Human platelet mitochondria improve the mitochondrial and cardiac function of donor heart.

Mitochondria transplantation emerges as an effective therapeutic strategy for ischemic-related diseases but the roles in the donor hearts for transplant remain unidentified. Here, we investigated whether the preservation of the donor heart with human platelet-derived mitochondria (pl-MT) could improve mitochondrial and cardiac function. Incubation with pl-MT resulted in the internalization of pl-MT and the enhancement of ATP production in primary cardiomyocytes. In addition, incubation of rat hearts with pl-MT ex vivo for 9 h clearly demonstrated pl-MT transfusion into the myocardium. Mitochondria isolated from the hearts incubated with pl-MT showed increased mitochondrial membrane potential and greater ATP synthase activity and citrate synthase activity. Importantly, the production of reactive oxygen species from cardiac mitochondria was not different with and without pl-MT incubation. Functionally, the heartbeat and the volume of coronary circulation perfusate were significantly increased in the Langendorff perfusion system and the viability of cardiomyocytes was increased from pl-MT hearts.Taken together, these results suggest that incubation with Pl-MT improves mitochondrial activity and maintains the cardiac function of rat hearts with prolonged preservation time. The study provides the proof of principle for pl-MT application as an enhancer of the donor heart.

PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function.

The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function.

Platelet-derived mitochondria transfer facilitates wound-closure by modulating ROS levels in dermal fibroblasts.

Platelets are known to improve the wound-repair capacity of mesenchymal stem cells (MSCs) by transferring mitochondria intercellularly. This study aimed to investigate whether direct transfer of mitochondria (pl-MT) isolated from platelets could enhance wound healing in vitro using a cell-based model. Wound repairs were assessed by 2D gap closure experiment in wound scratch assay using human dermal fibroblasts (hDFs). Results demonstrated that pl-MT were successfully internalized into hDFs. It increased cell proliferation and promoted the closure of wound gap. Importantly, pl-MT suppressed both intracellular and mitochondrial ROS production induced by hydrogen peroxide, cisplatin, and TGF-ß in hDFs. Taken together, these results suggest that pl-MT transfer might be used as a potential therapeutic strategy for wound repair.

What is the context? During the wound healing process, abnormal regulation of ROS and inflammation delays the healing process, resulting in chronic non-healing wounds.Mitochondria are key organelles responsible for the ROS generation. Mitochondrial dysfunction has been implicated in delayed wound repair.Mitochondria transfer, which utilizes intact mitochondria isolated from healthy cells to recover from disease, has been applied in various clinical studies, but additional evidence is needed to apply it to wound healing.What is new? In this study, we chose platelets as a cell source for mitochondrial transfer. We isolated the functional mitochondria from platelets and applied them to wound healing.What is the impact? This study provides evidence that platelet-derived mitochondria (pl-MT) improve the wound healing progress by increasing the viability of dermal fibroblasts and suppressing intracellular and mitochondrial ROS production.Platelets have also been demonstrated to be a suitable cell source for mitochondrial transfer.

Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage.

Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MTGFP). When MTGFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MTGFP injected intravenously into normal mice, MTGFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites.

Effect of cysteine-free human fibroblast growth factor-5s mutant (FGF5sC93S) on hair growth.

Treatment for hair loss is largely limited, and any beneficial effects are often transient. Based on the critical role of the FGF5 isoform, FGF5s, in the hair growth cycle, it may be a good therapeutic candidate for the prevention of hair loss, as well as the promotion of hair growth. To investigate its potential use for hair growth, a mutant form of the FGF5s protein (FGF5sC93S) was generated, expressed, and purified. The FGF5sC93S mutant was able to antagonize FGF5-induced mitogenic activity, which normally triggers the conversion of hair follicles from the anagen phase to the catagen phase. In addition, the FGF5sC93S mutant efficiently suppressed gene expression induced by FGF5 both human outer root sheath (hORS) and human dermal papilla (hDP) cells. Administration of FGF5sC93S proteins onto the scalps of human subjects significantly increased the total number of hairs at 24 weeks. Together, our data demonstrate that a mutant form of the FGF5s protein could be used as a potential hair promoting agent.

Efficient Generation of Dopamine Neurons by Synthetic Transcription Factor mRNAs.

Generation of functional dopamine (DA) neurons is an essential step for the development of effective cell therapy for Parkinson's disease (PD). The generation of DA neurons can be accomplished by overexpression of DA-inducible genes using virus- or DNA-based gene delivery methods. However, these gene delivery methods often cause chromosomal anomalies. In contrast, mRNA-based gene delivery avoids this problem and therefore is considered safe to use in the development of cell-based therapy. Thus, we used mRNA-based gene delivery method to generate safe DA neurons. In this study, we generated transformation-free DA neurons by transfection of mRNA encoding DA-inducible genes Nurr1 and FoxA2. The delivery of mRNA encoding dopaminergic fate inducing genes proved sufficient to induce naive rat forebrain precursor cells to differentiate into neurons exhibiting the biochemical, electrophysiological, and functional properties of DA neurons in vitro. Additionally, the generation efficiency of DA neurons was improved by the addition of small molecules, db-cAMP, and the adjustment of transfection timing. The successful generation of DA neurons using an mRNA-based method offers the possibility of developing clinical-grade cell sources for neuronal cell replacement treatment for PD.

Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease.

Parkinson's disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1-2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino-7-chloroquinoline, suggesting a critical structure-activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through physical interaction with its ligand binding domain (LBD). Remarkably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compounds significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.

Purification of functional reprogramming factors in mammalian cell using FLAG -Tag.

Induced pluripotent stem cells (iPSCs) technology is a method for generating pluripotent stem cells in vitro from fully differentiated cells such as fibroblast cells. The potential applications of iPSC technology in cell therapy and disease modeling could influence current medical practices. Despite current advances in iPSC technology, many patient-derived reprogrammed cells are not suitable for clinical trial because most protocols rely on virus-based techniques, which pose the risk of integration of the viral genome into the chromosomes. Therefore, non-viral methods such as mRNA and protein-based reprogramming are promising alternatives when generating clinically safe iPSCs. In a previous study, we generated human iPSCs using cell extracts with cell penetration peptide (CPP) for the delivery of reprogramming proteins [Kim et al. Cell Stem Cells, 2009]. In here, we show that the expression of reprogramming factors in mammalian cells and subsequent purification of these factors by FLAG-Tag could reprogram fibroblasts into iPSCs.

Daphnane Diterpenes from Daphne genkwa Activate Nurr1 and Have a Neuroprotective Effect in an Animal Model of Parkinson's Disease.

Nurr1 is an orphan nuclear receptor that is essential for the differentiation and maintenance of dopaminergic neurons in the brain, and it is a therapeutic target for Parkinson's disease (PD). During the screening for Nurr1 activators from natural sources using cell-based assay systems, a methanol extract of the combined stems and roots of Daphne genkwa was found to activate the transcriptional function of Nurr1 at a concentration of 3 µg/mL. The active components were isolated and identified as genkwanine N (1) and yuanhuacin (2). Both compounds 1 and 2 significantly enhanced the function of Nurr1 at 0.3 µM. Nurr1-specific siRNA abolished the activity of 1 and 2, strongly suggesting that transcriptional activation by 1 and 2 occurred through the modulation of Nurr1 function. Additionally, treatment with 1 and 2 inhibited 6-hydroxydopamine (6-OHDA)-induced neuronal cell death and lipopolysaccharide (LPS)-induced neuroinflammation. Moreover, in a 6-OHDA-lesioned rat model of PD, intraperitoneal administration of 2 (0.5 mg/kg/day) for 2 weeks significantly improved behavioral deficits and reduced tyrosine hydroxylase (TH)-positive dopaminergic neuron death induced by 6-OHDA injection and had a beneficial effect on the inflammatory response in the brain. Accordingly, compounds 1 and 2, the first reported Nurr1 activators of natural origin, are potential lead compounds for the treatment of PD.

Correlation between orphan nuclear receptor Nurr1 expression and amyloid deposition in 5XFAD mice, an animal model of Alzheimer's disease.

The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. As Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer's disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aß accumulation, that is, the subiculum and the frontal cortex, in the 5XFAD mouse and that Nurr1 is highly co-expressed with Aß at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5XFAD mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression. Using our newly developed Nurr1-selective antibody, we show that Nurr1 protein is prominently expressed in brain areas accumulating amyloid-beta (Aß) in the transgenic mouse model of Alzheimer's disease (AD) and that Nurr1 is highly co-expressed with Aß at early stages (upper panel). Furthermore, in the AD brain the number of Nurr1-expressing cells significantly declines in an age-dependent manner concomitant with increased Aß accumulation (lower diagram) highlighting a possible Nurr1 involvement in AD pathology.

Transcription elongation factor Tcea3 regulates the pluripotent differentiation potential of mouse embryonic stem cells via the Lefty1-Nodal-Smad2 pathway.

Self-renewal and pluripotency are hallmark properties of pluripotent stem cells, including embryonic stem cells (ESCs) and iPS cells. Previous studies revealed the ESC-specific core transcription circuitry and showed that these core factors (e.g., Oct3/4, Sox2, and Nanog) regulate not only self-renewal but also pluripotent differentiation. However, it remains elusive how these two cell states are regulated and balanced during in vitro replication and differentiation. Here, we report that the transcription elongation factor Tcea3 is highly enriched in mouse ESCs (mESCs) and plays important roles in regulating the differentiation. Strikingly, altering Tcea3 expression in mESCs did not affect self-renewal under nondifferentiating condition; however, upon exposure to differentiating cues, its overexpression impaired in vitro differentiation capacity, and its knockdown biased differentiation toward mesodermal and endodermal fates. Furthermore, we identified Lefty1 as a downstream target of Tcea3 and showed that the Tcea3-Lefty1-Nodal-Smad2 pathway is an innate program critically regulating cell fate choices between self-replication and differentiation commitment. Together, we propose that Tcea3 critically regulates pluripotent differentiation of mESCs as a molecular rheostat of Nodal-Smad2/3 signaling.

Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.

Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 â€‹mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD.

Primary astrocytic mitochondrial transplantation ameliorates ischemic stroke.

Mitochondria are important organelles that regulate adenosine triphosphate production, intracellular calcium buffering, cell survival, and apoptosis. They play therapeutic roles in injured cells via transcellular transfer through extracellular vesicles, gap junctions, and tunneling nanotubes. Astrocytes can secrete numerous factors known to promote neuronal survival, synaptic formation, and plasticity. Recent studies have demonstrated that astrocytes can transfer mitochondria to damaged neurons to enhance their viability and recovery. In this study, we observed that treatment with mitochondria isolated from rat primary astrocytes enhanced cell viability and ameliorated hydrogen peroxide-damaged neurons. Interestingly, isolated astrocytic mitochondria increased the number of cells under damaged neuronal conditions, but not under normal conditions, although the mitochondrial transfer efficiency did not differ between the two conditions. This effect was also observed after transplanting astrocytic mitochondria in a rat middle cerebral artery occlusion model. These findings suggest that mitochondria transfer therapy can be used to treat acute ischemic stroke and other diseases. [BMB Reports 2023; 56(2): 90-95].

P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration.

BACKGROUND: Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain. METHODS: We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro. FINDINGS: The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells. INTERPRETATION: Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis. FUNDING: This study was supported by a grant from the National Research Foundation of Korea.

Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase.

Human norepinephrine (NE) deficiency (or dopamine ß-hydroxylase (DBH) deficiency) is a rare congenital disorder of primary autonomic failure, in which neurotransmitters NE and epinephrine are undetectable. Although potential pathogenic mutations, such as a common splice donor site mutation (IVS1+2T→C) and various missense mutations, in NE deficiency patients were identified, molecular mechanisms underlying this disease remain unknown. Here, we show that the IVS1+2T→C mutation results in a non-detectable level of DBH protein production and that all three missense mutations tested lead to the DBH protein being trapped in the endoplasmic reticulum (ER). Supporting the view that mutant DBH induces an ER stress response, exogenous expression of mutant DBH dramatically induced expression of BiP, a master ER chaperone. Furthermore, we found that a pharmacological chaperone, glycerol, significantly rescued defective trafficking of mutant DBH proteins. Taken together, we propose that NE deficiency is caused by the combined abnormal processing of DBH mRNA and defective protein trafficking and that this disease could be treated by a pharmacological chaperone(s).

Lmx1a regulates dopamine transporter gene expression during ES cell differentiation and mouse embryonic development.

Midbrain dopaminergic neurons are implicated in various neurological and psychiatric diseases as well as drug addiction. Thus, the study of their generation and maintenance is pivotal to further our understanding of these disease-underlying mechanisms and development of novel therapeutics. Here, using an embryonic stem cell in vitro differentiation system and mutant dreher mouse, we showed that Lmx1a, an early regulator of midbrain dopamine neural progenitor phenotype specification, is also involved in the regulation of midbrain dopaminergic maturation by regulating gene expression of the dopamine transporter. Forced expression of Lmx1a induced dopamine transporter expression precociously in immature dopaminergic neurons, accompanied by significant increase in specific dopamine uptake. Lmx1a binds to well-conserved sequences in the dopamine transporter promoter region, and this binding sequence directs Lmx1a-dependent activation of reporter gene expression. Furthermore, during mouse embryonic development, dopamine transporter was more severely affected by Lmx1a mutation compared to other dopamine markers such as tyrosine hydroxylase and dopa decarboxylase, again supporting the role of Lmx1a in midbrain dopaminergic maturation in vivo. Thus, this study demonstrates that dopamine transporter is a direct target of Lmx1a and emphasizes a novel role of Lmx1a as one of regulators of mature midbrain dopaminergic neurotransmitter phenotypes.

Erratum to: Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.

[Erratum to: BMB Reports 2022; 55(3): 136-141, PMID: 34488927, PMCID: PMC8972135] The BMB Reports would like to correct in BMB Rep. 55(3):136-141, titled "Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway". This research was supported by NRF-2016R1A2B4007640 grant (to C-H Kim). Since grant number is incorrect, this information has now been corrected as follows: We would like to thank various Paean Biotechnology Inc. members who participated in the project. This work was supported by NRF-2018M3A9B5023055 grant (to C-H Kim). The authors apologize for any inconvenience or confusion that may be caused by this error. The ACKNOWLEDGEMENTS of Original PDF version have been corrected.

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.

Inflammation is one of the body's natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response. Therefore, treating inflammatory diseases by recovering mitochondrial function may be a potential therapeutic approach. Recently, mitochondrial transplantation has been proven to be beneficial in hyperinflammatory animal models. However, it is unclear how mitochondrial transplantation attenuates inflammatory responses induced by external stimuli. Here, we isolated mitochondria from umbilical cord-derived mesenchymal stem cells, referred as to PN-101. We found that PN-101 could significantly reduce LPS-induced mortality in mice. In addition, in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages, PN-101 attenuated LPS-induced increase production of pro-inflammatory cytokines. Furthermore, the anti-inflammatory effect of PN-101 was mediated by blockade of phosphorylation, nuclear translocation, and trans-activity of NFκB. Taken together, our results demonstrate that PN-101 has therapeutic potential to attenuate pathological inflammatory responses. [BMB Reports 2022; 55(3): 136-141].

LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming.

Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling. Mitochondria were also reprogrammed into healthy/fused mitochondria with improved functional capacity. The reprogramming allows SSCs to undergo cell proliferation more extensively with low levels of oxidative and mitochondrial stress. When the PDK1-mediated uncoupling was untethered upon differentiation, LIN28A-SSCs differentiated more efficiently with an increase of OxPhos by utilizing the reprogrammed mitochondria. This study provides mechanistic and practical approaches of utilizing LIN28A and metabolic reprogramming in order to improve SSCs utility in regenerative medicine.

Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1.

Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.