potentiates the transcriptional responsiveness of hRXRα suggesting both sites may cooperate in a DNA element-dependent context. Our findings highlight combinatorial effects of SUMOylation may regulate RXRα-directed signalling in a gene-specific fashion.

The magnitude of correlation between deadlift 1RM and jumping performance is sports dependent.

Introduction: Based on the assumption of maximal strength as a basic ability, several studies show a high influence of maximum strength on jumping performance in several sport athletes. However, there is a wide range of correlations from r = 0.17-0.9 between squat 1RM and jumping performance in different sports. Additionally, there are only a few studies investigating the influence of deadlift one repetition maximum (1RM) on jumping performance. Thus, this study aimed to investigate the correlations between 1RM in the deadlift on jumping performance using the countermovement jump height (CMJ) and squat jump height (SJ) considering different sports. Methods: 103 athletes with experience in the deadlift from soccer, basketball, American football, powerlifting as well as participants from different sports without any deadlift experience (control group) were included to this study. Results: Overall statistics showed a significant moderate influence of deadlift 1RM (r = 0.301-0.472) on jumping performance. However, subgroup analysis showed no significant correlation between deadlift 1RM and jumping performance in control participants, while moderate correlations could be detected in powerlifters (r = 0.34-0.39), soccer players (r = 0.437-0.46), American football players (0.584-0.62) and high correlations in basketball players (r = 0.809-0.848) showing significant influence of type of sport on correlations between deadlift maximum strength and jumping performance. Discussion: Presented results underline movement velocity- and task specificity of strength training routines which is discussed in the light of the respective sports.

Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein-Protein Interactions in a Yeast Two-Hybrid System.

Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo- and heterodimerize, and these protein-protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up- or downregulated. Expression analysis was performed in the U87 human glioblastoma cell line treated with a panel of rexinoids, and our analysis demonstrated that rexinoids with similar RXR EC50 values can have pronounced differences in differential gene expression. Rexinoid binding likely leads to distinctive RXR conformations that cause major downstream gene expression alterations via modulation of RXR interacting proteins. Yeast two-hybrid analysis of RXR bait with two RXR interacting partners demonstrates that rexinoids drive differential binding of RXR to distinctive protein partners. Physiochemical analysis of the rexinoids reveals that the molecules cluster similarly to their gene expression patterns. Thus, rexinoids with similar RXR binding affinities drive differential gene expression by stimulating additional binding patterns in RXR and its homo- and heteropartners, driven by the physicochemical characteristics of these molecules.

Synthesis and biological evaluation of halogenated curcumin analogs as potential nuclear receptor selective agonists.

This report describes the synthesis of analogs of curcumin, and their analysis in acting as nuclear receptor specific agonists. Curcumin (CM), a turmeric-derived bioactive polyphenol found in curry, has recently been identified as a ligand for the vitamin D receptor (VDR), and it is possible that CM exerts some of its bioeffects via direct binding to VDR and/or other proteins in the nuclear receptor superfamily. Using mammalian-two-hybrid (M2H) and vitamin D responsive element (VDRE) biological assay systems, we tested CM and 11 CM synthetic analogs for their ability to activate VDR signaling. The M2H assay revealed that RXR and VDR association was induced by CM and several of its analogs. VDRE-based assays demonstrated that pure curcumin and eight CM analogs activated transcription of a luciferase plasmid at levels approaching that of the endocrine 1,25 dihydroxyvitamin D(3) (1,25D) ligand in human colon cancer cells (HCT-116). Additional experiments were performed in HCT-116 utilizing various nuclear receptors and hormone responsive elements to determine the receptor specificity of curcumin binding. CM did not appear to activate transcription in a glucocorticoid responsive system. However, CM along with several analogs elicited transcriptional activation in retinoic acid and retinoid X receptor (RXR) responsive systems. M2H assays using RXR-RXR, VDR-SRC1 and VDR-DRIP revealed that CM and select analogs stimulate RXR homodimerization and VDR-coactivator interactions. These studies may lead to the discovery of novel curcumin analogs that activate nuclear receptors, including RXR, RAR and VDR, resulting in similar health benefits as those for vitamins A and D, such as lowering the risk of epithelial and colon cancers.

The influence of age and sex on speed-strength performance in children between 10 and 14 years of age.

Introduction: Speed-strength performance is important during human movements such as jumping, sprinting, and change of direction (COD) tasks, which are a substantial part of sports practice. Sex and age seem to influence performance output in young persons; however, few studies have focused on the influence of sex and age measured via standard protocols of performance diagnostics. Method: Therefore, the aim of this study was to investigate the influence of age and sex on linear sprint (LS), COD sprint, countermovement jump (CMJ) height, squat-jump (SJ) height, and drop-jump (DJ) height performance in untrained children and adolescents via a cross-sectional analysis. This study comprised 141 untrained male and female participants 10-14 years of age. Results: The results showed the influence of age in male participants on speed-strength performance, while in female participants, age did not significantly influence performance parameters. Moderate to high correlations between sprint and jump performance (r = 0.69-0.72), sprint and COD sprint performance (r = 0.58-0.72), and jump and COD sprint performance (r = 0.56-0.58) were found. Discussion: Based on the data from this study, it appears that the growth phase of age 10-14 does not necessarily lead to improvements in athletic performance. To ensure holistic motor development, female subjects in particular should be provided with specific training interventions with a focus on strength and power.

Maximal strength measurement: A critical evaluation of common methods-a narrative review.

Measuring maximal strength (MSt) is a very common performance diagnoses, especially in elite and competitive sports. The most popular procedure in test batteries is to test the one repetition maximum (1RM). Since testing maximum dynamic strength is very time consuming, it often suggested to use isometric testing conditions instead. This suggestion is based on the assumption that the high Pearson correlation coefficients of r ≥ 0.7 between isometric and dynamic conditions indicate that both tests would provide similar measures of MSt. However, calculating r provides information about the relationship between two parameters, but does not provide any statement about the agreement or concordance of two testing procedures. Hence, to assess replaceability, the concordance correlation coefficient (ρ c) and the Bland-Altman analysis including the mean absolute error (MAE) and the mean absolute percentage error (MAPE) seem to be more appropriate. Therefore, an exemplary model based on r = 0.55 showed ρ c = 0.53, A MAE of 413.58 N and a MAPE = 23.6% with a range of -1,000-800 N within 95% Confidence interval (95%CI), while r = 0.7 and 0.92 showed ρ c = 0.68 with a MAE = 304.51N/MAPE = 17.4% with a range of -750 N-600 N within a 95% CI and ρ c = 0.9 with a MAE = 139.99/MAPE = 7.1% with a range of -200-450 N within a 95% CI, respectively. This model illustrates the limited validity of correlation coefficients to evaluate the replaceability of two testing procedures. Interpretation and classification of ρ c, MAE and MAPE seem to depend on expected changes of the measured parameter. A MAPE of about 17% between two testing procedures can be assumed to be intolerably high.

Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.

Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4ß7 Integrin and Direct Their Migration In Vitro.

Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR9 and α4ß7 via binding to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to function. However, the unstable nature and toxicity of ATRA limit its use as a widespread treatment modality for mucosal diseases. Therefore, identifying alternatives that could reduce or eliminate the use of ATRA are needed. Rexinoids are synthetically derived compounds structurally similar to ATRA. Originally named for their ability to bind RXRs, rexinoids can enhance RAR-mediated gene transcription. Furthermore, rexinoids are more stable than ATRA and possess an improved safety profile, making them attractive candidates for use in clinical settings. Here we show that select novel rexinoids act as ATRA mimics, as they cause increased CCR9 and α4ß7 expression and enhanced migration to the CCR9 ligand, CCL25 in vitro, even in the absence of ATRA. Conversely, other rexinoids act synergistically with ATRA, as culturing cells with suboptimal doses of both compounds resulted in CCR9 expression and migration to CCL25. Overall, our findings show that rexinoids can be used independently or synergistically with ATRA to promote mucosal homing of T cells in vitro, and lends support for the prospective clinical use of these compounds in immunotherapeutic approaches for pathogenic infections or cancers at mucosal surfaces.

Sex differences in stretch-induced hypertrophy, maximal strength and flexibility gains.

Introduction: If the aim is to increase maximal strength (MSt) and muscle mass, resistance training (RT) is primarily used to achieve these outcomes. However, research indicates that long-duration stretching sessions of up to 2 h per day can also provide sufficient stimuli to induce muscle growth. In RT literature, sex-related differences in adaptations are widely discussed, however, there is a lack of evidence addressing the sex-related effects on MSt and muscle thickness (MTh) of longer duration stretch training. Therefore, this study aimed to investigate the effects of 6 weeks of daily (1 h) unilateral static stretch training of the plantar flexors using a calf-muscle stretching device. Methods: Fifty-five healthy (m = 28, f = 27), active participants joined the study. MSt and range of motion (ROM) were measured with extended and flexed knee joint, and MTh was investigated in the medial and lateral heads of the gastrocnemius. Results: Statistically significant increases in MSt of 6%-15% (p < .001-.049, d = 0.45-1.09), ROM of 6%-21% (p < .001-.037, d = 0.47-1.38) and MTh of 4%-14% (p < .001-.005, d = 0.46-0.72) from pre-to post-test were observed, considering both sexes and both legs. Furthermore, there was a significant higher increase in MSt, MTh and ROM in male participants. In both groups, participants showed more pronounced adaptations in MSt and ROM with an extended knee joint as well as MTh in the medial head of the gastrocnemius (p < .001-.047). Results for relative MSt increases showed a similar result (p < .001-.036, d = 0.48-1.03). Discussion: Results are in accordance with previous studies pointing out significant increases of MSt, MTh and ROM due to long duration static stretch training. Both sexes showed significant increases in listed parameters however, male participants showed superior increases.

Despite Good Correlations, There Is No Exact Coincidence between Isometric and Dynamic Strength Measurements in Elite Youth Soccer Players.

Speed strength performances are substantially dependent on maximum strength. Due to their importance, various methods have been utilized to measure maximum strength (e.g., isometric or dynamic) with discussed differences regarding transferability to sport-specific movements dependent upon the testing procedure. The aim of this study was to analyze whether maximum isometric force (MIF) during isometric back squats correlates with maximum strength measurements of the one repetition maximum (1RM) in the squat, with countermovement jump (CMJ) performance, and with drop jump (DJ) performances in elite youth soccer players (n = 16, 18.4 ± 1.5 [range: 17-23] years old). Additionally, concordance correlation coefficients (CCC, [ρc]) between isometric and dynamic measurements were calculated to verify whether one measurement can actually reproduce the results of the other. To improve comprehension, differences between isometric and dynamic testing values were illustrated by providing differences between both testing conditions. For this, the mean absolute error (MAE) and the mean absolute percentage error (MAPE) were calculated. To reach equality in scale, the 1RM measures were multiplicated by 9.81 to obtain a value of N. The 1RM demonstrated correlations of τ = |0.38| to |0.52| with SJ and CMJ performances, while MIF demonstrated correlations of τ = |0.21| to |0.32|. However, the correlations of both 1RM and MIF with the DJ reactive strength index (RSI = jump height /contact time) from different falling heights were of no statistical significance. The data showed significant correlations between both the absolute (τ = |0.54|) and the relative (τ = |0.40|) performances of 1RM and MIF, which were confirmed by CCC of ρc= |0.56| to |0.66|, respectively. Furthermore, the MAE and MAPE showed values of 2080.87 N and 67.4%, respectively. The data in this study show that, despite good correlations, there is no exact coincidence between isometric and dynamic strength measurements. Accordingly, both measurements may only represent an estimation of maximal strength capacity and cannot be substituted for each other. Therefore, maximal strength should be tested by using high similarity in the contraction condition, as it is used in the training process to counteract underestimation in strength because of unfamiliarity with the testing condition.

Using Long-Duration Static Stretch Training to Counteract Strength and Flexibility Deficits in Moderately Trained Participants.

Many sports injuries result in surgery and prolonged periods of immobilization, which may lead to significant atrophy accompanied by loss of maximal strength and range of motion and, therefore, a weak-leg/strong-leg ratio (as an imbalance index ∆ ) lower than 1. Consequently, there are common rehabilitation programs that aim to enhance maximal strength, muscle thickness and flexibility; however, the literature demonstrates existing strength imbalances after weeks of rehabilitation. Since no study has previously been conducted to investigate the effects of long-duration static stretch training to treat muscular imbalances, the present research aims to determine the possibility of counteracting imbalances in maximal strength and range of motion. Thirty-nine athletic participants with significant calf muscle imbalances in maximal strength and range of motion were divided into an intervention group (one-hour daily plantar flexors static stretching of the weaker leg for six weeks) and a control group to evaluate the effects on maximal strength and range of motion with extended and bent knee joint. Results show significant increases in maximal strength (d = 0.84-1.61, p < 0.001-0.005) and range of motion (d = 0.92-1.49, p < 0.001-0.002) following six weeks of static stretching. Group * time effects (p < 0.001-0.004, η² = 0.22-0.55) revealed ∆ changes in the intervention group from 0.87 to 1.03 for maximal strength and from 0.92 to 1.11 in range of motion. The results provide evidence for the use of six weeks of daily, one hour stretching to counteract muscular imbalances. Related research in clinical settings after surgery is suggested.

The rexinoid V-125 reduces tumor growth in preclinical models of breast and lung cancer.

Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.

Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells.

There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating off-target transcription is a concern with RXR ligands (rexinoids). This off-target gene modulation leads to unwanted side effects that can include low thyroid function and significant hyperlipidemia. There is a need to develop rexinoids that have binding specificity for subsets of RXR heterodimers, to drive desired gene modulation, but that do not induce spurious effects. Herein, we describe experiments in which we analyze a series of novel and previously reported rexinoids for their ability to modulate specific gene pathways implicated in neurodegenerative disorders employing a U87 cell culture model. We demonstrate that, compared to the FDA-approved rexinoid bexarotene (1), several of these compounds are equally or more effective at stimulating gene expression via LXREs or Nurr1/NBREs and are superior at inducing ApoE and/or tyrosine hydroxylase (TH) gene and protein expression, including analogs 8, 9, 13, 14, 20, 23, and 24, suggesting a possible therapeutic role for these compounds in Alzheimer's or Parkinson's disease (PD). A subset of these potent RXR agonists can synergize with a presumed Nurr1 ligand and antimalarial drug (amodiaquine) to further enhance Nurr1/NBREs-directed transcription. This novel discovery has potential clinical implications for treatment of PD since it suggests that the combination of an RXR agonist and a Nurr1 ligand can significantly enhance RXR-Nurr1 heterodimer activity and drive enhanced therapeutic expression of the TH gene to increase endogenous synthesis of dopamine. These data indicate that is it possible and prudent to develop novel rexinoids for testing of gene expression and side effect profiles for use in potential treatment of neurodegenerative disorders, as individual rexinoids can have markedly different gene expression profiles but similar structures.

2-Fluoro-4-(meth-oxy-carbon-yl)benzoic acid.

In the crystal of the title compound, C(9)H(7)FO(4), classical carboxylate inversion dimers are linked by pairs of O-H⋯O hydrogen bonds. The packing is consolidated by C-H⋯F and C-H⋯O interactions. The benzene ring and the methoxycarbonyl group are nearly coplanar, with a dihedral angle of 1.5 (3)° between them, whereas the carboxyl group has a dihedral angle of 20.2 (4)° with respect to the benzene ring.

Methods to Generate an Array of Novel Rexinoids by SAR on a Potent Retinoid X Receptor Agonist: A Case Study with NEt-TMN.

The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists.In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.