BACKGROUND: Cellular therapy has emerged as a promising strategy to minimize the use of conventional immunosuppressive drugs and ultimately induce long-term graft survival. Myeloid-derived suppressor cells (MDSCs) can be used for immunosuppressive treatment of solid organ transplants.
METHODS: Granular macrophage colony-stimulating factor (GM-CSF) and bexarotene, an X receptor-selective retinoid, were used for in vitro MDSC induction. Cell phenotypes were detected using flow cytometry, while mRNA was detected via real-time PCR. A mouse skin transplantation model was used to verify the inhibitory effects of this treatment.
RESULTS: The combination of GM-CSF and bexarotene-induced MDSC differentiation. MDSCs induce immune tolerance by inhibiting T-cell proliferation, influencing cytokine secretion, and inducing T-cell transformation into Treg cells. Combination treatment significantly up-regulated Arg-1 expression in MDSCs. The Arg-1 inhibitor nor-NOHA neutralized the immunosuppressive activity of MDSCs, suggesting the involvement of Arg-1 in MDSC-mediated immunosuppression. GM-CSF and bexarotene-induced MDSCs prolong graft survival in mouse skin transplants, exhibiting in vivo immunosuppressive effects.
CONCLUSIONS: A new method for inducing MDSCs is presented. The combination of GM-CSF and bexarotene induces MDSCs with remarkable regulatory functions. Adoptive transfer of the induced MDSCs extended allograft survival. These results suggest that MDSCs can potentially be used in future clinical transplants to inhibit rejection, reduce adverse events, and induce operative tolerance.

BACKGROUND: Bexarotene, also recognized as Targretin, is categorized as a retinoid, a type of cancer drug. Nevertheless, the precise mechanisms of bexarotene in relation to colon cancer remain unclear. In colon cancer, SEZ6L2 was suggested as one of the biomarkers and targets. This study presents a comprehensive exploration of the role of SEZ6L2 in colon cancer.
METHODS: We utilized both TCGA data and a cohort of Chinese patients. In a meticulous analysis of 478 colon cancer cases, SEZ6L2 expression levels were examined in relation to clinical characteristics, staging parameters, and treatment outcomes. Additionally, we investigated the pharmacological impact of bexarotene on SEZ6L2, demonstrating a significant downregulation of SEZ6L2 at both mRNA and protein levels in colon cancer patients following bexarotene treatment.
RESULTS: SEZ6L2 consistently overexpresses in colon cancer, serving as a potential universal biomarker with prognostic significance, validated in a diverse Chinese cohort. In vitro, SEZ6L2 promotes cell viability without affecting migration. Bexarotene treatment inhibits SEZ6L2 expression, correlating with reduced viability both in vitro and in vivo. SEZ6L2 overexpression accelerates declining survival rates in an in vivo context. Bexarotene\'s efficacy is context-dependent, effective in parental cells but not with SEZ6L2 overexpression. Computational predictions suggest a direct SEZ6L2-bexarotene interaction, warranting further experimental exploration.
CONCLUSIONS: The study provides valuable insights into SEZ6L2 as a prognostic biomarker in colon cancer, revealing its intricate relationship with clinical parameters, treatment outcomes, and bexarotene effects. Context-dependent therapeutic responses emphasize the nuanced understanding required for SEZ6L2\'s role in colon cancer, paving the way for targeted therapeutic strategies.

Psoriasis is a common systemic inflammatory skin disorder affecting over 60 million people globally. Some patients with psoriasis are associated with a higher risk of type 2 diabetes mellitus (T2DM). Psoriasis and T2DM occur concurrently in some patients; however, there is no effective drug for the treatment of psoriasis with T2DM. Bexarotene (BEX) is a specific RXR agonist and an antineoplastic agent indicated by the FDA for cutaneous T-cell lymphoma (CTLA). Metformin (MET) is the first-line treatment for T2DM. To develop novel effective drugs for the treatment of psoriasis with T2DM, multicomponent salts containing MET and BEX were designed and synthesized based on the drug-drug combination strategy. MET-BEX (1:1) and MET-BEX-H2O (1:1:1) were obtained and structurally characterized. The in vitro evaluation results showed that the hygroscopicity of MET was significantly optimized by the salt formation strategy, while the solubility of BEX was improved, which laid the foundation for improving the bioavailability of BEX in vivo. In a mouse model of imiquimod-induced psoriasis with T2DM, MET-BEX ameliorated imiquimod-induced psoriasis morphological features and systematic inflammation and improved glucolipid metabolism. These results showed that the multicomponent drug combination strategy in this study optimized the physicochemical properties of MET and BEX simultaneously, providing a promising candidate therapy for psoriasis with T2DM.

Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as - 10 kcal/mol while the docking score of Oxymorphone was predicted as - 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (- 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (- 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as - 36.8323 ± 3.4565, and - 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.

Bexarotene, a retinoid X receptor (RXR) agonist, is approved by FDA to treat cutaneous T-cell lymphoma. However, it has also demonstrated promising therapeutic potential for neurological diseases such as stroke, traumatic brain injury, Parkinson\'s disease, and particularly Alzheimer\'s disease(AD). In AD, bexarotene inhibits the production and aggregation of amyloid β (Aβ), activates Liver X Receptor/RXR heterodimers to increase lipidated apolipoprotein E to remove Aβ, mitigates the negative impact of Aβ, regulates neuroinflammation, and ultimately improves cognitive function. For other neurological diseases, its mechanisms of action include inhibiting inflammatory responses, up-regulating microglial phagocytosis, and reducing misfolded protein aggregation, all of which aid in alleviating neurological damage. Here, we briefly discuss the characteristics, applications, and adverse effects of bexarotene, summarize its pharmacological mechanisms and therapeutic results in various neurological diseases, and elaborate on the problems encountered in preclinical research, with the aim of providing help for the further application of bexarotene in central nervous system diseases.

Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction (MI) remains unclear. This study aimed to determine the effects of RXR agonists on MI and to dissect the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to MI and then treated (once daily for 4 weeks) with either RXR agonist bexarotene (10 or 30 mg/kg body weight) or vehicle. Heart function was determined using echocardiography and cardiac hemodynamic measurements. Four weeks post MI, myocardial tissues were collected to evaluate cardiac remodeling. Primary cardiac fibroblasts (CFs) were treated with or without RXR ligand 9-cis-RA followed by stimulation with TGF-β1. Immunoblot, immunofluorescence, and co-immunoprecipitation were performed to elucidate the regulatory role of RXR agonists in TGF-β1/Smad signaling. In vivo treatment with Bexarotene moderately affects systemic inflammation and apoptosis and ameliorated left ventricular dysfunction after MI in rat model. In contrast, bexarotene significantly inhibited post-MI myocardial fibrosis. Immunoblot analysis of heart tissue homogenates from MI rats revealed that bexarotene regulated the activation of the TGF-β1/Smad signaling pathway. In vitro, 9-cis-RA inhibited the TGF-β1-induced proliferation and collagen production of CFs. Importantly, upon activation by 9-cis-RA, RXRα interacted with p-Smad2 in cytoplasm, inhibiting the TGF-β1-induced nuclear translocation of p-Smad2, thereby negatively regulating TGF-β1/Smad signaling and attenuating the fibrotic response of CFs. These findings suggest that RXR agonists ameliorate post-infarction myocardial fibrosis, maladaptive remodeling, and heart dysfunction via attenuation of fibrotic response in CFs through inhibition of the TGF-β1/Smad pathway activation.

Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system. Therefore, early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury. Bexarotene, a type of retinoid, exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson\'s disease. Bexarotene has been proven to promote autophagy, but it has not been used in the treatment of spinal cord injury. To investigate the effects of bexarotene on spinal cord injury, we established a mouse model of T11-T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days. We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord, increased the number of synapses of nerve cells, reduced oxidative stress, inhibited pyroptosis, promoted the recovery of motor function, and reduced death. Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury. Bexarotene enhanced the nuclear translocation of transcription factor E3, which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways. Intravenous injection of transcription factor E3 shRNA or intraperitoneal injection of compound C, an AMP-activated protein kinase blocker, inhibited the effects of bexarotene. These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways, promotes autophagy, decreases reactive oxygen species level, inhibits pyroptosis, and improves motor function after spinal cord injury.

Bexarotene (BEX) was approved by the FDA in 1999 for the treatment of cutaneous T-cell lymphoma (CTCL). The poor aqueous solubility causes the low bioavailability of the drug and thereby limits the clinical application. In this study, we developed a GCN-based deep learning model (CocrystalGCN) for in-silico screening of the cocrystals of BEX. The results show that our model obtained high performance relative to baseline models. The top 30 of 109 coformer candidates were scored by CocrystalGCN and then validated experimentally. Finally, cocrystals of BEX-pyrazine, BEX-2,5-dimethylpyrazine, BEX-methyl isonicotinate, and BEX-ethyl isonicotinate were successfully obtained. The crystal structures were determined by single-crystal X-ray diffraction. Powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis were utilized to characterize these multi-component forms. All cocrystals present superior solubility and dissolution over the parent drug. The pharmacokinetic studies show that the plasma exposures (AUC0-8h) of BEX-pyrazine and BEX-2,5-dimethylpyrazine are 1.7 and 1.8 times that of the commercially available BEX powder, respectively. This work sets a good example for integrating virtual prediction and experimental screening to discover the new cocrystals of water-insoluble drugs.

Long noncoding RNAs have a major role in tumorigenesis, development, and metastasis in colorectal cancer (CRC), participate in the regulation of cell senescence and are related to the prognosis of CRC. Therefore, it is important to validate cell senescence-related lncRNAs that correlate with prognosis in CRC.
CRC expression profile data and clinical information were downloaded from TCGA. A gene list related to cellular senescence was obtained from Human Aging Genomic Resources. A coexpression network of cell senescence-related mRNA-lncRNA was explored with R. Six cell senescence-related lncRNA signatures were identified by univariate and multivariate analyses. The cell senescence-related risk model was generated by using six cell senescence-related lncRNAs, and the risk score was calculated. Furthermore, an internal validation set and GSE17537 were used to verify the risk model. The risk model demonstrated good stability and accuracy. Finally, we investigated the correlation between cell senescence-related risk scores and immune infiltration, immune function, immune checkpoints, and drug sensitivity.
We established a signature of six cell senescence-related lncRNAs. The cell senescence-related risk model revealed an exceptional ability to assess the prognosis of colorectal cancer and was correlated with clinical features. Additionally, we observed that risk models correlate with the tumor microenvironment and immune checkpoints, potentially predicting patient response to clinical immunotherapy. Finally, we validated the correlation between the cell senescence-related risk model and drug susceptibility. Our findings indicated that AICAR, cisplatin, nilotinib, and bexarotene exhibited lower IC50 values in the high-risk group.
Our current study identified 6 cell senescence-associated lncRNA signatures that may be vital biomarkers to predict the prognostic features and immune and chemotherapy responses in CRC.

Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP-binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time-course changes of cholesterol metabolism-related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post-TBI, we generated nestin-specific Abcg1 knockout (Abcg1-KO) mice using the Cre/loxP recombination system. These Abcg1-KO mice showed reduced plasma high-density lipoprotein cholesterol levels and increased plasma lower-density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1-KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1-KO exacerbated TBI-induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1-KO mice partly rescued TBI-induced neuronal damages mentioned above and improved functional deficits versus vehicle-treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI.