-
Signal Transduction and Targeted Therapy Jan 2024Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the... (Review)
Review
Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.
Topics: Animals; Reperfusion Injury; Reperfusion; Wnt Signaling Pathway; Apoptosis; Ischemia
PubMed: 38185705
DOI: 10.1038/s41392-023-01688-x -
Pharmacological Research Aug 2023Major depressive disorder (MDD) is a chronic relapsing psychiatric disorder. Conventional antidepressants usually require several weeks of continuous administration to... (Review)
Review
Major depressive disorder (MDD) is a chronic relapsing psychiatric disorder. Conventional antidepressants usually require several weeks of continuous administration to exert clinically significant therapeutic effects, while about two-thirds of the patients are prone to relapse of symptoms or are completely ineffective in antidepressant treatment. The recent success of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine as a rapid-acting antidepressant has propelled extensive research on the action mechanism of antidepressants, especially in relation to its role in synaptic targets. Studies have revealed that the mechanism of antidepressant action of ketamine is not limited to antagonism of postsynaptic NMDA receptors or GABA interneurons. Ketamine produces powerful and rapid antidepressant effects by affecting α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, adenosine A1 receptors, and the L-type calcium channels, among others in the synapse. More interestingly, the 5-HT2A receptor agonist psilocybin has demonstrated potential for rapid antidepressant effects in depressed mouse models and clinical studies. This article focuses on a review of new pharmacological target studies of emerging rapid-acting antidepressant drugs such as ketamine and hallucinogens (e.g., psilocybin) and briefly discusses the possible strategies for new targets of antidepressants, with a view to shed light on the direction of future antidepressant research.
Topics: Animals; Mice; Ketamine; Depressive Disorder, Major; Psilocybin; Antidepressive Agents; Disease Models, Animal; Receptors, N-Methyl-D-Aspartate
PubMed: 37379962
DOI: 10.1016/j.phrs.2023.106837 -
Annals of Medicine Dec 2023Tirofiban is a small non-peptide ligand-mimetic Glycoprotein (GP) IIb/IIIa inhibitor which can reversibly bind to the arginine-glycine-aspartic acid (RGD) recognition... (Review)
Review
Tirofiban is a small non-peptide ligand-mimetic Glycoprotein (GP) IIb/IIIa inhibitor which can reversibly bind to the arginine-glycine-aspartic acid (RGD) recognition site of GP IIb/IIIa to prevent platelet aggregation. It reduces the incidence of thrombotic cardiovascular events in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Although generally considered safe, tirofiban has been reported to be associated with thrombocytopenia in several case reports and clinical trials. The pathogenesis for this adverse reaction is not entirely understood, is thought to be due to immune-mediated reaction. This side effect caused by tirofiban is especially concerning given how frequently it is used in the practice of contemporary cardiovascular care. The present review provides an overview of the pathophysiology, clinical presentation, management, and risk factors associated with tirofiban-induced thrombocytopenia.
Topics: Humans; Tirofiban; Platelet Aggregation Inhibitors; Tyrosine; Thrombocytopenia; Platelet Glycoprotein GPIIb-IIIa Complex; Acute Coronary Syndrome
PubMed: 37439782
DOI: 10.1080/07853890.2023.2233425 -
Nutrients Sep 2023Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate... (Review)
Review
Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate-glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate-aspartate shuttle maintains NADH delivery to mitochondria and redox balance. L-Asp released from neurons connects with the glutamate-glutamine cycle and ensures glycolysis and ammonia detoxification in astrocytes. D-Asp has a role in brain development and hypothalamus regulation. The hereditary disorders in L-Asp metabolism include citrullinemia, asparagine synthetase deficiency, Canavan disease, and dicarboxylic aminoaciduria. L-Asp plays a role in the pathogenesis of psychiatric and neurologic disorders and alterations in BCAA levels in diabetes and hyperammonemia. Further research is needed to examine the targeting of L-Asp metabolism as a strategy to fight cancer, the use of L-Asp as a dietary supplement, and the risks of increased L-Asp consumption. The role of D-Asp in the brain warrants studies on its therapeutic potential in psychiatric and neurologic disorders.
PubMed: 37764806
DOI: 10.3390/nu15184023 -
Frontiers in Endocrinology 2023Human blood metabolites have demonstrated close associations with thyroid disorders in observational studies. However, it's essential to determine whether these...
BACKGROUND
Human blood metabolites have demonstrated close associations with thyroid disorders in observational studies. However, it's essential to determine whether these correlations imply causation. Mendelian Randomization (MR) offers a promising approach to investigate these patterns.
AIMS
The primary aim of our investigation is to establish causality between blood metabolites and three thyroid disorders: TC, GD, and HT.
METHODS
We employed a two-sample bidirectional MR analysis approach to assess the relationships between 452 blood metabolites and the three aforementioned thyroid disorders. Causal links were estimated using the IVW method, with sensitivity analyses conducted via MR-Egger, Weighted Median, and MR-PRESSO. We assessed potential heterogeneity and pleiotropy using MR-Egger intercept and Cochran's Q statistic. Additionally, we conducted pathway analysis to identify potential metabolic pathways.
RESULTS
We found 46 metabolites that showed suggestive associations with thyroid disease risk, especially Aspartate (OR=7.41; 95%CI: 1.51-36.27; P=0.013) and C-glycosyltryptophan (OR=0.04; 95%CI: 0.00-0.29; P=0.001) impacted TC, Kynurenine (OR=2.69; 95%CI: 1.08-6.66; P=0.032) and 4-androsten-3beta,17beta-diol disulfate 2 (OR=0.78; 95%CI: 0.48-0.91; P=0.024) significantly impacted GD, and Alpha-ketoglutarate (OR=46.89; 95%CI: 4.65-473.28; P=0.001) and X-14189-leucylalanine (OR=0.31; 95%CI: 0.15-0.64 P=0.001) significantly impacted HT. We also detected 23 metabolites influenced by TC and GD. Multiple metabolic pathways have been found to be involved in thyroid disease.
CONCLUSION
Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical thyroid disorder screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection.
Topics: Humans; Mendelian Randomization Analysis; Thyroid Diseases; Aspartic Acid
PubMed: 37876541
DOI: 10.3389/fendo.2023.1270336 -
Current Opinion in Neurobiology Aug 2023Cerebellins (Cbln1-4) are secreted adaptor proteins that connect presynaptic neurexins (Nrxn1-3) to postsynaptic ligands (GluD1/2 for Cbln1-3 vs. DCC and Neogenin-1 for... (Review)
Review
Cerebellins (Cbln1-4) are secreted adaptor proteins that connect presynaptic neurexins (Nrxn1-3) to postsynaptic ligands (GluD1/2 for Cbln1-3 vs. DCC and Neogenin-1 for Cbln4). Classical studies demonstrated that neurexin-Cbln1-GluD2 complexes organize cerebellar parallel-fiber synapses, but the role of cerebellins outside of the cerebellum has only recently been clarified. In synapses of the hippocampal subiculum and prefrontal cortex, Nrxn1-Cbln2-GluD1 complexes strikingly upregulate postsynaptic NMDA-receptors, whereas Nrxn3-Cbln2-GluD1 complexes conversely downregulate postsynaptic AMPA-receptors. At perforant-path synapses in the dentate gyrus, in contrast, neurexin/Cbln4/Neogenin-1 complexes are essential for LTP without affecting basal synaptic transmission or NMDA- or AMPA-receptors. None of these signaling pathways are required for synapse formation. Thus, outside of the cerebellum neurexin/cerebellin complexes regulate synapse properties by activating specific downstream receptors.
Topics: N-Methylaspartate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Nerve Tissue Proteins; Synapses; Receptors, AMPA
PubMed: 37209532
DOI: 10.1016/j.conb.2023.102727 -
Neural Regeneration Research Apr 2024Proteolytic cleavage of tau by asparagine endopeptidase (AEP) creates tau-N368 fragments, which may drive the pathophysiology associated with synaptic dysfunction and...
Proteolytic cleavage of tau by asparagine endopeptidase (AEP) creates tau-N368 fragments, which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer's disease patients. Nonetheless, the molecular mechanisms of truncated tau-induced cognitive deficits remain unclear. Evidence suggests that signal transduction and activator of transcription-3 (STAT3) is associated with modulating synaptic plasticity, cell apoptosis, and cognitive function. Using luciferase reporter assays, electrophoretic mobility shift assays, western blotting, and immunofluorescence, we found that human tau-N368 accumulation inhibited STAT3 activity by suppressing STAT3 translocation into the nucleus. Overexpression of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss, thereby improving the cognitive deficits in tau-N368 mice. Moreover, in tau-N368 mice, activation of STAT3 increased N-methyl-D-aspartic acid receptor levels, decreased Bcl-2 levels, reversed synaptic damage and neuronal loss, and thereby alleviated cognitive deficits caused by tau-N368. Taken together, STAT3 plays a critical role in truncated tau-related neuropathological changes. This indicates a new mechanism behind the effect of tau-N368 on synapses and memory deficits. STAT3 can be used as a new molecular target to treat tau-N368-induced protein pathology.
PubMed: 37843229
DOI: 10.4103/1673-5374.382253 -
Journal of Nuclear Medicine : Official... Aug 2023Radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and Arg-Gly-Asp (RGD) peptides have been extensively investigated for imaging of FAP- and integrin...
Radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and Arg-Gly-Asp (RGD) peptides have been extensively investigated for imaging of FAP- and integrin αβ-positive tumors. In this study, a FAPI-RGD heterodimer was radiolabeled with Ga and evaluated in patients with cancer. We hypothesized that the heterodimer, recognizing both FAP and integrin αβ, would be advantageous because of its dual-receptor-targeting property. The effective dose of Ga-FAPI-RGD was evaluated in 3 healthy volunteers. The clinical feasibility of Ga-FAPI-RGD PET/CT was evaluated in 22 patients with various types of cancer, and the results were compared with those of F-FDG and Ga-FAPI-46. Ga-FAPI-RGD was tolerated well, with no adverse events in any of the healthy volunteers or patients. The effective dose from Ga-FAPI-RGD PET/CT was 1.01 × 10 mSv/MBq. In clinical investigations with different types of cancer, the radiotracer uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in Ga-FAPI-RGD PET/CT were significantly higher than those in F-FDG PET/CT (primary tumors: SUV, 18.0 vs. 9.1 [ < 0.001], and TBR, 15.2 vs. 5.5 [ < 0.001]; lymph node metastases: SUV, 12.1 vs. 6.1 [ < 0.001], and TBR, 13.3 vs. 4.1 [ < 0.001]), resulting in an improved lesion detection rate and tumor delineation, particularly for the diagnosis of lymph node (99% vs. 91%) and bone (100% vs. 80%) metastases. Ga-FAPI-RGD PET/CT also yielded a higher radiotracer uptake and TBR than Ga-FAPI-46 PET/CT did. Ga-FAPI-RGD exhibited improved tumor uptake and TBR compared with F-FDG and Ga-FAPI PET/CT. This study demonstrated the safety and clinical feasibility of Ga-FAPI-RGD PET/CT for imaging of various types of cancer.
Topics: Humans; Integrin alphaVbeta3; Gallium Radioisotopes; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Oligopeptides; Positron-Emission Tomography; Lymphatic Metastasis; Fibroblasts; Quinolines
PubMed: 37142301
DOI: 10.2967/jnumed.122.265383 -
CMAJ : Canadian Medical Association... Jun 2023
Topics: Humans; Psychotic Disorders; Encephalitis
PubMed: 37308207
DOI: 10.1503/cmaj.220938-f