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Gene & Protein in Disease GPER1 in brain and heart diseases

In addition, the impact of nutrition, particularly polyphenol results in the secretion of inflammatory modulators,
metabolites, as well as environmental factors has been elimination of the burden, and the end of the inflammatory
widely discussed in terms of neurodegenerative 41-43 and process. Nevertheless, in several cases, clearance of
cardiovascular diseases. Moreover, the binding of the inflammatory region is not sufficient and chronic
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isoflavones to GPER1 is considered highly probable, as neuroinflammation occurs. Although several studies
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reported in several in silico molecular docking studies and have already demonstrated a neuroprotective role by
in vitro studies. As a central link between environmental the activation of GPER1 in animal models, 53-55 Bai et al.
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factors and genetics, epigenetic modifications of GPER1 showed that GPER1 is directly involved in the regulation of
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expression have recently been analyzed in the context of neuroinflammation by modulating microglial activation,
different diseases. Studies have shown that GPER1 thereby exerting cognitive-improving effects in rats. In
expression profiles are driven by sex-specific epigenetics in particular, not only reduced microglial activation but
a diabetic mouse model or drive cell apoptosis in SKBR3 also suppression of NOD-, leucine-rich repeat, and pyrin
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and MDA-MB-231 breast cancer cells through the domain-containing protein 3 (NLRP3)-inflammasome
epigenetic downregulation of GPER1 expression. activation and interleukin (IL)-1β signaling, as well
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Furthermore, endocrine-disrupting chemicals, such as as upregulation of the endogenous anti-inflammatory
ethinylestradiol, alter the DNA methylation of several factor IL-1 receptor antagonist, was demonstrated in
genes, with GPER1 being a gene with the highest number rat neurons in the hippocampal CA1 region after global
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of alterations in its methylation patterns across three cerebral ischemia. Similar results were demonstrated by
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generations of the model organism Menidia beryllina. In Pan et al., who reported reduced neuronal apoptosis and
a prenatal-exposure mouse model, benzophenone-3 favored microglial polarization to the anti-inflammatory
induced apoptosis and neurotoxicity, accompanied with an type M2 through the intravenous injection of G-1 into male
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altered methylation status of apoptosis-related and ER rats suffering from traumatic brain injury. Consistent
genes, including hypomethylation of GPER1. In addition, a with this, Zhang et al. revealed that G-1-mediated
decrease in the mRNA and protein expression levels of activation of GPER1 on microglia in ovariectomized
ERα and ERβ and additional upregulation of GPER1 (OVX) female mice after middle cerebral artery occlusion
expression were detected. Recently, epigenetic modulation inhibited toll-like receptor 4 (TLR4)-mediated microglial
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has been explored in Alzheimer’s disease (AD) and inflammation and improved neurological deficits as well
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Parkinson’s disease (PD), wherein resveratrol (grapes), as alleviated neuronal injuries. This GPER1-associated
curcumin (turmeric), and epigallocatechin gallate (EGCG; neuroprotective mechanism was also reported by Peng
green tea) exhibited their neuroprotective ability by et al., who depicted a neural stem cell-derived exosome-
modifying DNA methylation patterns, histone acetylation, mediated transport of zinc-finger-enhancer-binding
and non-coding RNA expression. Nevertheless, in the protein 1 to microglia promoting the expression of GPER1
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context of neurological or cardiovascular diseases, there is and reducing the activation of the TLR4/nuclear factor
a lack of information on the direct relationship between kappa-light-chain-enhancer of activated B-cells (NF-κB)
epigenetic modifications that result in GPER1 alterations. pathway and neuroinflammation. However, not only
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In this review, we have provided bundled information on microglia but also astrocytes were shown to be regulated
GPER1 and its key role in sex-specific differences in by GPER1 activation in the context of neuroprotection.
cardiovascular and neurological diseases, based on state- For instance, Wang et al. demonstrated that G-1-mediated
of-the-art research that provided a deep insight into the neuroprotection in mice after middle cerebral artery
role of GPER1 in several pathways and receptor interactions occlusion is completely blocked in GPER1-knockout (KO)
in both in vitro and in vivo models. mice (no statement on sex) and that GPER1 activation led
to reduced inflammatory cytokine release and restoration
2. GPER1 and its role in neurological of autophagy imbalance in glutamate-exposed cultured
diseases murine astrocytes. This anti-inflammatory effect of
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GPER1 activation in astrocytes was also reported by
2.1. Neuroinflammation, learning, and memory Yuan et al., who demonstrated that silencing GPER1
Neuroinflammation is not only an obvious link between inhibited the protective effect of insulin-like growth factor
several neurodegenerative diseases, such as AD, PD, and 1 (IGF-1) on 1-methyl-4-phenylpyridinium-induced
Huntington’s disease but also a potentially crucial player inflammatory responses both in vitro and in vivo in male
in the pathophysiology of these diseases. In general, mice. Finally, in the context of the gut–brain axis, Yin
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neuroinflammation acts as an inherent protective et al. showed an ameliorative effect of dietary tryptophan
mechanism in the CNS, where glial cells react to injury on neurodegeneration and inflammation in aging male
and disease by recognizing specific patterns, which mice accompanied with an increase in the expression

Volume 4 Issue 1 (2025) 3 doi: 10.36922/gpd.4632