BACKGROUND: Prostate cancer has emerged as a widespread health concern, with systemic inflammation believed to substantially contribute to its development and progression. The presence of systemic inflammatory responses has been established as an independent predictor of unfavorable long-term outcomes in prostate cancer patients. The goal of this study is to inhibit RXRα and RXRβ receptors, which are involved in prostate cancer, with Luteolin, Formononetin, and Kaempferol, with varying success.
METHODS: Retinoid X receptors (RXRs) hold crucial roles within the nuclear receptor (NR) superfamily, and compelling evidence from preclinical studies underscores the therapeutic potential of targeting RXRs for treating neurodegenerative and inflammatory conditions. Consequently, the ability to regulate and modulate RXRs using phytoestrogen ligands, Formononetin, Kaempferol, and Luteolin, assume paramount importance in treatment strategies.
RESULTS: The comprehensive in silico findings of this study vividly demonstrate the remarkable efficacy of Luteolin in inhibiting and modulating RXRα and RXRβ, while Formononetin emerges as a notably potent suppressor of RXRβ. Kaempferol, as the third compound, also exhibits commendable inhibitory attributes, although its impact is slightly less pronounced compared to the other two.
CONCLUSIONS: These findings highlight the notable binding and inhibition capabilities to RXRα and RXRβ, offering valuable insights for potential prostate cancer treatment avenues warranting further exploration through in vitro and in vivo analyses.

Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. As the global obesity rate rises, non-alcoholic fatty liver disease (NAFLD) has emerged as the most rapidly increasing cause of HCC. Consequently, the regulation of lipid metabolism has become a crucial target for the prevention and treatment of HCC. Liquidambaric acid (LDA), a pentacyclic triterpenoid compound derived from various plants, exhibits diverse biological activities. We found that LDA could inhibit HCC cell proliferation by arresting cell cycle and prompting apoptosis. Additionally, LDA can augment the therapeutic efficacy of Regorafenib in HCC in vitro and vivo. Our study utilized transcriptome analysis, luciferase reporter assays, and co-immunocoprecipitation experiments to elucidate the anti-HCC mechanism of LDA. We discovered that LDA disrupts the formation of the PPARα-RXRα heterodimer, leading to the down-regulation of the ACSL4 gene and subsequently impacting the fatty acid metabolism of HCC cells, ultimately inhibiting HCC proliferation. Our research contributes to the identification of novel therapeutic agents and targets for the treatment of HCC.

Fascioliasis is a parasitic infection in animals and humans caused by the parasitic flatworm genus Fasciola, which has two major species, F. hepatica and F. gigantica. A major concern regarding this disease is drug resistance, which is increasingly reported worldwide. Hence, the discovery of a novel drug as well as drug targets is crucially required. Therefore, this study aims to characterize the novel drug target in the adult F. gigantica. In the beginning, we hypothesized that the parasite might interact with some host molecules when it lives inside the liver parenchyma or bile ducts, specifically hormones and hormone-like molecules, through the specific receptors, primarily nuclear receptors (NRs), which are recognized as a major drug target in various diseases. The retinoid X receptor (RXR) is a member of subfamily 2 NRs that plays multitudinous roles in organisms by forming homodimers or heterodimers with other NRs. We obtained the full-length amino acid sequences of F. gigantica retinoid X receptor-alpha (FgRXRα-A) from the transcriptome of F. gigantica that existed in the NCBI database. The FgRXRα-A were computationally predicted for the basic properties, multiple aligned, phylogeny analyzed, and generated of 2D and 3D models. Moreover, FgRXRα-A was molecular cloned and expressed as a recombinant protein (rFgRXRα-A), then used for immunization for specific polyclonal antibodies. The native FgRXRα-A was detected in the parasite extracts and tissues, and the function was investigated by in vitro binding assay. The results demonstrated the conservation of FgRXRα-A to the other RXRs, especially RXRs from the trematodes. Interestingly, the native FgRXRα-A could be detected in the testes of the parasite, where the sex hormones are accumulated. Moreover, the binding assay revealed the interaction of 9-cis retinoic acid and FgRXRα-A, suggesting the function of FgRXRα-A. Our findings suggested that FgRXRα-A will be involved with the sexual reproduction of the parasite by forming heterodimers with other NRs, and it could be the potential target for further drug development of fascioliasis.

Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such as GLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 ChIP-seq peaks significantly overlapped with PPARγ ChIP-seq peaks, with more than half of ZFP407 peaks overlapping with PPARγ peaks. Transcription factor binding motifs enriched in these overlapping sites included CTCF, RARα/RXRγ, TP73, and ELK1, which regulate cellular development and function within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 domains potentially necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 ChIP-seq analyses identified regions that did not overlap with PPARγ peaks. These non-overlapping peaks were significantly enriched for the transcription factor binding motifs of TBX19, PAX8, HSF4, and ZKSCAN3, which may contribute to the PPARγ-independent functions of ZFP407 in adipocytes and other cell types.

The effective treatment of diabetes with comorbid depression is a big challenge so far. Honokiol, a bioactive compound from the dietary supplement Magnolia officinalis extract, possesses multiple health benefits. The present study aims to propose a network pharmacology-based method to elucidate potential targets of honokiol in treating diabetes with comorbid depression and related mechanisms. The antidepressant-like efficacy of honokiol was evaluated in high-fat diet (HFD) induced diabetic mice using animal behavior testing, immuno-staining and western blotting assay. Through network pharmacology analysis, retinoid X receptor alpha (RXRα) and vitamin D receptor (VDR) were identified as potential targets related to diabetes and depression. The stable binding conformation between honokiol and RXR/VDR was determined by molecular docking simulation. Moreover, hononkiol effectively alleviated depression-like behaviors in HFD diabetic mice, presented anti-diabetic and anti-neuroinflammatory functions, and protected the hippocampal neuroplasticity. Importantly, honokiol could activate RXR/VDR heterodimer in vivo. The beneficial effects of honokiol on HFD mice were significantly suppressed by UVI3003 (a RXR antagonist), while enhanced by calcitriol (a VDR agonist). Additionally, the disruption of autophagy in the hippocampus of HFD mice was ameliorated by honokiol, which was attenuated by UVI3003 but strengthened by calcitriol. Taken together, the data provide new evidence that honokiol exerts the antidepressant-like effect in HFD diabetic mice via activating RXR/VDR heterodimer to restore the balance of autophagy. Our findings indicate that the RXR/VDR-mediated signaling might be a potential target for treating diabetes with comorbid depression.

Delirium is a common psychiatric complication of chronic obstructive pulmonary disease (COPD). The relief of delirium is considered one of the beneficial ways to treat COPD. However, there are currently no specific drugs that alleviate delirium in COPD patients. Our research aimed to elucidate the specific mechanisms underlying delirium in COPD mice, while also seeking more effective therapeutic targets. In our study, bioinformatics analysis and qRT PCR were used to identify key factors in the development of delirium in COPD animal models. Open field and elevated plus maze tests were used to detect delirium in mice. Tunel staining and HE staining were used to analyze the apoptosis of mouse hippocampus cells. EdU and CCK-8 experiments were used to analyze PC-12 cells vitality and proliferation. JASPAR online database, dual luciferase reporting experiments, ChIP experiments, and IF staining were used to analyze the interaction between RXRA and PLA2G2A. RXRA is highly expressed in the brain tissue of COPD mice with delirium symptoms. The downregulation of RXRA inhibits the delirium state in COPD mice. This is mainly due to the reduction of endoplasmic reticulum stress and cell apoptosis by inhibiting the expression of RXRA. In addition, we also confirmed that RXRA is a transcription factor of PLA2G2A. RXRA has an inhibitory effect on the expression of PLA2G2A. In vitro experiments have confirmed that inhibition of the RXRA/PLA2G2A axis reduces cell apoptosis, thereby alleviating the occurrence and development of delirium in COPD mice. Inhibition of the RXRA/PLA2G2A axis reduces endoplasmic reticulum stress and cell apoptosis. This process alleviates the development of delirium in COPD mice.

暂无摘要。

Nuclear receptors are the fundamental building blocks of gene expression regulation and the focus of many drug targets. While binding to DNA, nuclear receptors act as transcription factors, governing a multitude of functions in the human body. Peroxisome proliferator-activator receptor γ (PPARγ) and the retinoid X receptor α (RXRα) form heterodimers with unique properties and have a primordial role in insulin sensitization. This PPARγ/RXRα heterodimer has been shown to be impacted by per- and polyfluoroalkyl substances (PFAS) and linked to a variety of significant health conditions in humans. Herein, a selection of the most common PFAS (legacy and emerging) was studied utilizing molecular dynamics simulations for PPARγ/RXRα. The local and global structural effects of PFAS binding on the known ligand binding pockets of PPARγ and RXRα as well as the DNA binding domain (DBD) of RXRα were inspected. The binding free energies were predicted computationally and were compared between the different binding pockets. In addition, two electronic structure approaches were utilized to model the interaction of PFAS within the DNA binding domain, density functional theory (DFT) and domain-based pair natural orbital coupled cluster with perturbative triples (DLPNO-CCSD(T)) approaches, with implicit solvation. Residue decomposition and hydrogen-bonding analysis were also performed, detailing the role of prominent residues in molecular recognition. The role of l-carnitine is explored as a potential in vivo remediation strategy for PFAS interaction with the PPARγ/RXRα heterodimer. In this work, it was found that PFAS can bind and act as agonists for all of the investigated pockets. For the first time in the literature, PFAS are postulated to bind to the DNA binding domain in a nonspecific manner. In addition, for the PPARγ ligand binding domain, l-carnitine shows promise in replacing smaller PFAS from the pocket.

The rubber antioxidant 6PPD has gained significant attention due to its highly toxic transformation product, 6PPD-quinone (6PPDQ). Despite their detection in urines of pregnant women, the placental transfer and developmental toxicity of 6PPD and 6PPDQ are unknown. Here, we treated C57Bl/6 mice with 4 mg/kg 6PPD or 6PPDQ to investigate their urine excretion and placental transfer. Female and male mice exhibited sex difference in excretion profiles of 6PPD and 6PPDQ. Urine concentrations of 6PPDQ were one order of magnitude lower than those of 6PPD, suggesting lower excretion and higher bioaccumulation of 6PPDQ. In pregnant mice treated with 6PPD or 6PPDQ from embryonic day 11.5 to 15.5, 6PPDQ showed ∼1.5-8 times higher concentrations than 6PPD in placenta, embryo body, and embryo brain, suggesting higher placental transfer of 6PPDQ. Using in vitro dual-luciferase reporter assays, we revealed that 6PPDQ activated the human retinoic acid receptor α (RARα) and retinoid X receptor α (RXRα) at concentrations as low as 0.3 μM, which was ∼10-fold higher than the concentrations detected in human urines. 6PPD activated the RXRα at concentrations as low as 1.2 μM. These results demonstrate the exposure risks of 6PPD and 6PPDQ during pregnancy and emphasize the need for further toxicological and epidemiological investigations.

OBJECTIVE: Primary hypothyroidism due to abnormality in the thyroid gland is the most common endocrine disease The recommended starting dose of levothyroxine replacement therapy is 1.6 µg/kg. This dose however is not optimal for every patient and dose adjustments are frequently done. Genetic polymorphisms in the absorption and metabolism pathway of levothyroxine are likely to influence its dose requirements. This study aimed to study the influence of genetic polymorphisms on levothyroxine replacement requirements.
METHODS: This was a cross-sectional study. Participants were recruited through a private nutrition clinic and through announcements distributed in the University of Petra in Amman, Jordan between September 2020 and February 2021. Hypothyroid patients had already been on stable doses of levothyroxine for the previous 3 months. A questionnaire was distributed to collect demographic and clinical information and a blood sample was taken for DNA extraction and clinical biochemistry analysis. rs11249460, rs2235544, rs225014, rs225015, rs3806596, rs11185644, rs4588, rs602662 were analyzed using Applied Biosystems TaqMan™ SNP Genotyping Assays on Rotor-Gene® Q and rs3064744 by direct sequencing. SPSS and Excel were used to perform analysis.
RESULTS: 76 patients were studied. The equation we calculated to find predicted daily dose of levothyroxine (mcg/kg) is 3.22+ (0.348 for CT genotype of rs11185644, 0 for other genotypes) + 0.027*disease duration (years) - 0.014*age (years) - 0.434*T3 (pmol/L) levels+ (0.296 for CC genotype of rs2235544, 0 for other genotypes).
CONCLUSIONS: SNP rs11185644 in RXRA gene and SNP rs2235544 in DIO1 affect dose requirement in hypothyroid patients and if confirmed in larger trials they can be used to individualize thyroxine starting doses.