Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage

Liu, Han‐Wei; Gong, Li-Na; Lai, Ke; Yu, Xiafei; Liu, Zhen-Qi; Li, Mingxian; Yin, Xuedong; Liang, Min; Shi, Hao-Song; Jiang, Linhua; Yang, Wei; Shi, Haibo; Wang, Lu-Yang; Yin, Shankai

doi:10.1016/j.neuron.2023.02.022

Cited by 15 publications

(14 citation statements)

References 83 publications

(102 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, this classification did not take the gender difference and pathological states into account. A recent study suggests that ischemic insults triggers the release of endogenous bilirubin from injured cells, which activates the transient receptor potential melastatin 2 (TRPM2) channels and aggravates Ca 2+ -dependent brain injury ( 28 ). This vicious cycle of ischemic injury might partly contribute to the transformation of bilirubin from benefit to toxicity in ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Higher baseline serum bilirubin levels are associated with increased risk of early neurological deterioration in women with acute ischemic stroke

Sun,

Weng,

Cheng

et al. 2024

Front. Neurol.

View full text Add to dashboard Cite

Background and objectivesEarly neurological deterioration (END) occurs in up to one-third of patients with acute ischemic stroke (AIS) and associated with poor outcome. The role of serum bilirubin in END remains controversial. This study aims to investigate the association of total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) with END.MethodsThis study was a cross-sectional retrospective study with 344 AIS patients enrolled. We retrospectively reviewed consecutive AIS patients with END through a medical record retrieval system and enrolled patients as control randomly from the AIS patients without END at the same period. The bilirubin levels were compared between the END group and No END group. The correlations of bilirubin with END were assessed according to the bilirubin tertiles on the cohort of different genders.ResultsIn women, as the bilirubin level increased, the occurrence of END showed an increasing trend. The linear association was significant based on the tertiles of all bilirubin types (TBIL p = 0.003; DBIL p = 0.025; IBIL p = 0.025), while in men no similar trend was observed. After adjustment for confounders, higher TBIL (p for trend 0.009) and DBIL (p for trend 0.033) levels were associated with increased risk of END in women. The adjusted OR for T3 relative to T1 was 5.240 (95% CI 1.496–18.347) in TBIL and 3.549 (95% CI 1.089–11.566) in DBIL. Multivariate logistic regression showed that DBIL was independently associated with END in women (OR 1.717, 95% CI 1.106–2.666). The study also found that DBIL was superior to TBIL and IBIL in prediction of END occurrence in women, with greater predictive value.DiscussionThere were gender differences in the relationship between bilirubin and END, and DBIL level was positively associated with END occurrence in women, not in men. DBIL had greater incremental predictive value for END than TBIL and IBIL.

show abstract

Section: Discussionmentioning

confidence: 99%

Higher baseline serum bilirubin levels are associated with increased risk of early neurological deterioration in women with acute ischemic stroke

Sun,

Weng,

Cheng

et al. 2024

Front. Neurol.

View full text Add to dashboard Cite

show abstract

“…For multiple fluorescence immunohistochemistry, Liu et al. can be referred to ( 26 ), and a four-color multiple fluorescence immunohistochemistry staining kit (Absin, Shanghai, China) was used. Briefly, the slices were processed for heat-mediated antigen retrieval by using citric acid buffer.…”

Section: Methodsmentioning

confidence: 99%

The expression of CTLA-4 in hepatic alveolar echinococcosis patients and blocking CTLA-4 to reverse T cell exhaustion in Echinococcus multilocularis-infected mice

Yang,

Wuren,

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Alveolar echinococcosis (AE) is a zoonotic parasitic disease caused by the infection of Echinococcus multilocularis (E. multilocularis) larvae. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) produces inhibitory signals and induces T cell exhaustion, thereby inhibiting the parasiticidal efficacy of the liver immune system. Therefore, the purpose of this study is to explore how T-cell exhaustion contributes to AE and whether blocking CTLA-4 could reverse T cell exhaustion. Here we discovered that the expression of CTLA-4 was increased in the infiltrating margin around the lesion of the liver from AE patients by using western blot and immunohistochemistry assay. Multiple fluorescence immunohistochemistry identified that CTLA-4 and CD4/CD8 molecules were co-localized. For in vitro experiments, it was found that the sustained stimulation of E. multilocularis antigen could induce T cell exhaustion, blocking CTLA-4-reversed T cell exhaustion. For in vivo experiments, the expression of CTLA-4 was increased in the liver of E. multilocularis-infected mice, and the CTLA-4 and CD4/CD8 molecules were co-localized. Flow cytometry analysis demonstrated that the percentages of both CD4+ T cells and CD8+ T cells in the liver and peripheral blood were significantly increased and induced T exhaustion. When the mice were treated with anti-CTLA-4 antibodies, the number and weight of the lesions decreased significantly. Meanwhile, the flow cytometry results suggested that blocking CTLA-4 could effectively reverse T cell exhaustion and reactivate immune function. Our work reveals that blocking CTLA-4 could effectively reverse the T cell exhaustion caused by E. multilocularis and could be used as a novel target for the treatment of AE.

show abstract

“…Current studies also show that bilirubin can decrease adiposity and prevent metabolic and cardiovascular diseases [25]. Bilirubin can act as an agonist activate the (melastatinlike transient receptor potential 2) TRPM2 channel to exacerbate neurotoxicity [26].The structure of bilirubin was presented in Figure 1b. The combination of substances can be achieved in a variety of ways such as self-assembly [27,28], co-precipitation [29,30] and immobilization [31,32].…”

Section: Introductionmentioning

confidence: 99%

The Impact of Bilirubin on 7α- and 7β- Hydroxysteroid Dehydrogenases: Spectra and Docking Analysis

Ji¹,

Chen²,

Zhu³

et al. 2023

Preprint

View full text Add to dashboard Cite

7α- and 7β-hydroxysteroid dehydrogenases (HSDH) are a pair of enzymes that can catalyze the isomerization of hydroxyl group at site 7 of bile acids. In previous study, we found that the activities of 7α- and 7β-HSDH can be inhibited by bilirubin. In order to clarify the impact, the effects of bilirubin on enzymes were studied by kinetics, spectrum and docking analysis. Relative activity of 7α-HSDH remained less than 40 % under 1 mM bilirubin, for 7β-HSDH, only 18 % activity left at the same condition. Using taurochenodeoxycholic acid (TCDCA) as substrate, the Km of 7α-HSDH was up to 0.63 mM from 0.24 mM after binding with bilirubin, the Km of 7β-HSDH rose from 1.14 mM to 1.87 mM for the catalysis of tauroursodeoxycholic acid (TUDCA). The affinity of 7α- and 7β-HSDH to substrate decreased with the effect of bilirubin. The binding of bilirubin with 7α- or 7β-HSDH were analyzed by UV–Vis spectra, Fluorescence spectra and Circular dichroism (CD) spectra. The results reflected that bilirubin caused a slight change in the secondary structure of 7α- or 7β-HSDH, and the changes were correlated with the ratio of bilirubin to enzyme. 10 candidate molecular docking results were presented to reflect the binding of bilirubin with 7α- or 7β-HSDH and to explore the inhibition mechanism. This research not only provides the more in-depth understanding of 7α- and 7β-HSDH, but also reminds us to avoid the inhibition of bilirubin on hydroxysteroid dehydrogenases.

show abstract

Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage

Cited by 15 publications

References 83 publications

Higher baseline serum bilirubin levels are associated with increased risk of early neurological deterioration in women with acute ischemic stroke

Higher baseline serum bilirubin levels are associated with increased risk of early neurological deterioration in women with acute ischemic stroke

The expression of CTLA-4 in hepatic alveolar echinococcosis patients and blocking CTLA-4 to reverse T cell exhaustion in Echinococcus multilocularis-infected mice

The Impact of Bilirubin on 7α- and 7β- Hydroxysteroid Dehydrogenases: Spectra and Docking Analysis

Contact Info

Product

Resources

About