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The use of Bisphenol A (BPA) and its analogs in industries, as well as the products made from them, is becoming a significant concern for human health. Scientific studies have revealed that BPA functions as an endocrine disruptor. While some analogs of BPA (bisphenols) have been used for a longer time, it was later discovered that they are toxic, similar to BPA. Their widespread use ensures their presence in the environment, and thus, everyone is exposed to them. Scientific research has shown that BPA interacts with estrogen-related receptor gamma (ERRγ), affecting its normal function. ERRγ is involved in biological processes including energy metabolism and mitochondrial function. Therefore, continuous exposure to bisphenols increases the risk of various diseases. In our previous study, we observed that some analogs of BPA had a higher binding affinity to ERRγ compared to BPA itself and analyzed the amino acid residues involved in this interaction. We hypothesized that by antagonizing the interaction between bisphenols and ERRγ, we could neutralize their toxic effects. Taking into account the health benefits of millets and their toxin removal properties, virtual screening of millet-derived compounds was conducted along with prediction of their ADMET profiles. Top five candidates were prioritized for Density Functional Theory (DFT) calculations and further analyses. Long-term molecular dynamics simulation (1 µs) were utilized to evaluate their binding, stability, and antagonizing abilities. Furthermore, reevaluation of their binding energy was conducted using the MM-PBSA method. This study reports millet-derived compounds, namely, Tricin 7-rutinoside, Tricin 7-glucoside, Glucotricin, Kaempferol, and Setarin. These compounds are predicted to be potent competitive inhibitors that can antagonize the interactions between bisphenols and ERRγ. These compounds could potentially assist in the development of future therapeutics. They may also be considered for use as food supplements, although further investigations, including wet-lab experiments and clinical studies, are needed.

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Renal tubular injury is considered as the main pathological feature of acute kidney injury (AKI), and mitochondrial dysfunction in renal tubular cells is implicated in the pathogenesis of AKI. The estrogen-related receptor γ (ERRγ) is a member of orphan nuclear receptors which plays a regulatory role in mitochondrial biosynthesis, energy metabolism and many metabolic pathways. Online datasets showed a dominant expression of ERRγ in renal tubules, but the role of ERRγ in AKI is still unknown. In the present study, we investigated the role of ERRγ in the pathogenesis of AKI and the therapeutic efficacy of ERRγ agonist DY131 in several murine models of AKI. ERRγ expression was reduced in kidneys of AKI patients and AKI murine models along with a negative correlation to the severity of AKI. Consistently, silencing ERRγ in vitro enhanced cisplatin-induced tubular cells apoptosis, while ERRγ overexpression in vivo utilizing hydrodynamic-based tail vein plasmid delivery approach alleviated cisplatin-induced AKI. ERRγ agonist DY131 could enhance the transcriptional activity of ERRγ and ameliorate AKI in various murine models. Moreover, DY131 attenuated the mitochondrial dysfunction of renal tubular cells and metabolic disorders of kidneys in AKI, and promoted the expression of the mitochondrial transcriptional factor A (TFAM). Further investigation showed that TFAM could be a target gene of ERRγ and DY131 might ameliorate AKI by enhancing ERRγ-mediated TFAM expression protecting mitochondria. These findings highlighted the protective effect of DY131 on AKI, thus providing a promising therapeutic strategy for AKI., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Macrophage stimulating protein (MSP) is a multifunctional serum protein produced in the liver, belonging to the plasminogen-related kringle protein family. It exerts diverse biological functions by activating a transmembrane receptor protein-tyrosine kinase known as RON in humans and SKT in mice. MSP plays a pivotal role in innate immunity and is involved in various activities such as cell survival, migration, and phagocytosis. Elucidating the regulatory mechanisms governing MSP gene expression is of great importance. In this study, we comprehensively elucidate the molecular mechanism underlying hepatic MSP gene expression in response to alcoholism. Exposure to ethanol specifically upregulated the expression of ERRγ and MSP in the liver, while not in other organs. Liver-specific knockout of the cannabinoid receptor type 1 (CB1R), an upstream regulator of ERRγ, inhibited the alcohol-induced upregulation of MSP expression. Overexpression of ERRγ alone was sufficient to enhance MSP expression in hepatic cell lines and in mice. Conversely, knockdown of ERRγ in cell lines or liver-specific knockout of ERRγ in mice reversed ethanol-induced MSP gene expression. Promoter studies revealed the direct binding of ERRγ to the MSP gene promoter at the ERR response element (ERRE), resulting in the positive regulation of MSP gene expression in response to alcohol. This finding was further supported by ERRE-mutated MSP-luciferase reporter assays. Notably, treatment with GSK5182, an ERRγ-specific inverse agonist, significantly suppressed alcohol-induced hepatic MSP expression. Collectively, we exposed a novel mechanistic understanding of how alcohol-induced ERRγ controls the transcriptional regulation of MSP gene expression in the liver. • ERRγ is a novel transcriptional regulator of MSP. • ERRγ binds to the MSP gene promoter, thereby enhancing its transcription. • The loss of ERRγ or inhibition of ERRγ transactivation prevents alcohol-induced MSP gene expression. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a very important chemical from the commercial perspective. Many useful products are made from it, so its production is increasing day by day. It is widely known that Bisphenol A (BPA) and its analogs are present in the environment and that they enter our body through various routes on a daily basis as we use things made of this chemical in our daily lives. BPA has already been reported to be an endocrine disruptor. Studies have shown that BPA binds strongly to the human estrogen-related receptor gamma (ERRγ) and is an important target of it. This study seeks to understand how it interacts with ERRγ. Molecular docking of BPA and its analogs with ERRγ was performed, and estradiol was taken as a reference. Then, physico-chemical and toxicological analysis of BPA compounds was performed. Subsequently, the dynamic behavior of ERRγ and ERRγ-BPA compound complexes was studied by molecular dynamics simulations over 500 ns, and using this simulated data, their binding energies were again calculated using the MM-PBSA method. We observed that the binding affinity of BPA and its analogs was much higher than that of estradiol, and apart from being toxic, they can be easily absorbed in our body as their physicochemical properties are similar to those of oral medicines. Therefore, this study facilitates the understanding of the structure–activity relationship of ERRγ and BPA compounds and provides information about the key amino acid residues of ERRγ that interact with BPA compounds, which can be helpful to design competitive inhibitors so that we can interrupt the interaction of BPA with ERRγ. In addition, it provides information on BPA and its analogs and will also be helpful in developing new therapeutics. [Display omitted] • The study comprehended interaction of BPA and its analogs with ERRγ. • The physicochemical and toxicity properties of BPA and its analogs were analyzed. • The key amino acid residues contributing to the interaction have been identified. • These amino acid residues will help in antagonizing BPA-ERRγ interactions. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)