Tyrosine hydroxylase (TH) catalyzes the first and rate‐limiting step of catecholamine synthesis and its expression is necessary for neurotransmitter specification of all catecholaminergic neurons, while dopamine β‐hydroxylase (DBH) is essential for the noradrenergic phenotype. In the present study, we show that Nurr1, an orphan nuclear receptor critical for dopaminergic (DA) neuron development, directly transactivates the promoter activity of the TH gene in a cell type‐dependent manner, while it does not regulate the DBH promoter. Consistent with these results, only the TH promoter contains multiple sequence motifs homologous to the known Nurr1‐binding motif, NBRE. TH promoter deletional analysis indicates that < 1.0 kb upstream sequences, encompassing three NBRE‐like motifs (i.e. NL1, NL2 and NL3) are mostly responsible for the effects of Nurr1. Among these potential motifs, site‐directed mutational analysis showed that NL1, residing from − 35 to − 28 bp, was most critical for mediating the transactivation by Nurr1. Strikingly, however, both DNase I footprinting and electrophoretic mobility shift assays showed that NL3, but not NL1 or NL2, has high binding affinity to Nurr1. To determine whether the proximity of these motifs may be important for transactivation by Nurr1 in the transient transfection assay, we generated reporter gene constructs in which NL3 is immediately proximal to the TATA box. Indeed, NL3 was more efficient in this position than NL1 or NL2 for mediating the transactivation by Nurr1. Our results suggest that Nurr1 may play a direct role for specification of DA neurotransmitter identity by activating TH gene transcription in a cell context‐dependent manner.

In the process of screening for pancreatic lipase inhibitors, which could be used as an anti-obesity measure, the methanol extract of Dioscorea nipponica Makino powder (DP) appeared to have potent inhibitory activity against porcine pancreatic lipase with an IC50 value of 5-10 microg/ml, where the enzyme activity was assayed by using 4-methylumbelliferyl oleate as a substrate. Further purification of active components present in the herb generated dioscin that belongs to the saponin family. Dioscin and its aglycone, diosgenin, both suppressed the time-dependent increase of blood triacylglycerol level when orally injected with corn oil to mice, suggesting their inhibitory potential against fat absorption. Sprague-Dawley rats fed on a high-fat diet containing 5% Dioscorea nipponica Makino and 40% beef tallow gained significantly less body weight and adipose tissue than control animals fed on a high-fat diet alone during an 8-week experimental period (P<0.05).

Heterozygous mutations of the PHOX2B gene account for a broad variety of disorders of the autonomic nervous system, either isolated or combined, including congenital central hypoventilation syndrome (CCHS), tumours of the sympathetic nervous system and Hirschsprung disease. In CCHS, the prevalent mutation is an expansion of a 20-alanine stretch ranging from +5 to +13 alanines, whereas frameshift and missense mutations are found occasionally. To determine the molecular basis of impaired PHOX2B function, we assayed the transactivation and DNA binding properties of wild-type and mutant PHOX2B proteins. Furthermore, we investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. We found that transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. Such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations. However, additional mechanisms such as toxic gain-of-function may play a role in the pathogenic process.

Alzheimer's disease (AD) is a progressive degenerative neurological condition characterized by cognitive decline, primarily affecting memory and logical thinking, attributed to amyloid-β plaques and tau protein tangles in the brain, leading to neuronal loss and brain atrophy. Neuroinflammation, a hallmark of AD, involves the activation of microglia and astrocytes in response to pathological changes, potentially exacerbating neuronal damage. The gut-brain axis is a bidirectional communication pathway between the gastrointestinal and central nervous systems, crucial for maintaining brain health. Phytochemicals, natural compounds found in plants with antioxidant and anti-inflammatory properties, such as flavonoids, curcumin, resveratrol, and quercetin, have emerged as potential modulators of this axis, suggesting implications for AD prevention. Intake of phytochemicals influences the gut microbial composition and its metabolites, thereby impacting neuroinflammation and oxidative stress in the brain. Consumption of phytochemical-rich foods may promote a healthy gut microbiota, fostering the production of anti-inflammatory and neuroprotective substances. Early dietary incorporation of phytochemicals offers a non-invasive strategy for modulating the gut-brain axis and potentially reducing AD risk or delaying its onset. The exploration of interventions targeting the gut-brain axis through phytochemical intake represents a promising avenue for the development of preventive or therapeutic strategies against AD initiation and progression.