Homocysteinylation and Sulfhydration in Diseases

Chen, Si-Min; Tang, Xiao‐Qing

doi:10.2174/1570159x20666211223125448

Cited by 8 publications

(2 citation statements)

References 133 publications

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“…Therefore, enhanced 9-OH-RIS excretion linked to hyperhomocysteinemia (induced by the MTHER mutation) via oxidation is assumed to be a superior postulated mechanism. In addition, homocysteine is a sulfur-containing amino acid ( Lentz, 2005 ), which could serve as a co-factor in the conjugation of a drug metabolite by sulphation ( Chen and Tang, 2022 ), leading to increased facilitated excretion in urine ( Pan et al, 2020 ). However, these hypotheses remain uncertain.…”

Section: Discussionmentioning

confidence: 99%

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism

Shilbayeh,

Adeen,

Ghanem

et al. 2024

Front. Pharmacol.

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Background: Autism spectrum disorders (ASDs) encompass a broad range of phenotypes characterized by diverse neurological alterations. Genomic studies have revealed considerable overlap between the molecular mechanisms implicated in the etiology of ASD and genes involved in the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of antipsychotic drugs employed in ASD management. Given the conflicting data originating from candidate PK or PD gene association studies in diverse ethnogeographic ASD populations, dosage individualization based on “actionable” pharmacogenetic (PGx) markers has limited application in clinical practice. Additionally, off-label use of different antipsychotics is an ongoing practice, which is justified given the shortage of approved cures, despite the lack of satisfactory evidence for its safety according to precision medicine. This exploratory study aimed to identify PGx markers predictive of risperidone (RIS) exposure in autistic Saudi children.Methods: This prospective cohort study enrolled 89 Saudi children with ASD treated with RIS-based antipsychotic therapy. Plasma levels of RIS and 9-OH-RIS were measured using a liquid chromatography–tandem mass spectrometry system. To enable focused exploratory testing, genotyping was performed with the Axiom PharmacoFocus Array, which included a collection of probe sets targeting PK/PD genes. A total of 720 PGx markers were included in the association analysis.Results: A total of 27 PGx variants were found to have a prominent impact on various RIS PK parameters; most were not located within the genes involved in the classical RIS PK pathway. Specifically, 8 markers in 7 genes were identified as the PGx markers with the strongest impact on RIS levels (p < 0.01). Four PGx variants in 3 genes were strongly associated with 9-OH-RIS levels, while 5 markers in 5 different genes explained the interindividual variability in the total active moiety. Notably, 6 CYP2D6 variants exhibited strong linkage disequilibrium; however, they significantly influenced only the metabolic ratio and had no considerable effects on the individual estimates of RIS, 9-OH-RIS, or the total active moiety. After correction for multiple testing, rs78998153 in UGT2B17 (which is highly expressed in the brain) remained the most significant PGx marker positively adjusting the metabolic ratio. For the first time, certain human leukocyte antigen (HLA) markers were found to enhance various RIS exposure parameters, which reinforces the gut–brain axis theory of ASD etiology and its suggested inflammatory impacts on drug bioavailability through modulation of the brain, gastrointestinal tract and/or hepatic expression of metabolizing enzymes and transporters.Conclusion: Our hypothesis-generating approach identified a broad spectrum of PGx markers that interactively influence RIS exposure in ASD children, which indicated the need for further validation in population PK modeling studies to define polygenic scores for antipsychotic efficacy and safety, which could facilitate personalized therapeutic decision-making in this complex neurodevelopmental condition.

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Section: Discussionmentioning

confidence: 99%

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism

Shilbayeh,

Adeen,

Ghanem

et al. 2024

Front. Pharmacol.

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“…In addition, as cancer cells mainly depend on the methylation cycle, this also produces a high amount of Hcy, which induces homocysteinylation of protein and further activates ER stress [ 264 ]. There is also the possibility that H 2 S can reverse protein homocysteinylation [ 265 ].…”

Section: Multifactorial Role Of H 2 S In Cancermentioning

confidence: 99%

Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment

Majumder

2023

Antioxidants

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A high level of homocysteine (Hcy) is associated with oxidative/ER stress, apoptosis, and impairment of angiogenesis, whereas hydrogen sulfide (H2S) has been found to reverse this condition. Recent studies have shown that cancer cells need to produce a high level of endogenous H2S to maintain cell proliferation, growth, viability, and migration. However, any novel mechanism that targets this balance of Hcy and H2S production has yet to be discovered or exploited. Cells require homocysteine metabolism via the methionine cycle for nucleotide synthesis, methylation, and reductive metabolism, and this pathway supports the high proliferative rate of cancer cells. Although the methionine cycle favors cancer cells for their survival and growth, this metabolism produces a massive amount of toxic Hcy that somehow cancer cells handle very well. Recently, research showed specific pathways important for balancing the antioxidative defense through H2S production in cancer cells. This review discusses the relationship between Hcy metabolism and the antiapoptotic, antioxidative, anti-inflammatory, and angiogenic effects of H2S in different cancer types. It also summarizes the historical understanding of targeting antioxidative defense systems, angiogenesis, and other protective mechanisms of cancer cells and the role of H2S production in the genesis, progression, and metastasis of cancer. This review defines a nexus of diet and precision medicine in targeting the delicate antioxidative system of cancer and explores possible future therapeutics that could exploit the Hcy and H2S balance.

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FGF2 Functions in H2S’s Attenuating Effect on Brain Injury Induced by Deep Hypothermic Circulatory Arrest in Rats

Zhu,

Yang,

Zhang

et al. 2023

Mol Biotechnol

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Deep hypothermic circulatory arrest (DHCA) can protect the brain during cardiac and aortic surgery by cooling the body, but meanwhile, temporary or permanent brain injury may arise. H2S protects neurons and the central nervous system, especially from secondary neuronal injury. We aim to unveil part of the mechanism of H2S’s attenuating effect on brain injury induced by DHCA by exploring crucial target genes, and further promote the clinical application of H2S in DHCA. Nine SD rats were utilized to provide histological and microarray samples, and further the differential expression analysis. Then we conducted GO and KEGG pathway enrichment analyses on candidate genes. The protein-protein interaction (PPI) networks were performed by STRING and GeneMANIA. Crucial target genes’ expression was validated by qRT-PCR and western blot. Histological study proved DHCA’s damaging effect and H2S’s repairing effect on brain. Next, we got 477 candidate genes by analyzing differentially expressed genes. The candidate genes were enriched in 303 GO terms and 28 KEGG pathways. Then nine genes were selected as crucial target genes. The function prediction by GeneMANIA suggested their close relation to immunity. FGF2 was identified as the crucial gene. FGF2 plays a vital role in the pathway when H2S attenuates brain injury after DHCA. Our research provides more information for understanding the mechanism of H2S attenuating brain injury after DHCA. We infer the process might probably be closely associated with immunity.

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Homocysteinylation and Sulfhydration in Diseases

Cited by 8 publications

References 133 publications

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism

Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment

FGF2 Functions in H2S’s Attenuating Effect on Brain Injury Induced by Deep Hypothermic Circulatory Arrest in Rats

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