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Biochimica Et Biophysica Acta.... Jul 2023Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and...
Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.
Topics: Humans; PPAR gamma; Podocytes; Pioglitazone; Thiazolidinediones; Kidney Diseases; Bexarotene
PubMed: 37156296
DOI: 10.1016/j.bbalip.2023.159329 -
Neural Regeneration Research Dec 2023Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system. Therefore, early treatment to prevent lesion...
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.
PubMed: 37449638
DOI: 10.4103/1673-5374.373676 -
Biochemistry and Biophysics Reports Mar 2024Globally cancer and Alzheimer's disease (AD) are two major diseases and still, there is no clearly defined molecular mechanism. There is an opposite relation between... (Review)
Review
Globally cancer and Alzheimer's disease (AD) are two major diseases and still, there is no clearly defined molecular mechanism. There is an opposite relation between cancer and AD which are the proportion of emerging cancer was importantly slower in AD patients, whereas slow emerging AD in patients with cancer. In cancer, regulation of cell mechanisms is interrupted by an increase in cell survival and proliferation, while on the contrary, AD is related to augmented neuronal death, that may be either produced by or associated with amyloid-β (Aβ) and tau deposition. Stated that the probability that disruption of mechanisms takes part in the regulation of cell survival/death and might be implicated in both diseases. The mechanism of actions such as DNA-methylation, genetic polymorphisms, or another mechanism of actions that induce alteration in the action of drugs with significant roles in resolving the finding to repair and live or die might take part in the pathogenesis of these two ailments. The functions of miRNA, p53, Pin1, the Wnt signaling pathway, PI3 KINASE/Akt/mTOR signaling pathway GRK2 signaling pathway, and the pathophysiological role of oxidative stress are presented in this review as potential candidates which hypothetically describe inverse relations between cancer and AD. Innovative materials almost mutual mechanisms in the aetiology of cancer and AD advocates novel treatment approaches. Among these treatment strategies, the most promising use treatment such as tyrosine kinase inhibitor, nilotinib, protein kinase C, and bexarotene.
PubMed: 38225990
DOI: 10.1016/j.bbrep.2023.101625 -
International Journal of General... 2023associated protein 1 () is shown to regulate cell proliferation and cancer progression. However, the immune-infiltrating correlation and the therapeutics guidance of...
BACKGROUND
associated protein 1 () is shown to regulate cell proliferation and cancer progression. However, the immune-infiltrating correlation and the therapeutics guidance of in hepatocellular carcinoma (HCC) still need further investigation.
METHODS
In this study, comprehensive bioinformatic analysis of on differential expression, clinicopathologic correlation, prognostic value, and function enrichment were performed in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO; GSE14520 and GSE76427), and International Cancer Genome Consortium (ICGC) datasets. Besides, the Guangxi cohort containing 50 pairs HCC and adjacent non-cancerous samples from First Affiliated Hospital of Guangxi Medical University was served as validation cohort. Moreover, we explored the predictive value of to therapeutics response and its underlying correlation with HCC immunoinfiltration.
RESULTS
was significantly overexpressed in HCC tissues and had a high diagnostic value of HCC. The shorter survival time and poorer clinical features were showed when upregulated, and then a nomogram featuring expression and other clinicopathologic factors was established to predict prognosis. In CIBERSORT analysis, higher T cells follicular helper but lower T cells CD4+ memory resting infiltration levels were exhibited when upregulated. The ssGSEA analysis demonstrated that high- expression subgroup had higher macrophages, Th2 and Treg cells infiltration levels, but lower type II IFN response function. Furthermore, high- expression subgroup exhibited the upregulated expression levels of immune-related checkpoint genes, but lower IPS and TIDE scores which suggested a possibly better immunotherapy response. The drug sensitivity analysis showed the high-expression subgroup may be more susceptible to Bexarotene, Doxorubicin, Gemcitabine and Tipifarnib.
CONCLUSION
Taken together, is a potential diagnostic and prognostic biomarker. It may be related to the immunosuppressive microenvironment and could be an underlying HCC treatment strategy. However, the conclusions still require further validation studies.
PubMed: 37789880
DOI: 10.2147/IJGM.S431206 -
Cancers Jan 2024Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use.... (Review)
Review
Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.
PubMed: 38339295
DOI: 10.3390/cancers16030544 -
JCEM Case Reports Apr 2024The synthetic retinoid bexarotene (BXT), used in the treatment of cutaneous T-cell lymphoma (CTCL), has been associated with central hypothyroidism due to suppression of...
The synthetic retinoid bexarotene (BXT), used in the treatment of cutaneous T-cell lymphoma (CTCL), has been associated with central hypothyroidism due to suppression of thyrotropin (TSH) secretion and upregulation of peripheral thyroxine (T4) and triiodothyronine (T3) metabolism. We present a case of a 41-year-old man with CTCL who developed central hypothyroidism within 1 month of receiving BXT. He required sequential uptitration of levothyroxine (LT4) over 15 months, and free T4 (FT4) and total T3 levels were normalized by a daily regimen of LT4 600 mcg and liothyronine (LT3) 15 mcg. While almost all patients regain normal hypothalamic-pituitary-thyroid axis function after cessation of BXT, there are limited data regarding LT4 and LT3 dosing required to adequately treat central hypothyroidism in patients on BXT. Our patient required an LT4 dose approximately 2.8 times the calculated weight-based dose and LT3 supplementation, demonstrating a large LT4/LT3 combination dose may be required to compensate for BXT-induced central hypothyroidism.
PubMed: 38562989
DOI: 10.1210/jcemcr/luae041 -
Hereditas Jul 2023Copper-induced cell death (cuproptosis) is a new regulatory cell death mechanism. Long noncoding RNAs (lncRNAs) are related to tumor immunity and metastasis. However,...
BACKGROUND
Copper-induced cell death (cuproptosis) is a new regulatory cell death mechanism. Long noncoding RNAs (lncRNAs) are related to tumor immunity and metastasis. However, the correlation of cuproptosis-related lncRNAs with the immunotherapy response and prognosis of lung adenocarcinoma (LUAD) patients is not clear.
METHODS
We obtained the clinical characteristics and transcriptome data from TCGA-LUAD dataset (containing 539 LUAD and 59 paracancerous tissues). By utilizing LASSO-penalized Cox regression analysis, we identified a prognostic signature composed of cuproptosis-related lncRNAs. This signature was then utilized to segregate patients into two different risk categories based on their respective risk scores. The identification of differentially expressed genes (DEGs) between high- and low-risk groups was carried out using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We evaluated the immunotherapy response by analyzing tumor mutational burden (TMB), immunocyte infiltration and Tumor Immune Dysfunction and Exclusion (TIDE) web application. The "pRRophetic" R package was utilized to conduct further screening of potential therapeutic drugs for their sensitivity.
RESULTS
We ultimately identified a prognostic risk signature that includes six cuproptosis-related lncRNAs (AP003778.1, AC011611.2, CRNDE, AL162632.3, LY86-AS1, and AC090948.1). Compared with clinical characteristics, the signature was significantly correlated with prognosis following the control of confounding variables (HR = 2.287, 95% CI = 1.648-3.174, p ˂ 0.001), and correctly predicted 1-, 2-, and 3-year overall survival (OS) rates (AUC value = 0.725, 0.715, and 0.662, respectively) in LUAD patients. In terms of prognosis, patients categorized as low risk exhibited more positive results in comparison to those in the high-risk group. The enrichment analysis showed that the two groups had different immune signaling pathways. Immunotherapy may offer a more appropriate treatment option for high-risk patients due to their higher TMB and lower TIDE scores. The higher risk score may demonstrate increased sensitivity to bexarotene, cisplatin, epothilone B, and vinorelbine.
CONCLUSIONS
Based on cuproptosis-related lncRNAs, we constructed and validated a novel risk signature that may be used to predict immunotherapy efficacy and prognosis in LUAD patients.
Topics: Humans; Adenocarcinoma; Immunotherapy; Lung; Prognosis; RNA, Long Noncoding; Copper; Apoptosis
PubMed: 37482612
DOI: 10.1186/s41065-023-00293-w -
Cells Nov 2023Bexarotene, 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...
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.
Topics: Humans; Bexarotene; Tetrahydronaphthalenes; Lymphoma, T-Cell, Cutaneous; Retinoid X Receptors; Skin Neoplasms
PubMed: 37947652
DOI: 10.3390/cells12212575 -
Life Sciences Sep 2023Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction...
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.
Topics: Rats; Animals; Rats, Sprague-Dawley; Retinoid X Receptors; Bexarotene; Transforming Growth Factor beta1; Ventricular Remodeling; Myocardial Infarction; Cardiomyopathies; Fibroblasts; Fibrosis; Myocardium
PubMed: 37453576
DOI: 10.1016/j.lfs.2023.121936 -
Journal of the National Cancer Institute Jul 2023Adenoid cystic carcinoma (ACC) is a lethal malignancy of exocrine glands, characterized by the coexistence within tumor tissues of 2 distinct populations of cancer...
BACKGROUND
Adenoid cystic carcinoma (ACC) is a lethal malignancy of exocrine glands, characterized by the coexistence within tumor tissues of 2 distinct populations of cancer cells, phenotypically similar to the myoepithelial and ductal lineages of normal salivary epithelia. The developmental relationship linking these 2 cell types, and their differential vulnerability to antitumor treatments, remains unknown.
METHODS
Using single-cell RNA sequencing, we identified cell-surface markers (CD49f, KIT) that enabled the differential purification of myoepithelial-like (CD49fhigh/KITneg) and ductal-like (CD49flow/KIT+) cells from patient-derived xenografts (PDXs) of human ACCs. Using prospective xenotransplantation experiments, we compared the tumor-initiating capacity of the 2 cell types and tested whether one could differentiate into the other. Finally, we searched for signaling pathways with differential activation between the 2 cell types and tested their role as lineage-specific therapeutic targets.
RESULTS
Myoepithelial-like cells displayed higher tumorigenicity than ductal-like cells and acted as their progenitors. Myoepithelial-like and ductal-like cells displayed differential expression of genes encoding for suppressors and activators of retinoic acid signaling, respectively. Agonists of retinoic acid receptor (RAR) or retinoid X receptor (RXR) signaling (all-trans retinoic acid, bexarotene) promoted myoepithelial-to-ductal differentiation, whereas suppression of RAR/RXR signaling with a dominant-negative RAR construct abrogated it. Inverse agonists of RAR/RXR signaling (BMS493, AGN193109) displayed selective toxicity against ductal-like cells and in vivo antitumor activity against PDX models of human ACC.
CONCLUSIONS
In human ACCs, myoepithelial-like cells act as progenitors of ductal-like cells, and myoepithelial-to-ductal differentiation is promoted by RAR/RXR signaling. Suppression of RAR/RXR signaling is lethal to ductal-like cells and represents a new therapeutic approach against human ACCs.
Topics: Humans; Antineoplastic Agents; Carcinoma, Adenoid Cystic; Drug Inverse Agonism; Prospective Studies; Receptors, Retinoic Acid; Retinoid X Receptors; Tretinoin
PubMed: 37040084
DOI: 10.1093/jnci/djad062