Bile acids (BA) are important physiological molecules not only mediating nutrients absorption and metabolism in peripheral tissues, but exerting neuromodulation effect in the central nerve system (CNS). The catabolism of cholesterol to BA occurs predominantly in the liver by the classical and alternative pathways, or in the brain initiated by the neuronal-specific enzyme CYP46A1 mediated pathway. Circulating BA could cross the blood brain barrier (BBB) and reach the CNS through passive diffusion or BA transporters. Brain BA might trigger direct signal through activating membrane and nucleus receptors or affecting activation of neurotransmitter receptors. Peripheral BA may also provide the indirect signal to the CNS via farnesoid X receptor (FXR) dependent fibroblast growth factor 15/19 (FGF15/19) pathway or takeda G protein coupled receptor 5 (TGR5) dependent glucagon-like peptide-1 (GLP-1) pathway. Under pathological conditions, alterations in BA metabolites have been discovered as potential pathogenic contributors in multiple neurological disorders. Attractively, hydrophilic ursodeoxycholic acid (UDCA), especially tauroursodeoxycholic acid (TUDCA) can exert neuroprotective roles by attenuating neuroinflammation, apoptosis, oxidative or endoplasmic reticulum stress, which provides promising therapeutic effects for treatment of neurological diseases. This review summarizes recent findings highlighting the metabolism, crosstalk between brain and periphery, and neurological functions of BA to elucidate the important role of BA signaling in the brain under both physiological and pathological conditions.

Disturbed sleep is closely associated with an increased risk of metabolic diseases. However, the underlying mechanisms of circadian clock genes linking sleep and lipid profile abnormalities have not been fully elucidated. This study aimed to explore the important role of the circadian clock in regulating impaired cholesterol metabolism at an early stage of sleep deprivation (SD). Sleep disturbance was conducted using an SD instrument. Our results showed that SD increased the serum cholesterol levels. Concentrations of serum leptin and resistin were much lower after SD, but other metabolic hormone concentrations (adiponectin, glucagon, insulin, thyroxine, norepinephrine, and epinephrine) were unchanged before and after SD. Warning signs of cardiovascular diseases [decreased high density lipoprotein (HDL)-cholesterol and increased corticosterone and 8-hydroxyguanosine levels] and hepatic cholestasis (elevated total bile acids and bilirubin levels) were observed after SD. Cholesterol accumulation was also observed in the liver after SD. The expression levels of HMGCR, the critical enzyme for cholesterol synthesis, remained unchanged in the liver. However, the expression levels of liver CYP7A1, the enzyme responsible for the conversion of cholesterol into bile acids, significantly reduced after SD. Furthermore, expression of NR1D1, a circadian oscillator and transcriptional regulator of CYP7A1, strikingly decreased after SD. Moreover, NR1D1 deficiency decreased liver CYP7A1 levels, and SD could exacerbate the reduction of CYP7A1 expression in NR1D1^−/− mouse livers. Additionally, NR1D1 deficiency could further increase serum cholesterol levels under SD. These results suggest that sleep disturbance can induce increased serum cholesterol levels and liver cholesterol accumulation by NR1D1 mediated CYP7A1 inhibition.

One of the health hazards of PM2.5 exposure is to induce pulmonary inflammatory responses. In our previous study, we demonstrated that exposing both the immortalized and primary human bronchial epithelial cells to PM2.5 results in a significant upregulation of VEGF production, a typical signaling event to trigger chronic airway inflammation. Further investigations showed that PM2.5 exposure strongly induces ATR/CHK1/p53 cascade activation, leading to the induction of DRAM1-dependent autophagy to mediate VEGF expression by activating Src/STAT3 pathway. In the current study, we further revealed that TIGAR was another transcriptional target of p53 to trigger autophagy and VEGF upregulation in Beas-2B cells after PM2.5 exposure. Furthermore, LKB1, but not ATR and CHK1, played a critical role in mediating p53/TIGAR/autophagy/VEGF pathway activation also by linking to Src/STAT3 signaling cascade. Therefore, on combination of the previous report, we have identified both ATR/CHK1/p53/DRAM1- and LKB1/p53/TIGAR- dependent autophagy in mediating VEGF production in the bronchial epithelial cells under PM2.5 exposure. Moreover, the in vivo study further confirmed VEGF induction in the airway potentially contributed to the inflammatory responses in the pulmonary vascular endothelium of PM2.5-treated rats. Therefore, blocking VEGF expression or autophagy induction might be the valuable strategies to alleviating PM2.5-induced respiratory injuries.

Our previous studies revealed that GADD45α is a liable protein, which undergoes MDM2-dependent constitutive ubiquitination and degradation in resting HepG2 hepatoma cells. Arsenite exposure induces ribosomal stress responses mediated by the ribosomal protein S7, which can block MDM2 activity and result in GADD45α accumulation and cell apoptosis. In the present study, we found that one of the catalytic subunits of IκB kinase (IKK), IKKβ, exerted a novel IKKα- and NF-κB-independent function in stabilizing MDM2 and therefore contributed to ubiquitination-dependent degradation of GADD45α in resting HepG2 cells. Arsenite stimulation induced transactivation of p53, which formed a complex with its downstream target, Ets-1, and then synergistically repressed IKKβ transcription, reduced MDM2 stability, and ultimately removed the inhibitory effect of MDM2 on GADD45α induction. In addition, DAPK1 functioned as an upstream protein kinase triggering p53/Ets-1-dependent IKKβ and MDM2 reduction and GADD45α accumulation, thus promoting apoptosis in HepG2 cells. Subsequent studies further revealed that the activation of the DAPK1/p53/Ets-1/IKKβ/MDM2/GADD45α cascade was a common signaling event in mediating apoptosis of diverse cancer cells induced by arsenite and other tumor therapeutic agents. Therefore, we conclude that data in the current study have revealed a novel role for IKKβ in negatively regulating GADD45α protein stability and the contribution of p53-dependent IKKβ reduction to mediating cancer cell apoptosis.

Exposure to ultraviolet B (UVB) has been demonstrated to induce DNA damage as well as angiogenesis-related photo-damages, which are implicated in a variety of medical problems, including sunburn, photo-aging and skin cancers. However, the molecular mechanism related to UVB-induced photo-injuries remained fully elucidated. Here we revealed that one of the catalytic subunits of the IKK complex, IKKα, played a critical role in mediating UVB-induced apoptotic responses in two kinds of UVB sensitive cells, human keratinocyte (HaCat) and mouse embryonic fibroblasts (MEFs). This function of IKKα was unrelated to NF-κB activity, but was delivered by inducing phosphorylation and acetylation of p53 and upregulating the expression of the pro-apoptotic p53 target gene, PERP. Although IKKα kinase activity was required for mediating post-translational modifications and transactivation of 53 and PERP induction, IKKα did not show direct binding ability toward p53. Instead, IKKα could interact with CHK1, the protein kinase leading to p53 phosphorylation, and trigger CHK1 activation and CHK1/p53 complex formation. At the same time, IKKα could also interact with p300 and CBP, the acetyltransferases responsible for p53 acetylation, and trigger p300/CBP activation and p300/p53 or CBP/p53 complex formation under UVB exposure. Taken together, we have identified a novel NF-κB-independent role of IKKα in mediating UVB-induced apoptosis by regulating p53 pathway activation. Targeting IKKα/p53/PERP pathway might be helpful to prevent skin photo-damages induced by sunlight.