RUSSIAN CHEMICAL BULLETIN
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2025
·Vol. 74
·期 3
·807-817
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IF 0
Balakina A. A.,Amozova V. I.,Stupina T. S.,Mumyatova V. A.,Podgurskaya A. D.,Gadomsky S. Ya.
A new method for the synthesis of pyridoxine salts with dicarboxylic acids was proposed. The specific features of the synthesis include the preliminary generation of free pyridoxine from the hydrochloride form by treatment with a solution of triethylamine in chloroform and conduction of the reaction of pyridoxine with dicarboxylic acid in a specially selected solvent mixture. The combination of pyridoxine as a known antioxidant and fumarate as an activator of the transcription factor Nrf2 in one molecule gave rise to a unique structure, bis[3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridinium] fumarate (DPNF). In vitro experiments showed the ability of this compound to bind superoxide, suppress lipid peroxidation processes, and behave as a mitochondrial cytoprotective agent and Nrf2 activator. The results of the study can be used to develop a new type of drugs based on activators of the transcription factor Nrf2 to protect cells and tissues from oxidative damage.
研究领域:
药物化学
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生物化学
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分子生物学
✓ 已验证
DOI
Autophagy
·
2024
·
IF 14.6
Jiajia Wang,Yueping Qiu,Lijun Yang,Jincheng Wang,Jie He,Chengwu Tang,Zhaoxu Yang,Wenxiang Hong,Bo Yang,Qiaojun He,Qinjie Weng
Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic – pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.
研究领域:
肝病学
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细胞生物学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 14
·
IF 11.7
Jianfei Yan,Junjie Wu,Mingyue Xu,Min Wang,Weixiang Guo
Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.
研究领域:
神经科学
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分子生物学
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药理学
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遗传学
✓ 已验证
DOI
PubMed
高影响因子
BMC Nephrology
·
2018
·Vol. 19
·期 1
·1-12
·
IF 2.395
Yang Huan,Male Musa,Li Yang,Wang Ning,Zhao Chenming,Jin Shan,Hu Juncheng,Chen Zhiqiang,Ye Zhangqun,Xu Hua
Background Substrate reduction therapy with analogs reduces the accumulation of substrates by inhibiting the metabolic pathways involved in their biosynthesis, providing new treatment options for patients with primary hyperoxalurias (PHs) that often progress to end-stage renal disease (ESRD). This research aims to evaluate the inhibition efficacy of Hydroxy-L-proline (HYP) analogs against calcium oxalate (CaOx) crystal formation in the Drosophila Melanogaster ( D. Melanogaster ) by comparing them with Pyridoxine (Vitamin B6). Methods Three stocks of Drosophila Melanogaster (W 118 , CG3926 RNAi, and Act5C-GAL4/CyO) were utilized. Two stocks (CG3926 RNAi and Act5C-GAL4 /CyO) were crossed to generate the Act5C > dAGXT RNAi recombinant line (F 1 generation) of D. Melanogaster which was used to compare the efficacy of Hydroxy-L-proline (HYP) analogs inhibiting CaOx crystal formation with Vitamin B 6 as the traditional therapy for primary hyperoxaluria. Results Nephrolithiasis model was successfully constructed by downregulating the function of the dAGXT gene in D. Melanogaster ( P -Value = 0.0045) . Furthermore, the efficacy of Hydroxy-L-proline (HYP) analogs against CaOx crystal formation was demonstrated in vivo using D. Melanogaster model; the results showed that these L-Proline analogs were better in inhibiting stone formation at very low concentrations than Vitamin B 6 (IC 50 = 0.6 and 1.8% for standard and dietary salt growth medium respectively) compared to N-acetyl-L-Hydroxyproline (IC 50 = 0.1% for both standard and dietary salt growth medium) and Baclofen (IC 50 = 0.06 and 0.1% for standard and dietary salt growth medium respectively). Analysis of variance (ANOVA) also showed that Hydroxy-L-proline (HYP) analogs were better alternatives for CaOx inhibition at very low concentration especially when both genetics and environmental factors are intertwined ( p < 0.0008) for the dietary salt growth medium and ( P < 0.063) for standard growth medium. Conclusion Addition of Hydroxy-L-Proline analogs to growth medium resulted in the reduction of CaOx crystals formation. These analogs show promise as potential inhibitors for oxalate reduction in Primary Hyperoxaluria.
研究领域:
药理学
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遗传学
·
分子生物学
·
肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Endocrinology
·
2022
·
IF 6.055
Cao Lin-Lin,Han Yi,Wang Yuanxiao,Pei Lin,Yue Zhihong,Qin Li,Liu Boyu,Cui Jingwen,Jia Mei,Wang Hui
Metabolic syndrome (MetS) is an independent risk factor for hepatocellular cancer (HCC). Currently, there is no highly sensitive and specific biomarkers for HCC surveillance in MetS population. Metabolomics has been reported as a powerful technology for biomarker discovery. In the present study, we aimed to explore novel biomarkers with high sensitivity and specificity for MetS-positive [MetS(+)] HCC by metabolomic analysis. At first, many serum metabolites were found dysregulated in MetS(+) HCC individuals. Validation of the dysregulated metabolites by targeted metabolite analyses revealed that serum L-glutamic acid (L-glu), pipecolic acid (PA) and 7-methylguanine (7-mG) were increased in MetS(+) HCC compared to MetS group. Then a biomarker panel including L-glu, PA and alpha-fetoprotein (AFP) was identified as a novel biomarker for the diagnosis of MetS(+) HCC. Receiver operating characteristic (ROC) curve was drawn and the area under the ROC curve (AUC) was 0.87 for discriminating MetS(+) HCC from MetS group. The biomarker panel was capable of detecting small (AUC = 0.82) and early-stage (AUC = 0.78) tumors as well. Moreover, it exhibited great diagnostic performance (AUC = 0.93) for discriminating MetS(+) HCC from other MetS-associated cancers, including colorectal cancer and gastric cancer. Collectively, our study establishes a novel diagnostic tool for MetS(+) HCC.
研究领域:
肿瘤学
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代谢组学
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分子生物学
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癌症诊断
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2024
·
IF 5.6
Rong Wu,Minmin Zou,Jiarui Cao,Manman Shi,Guobin Jiang,Fuliang Cao,Erzheng Su
Ginkgo seeds are rich in nutrients and bioactive compounds, but they cause poisoning after excessive consumption, thus limiting their application. In this work, enzymatic degradation technology was employed to remove ginkgotoxins presented in ginkgo seeds, including 4’-O-methylpyridoxine (MPN) and MPN-5’-glucoside (MPNG). Through the screening of four oxidases and ten reaction mediators, the laccase-syringaldehyde system was successfully established. After optimizing the reaction conditions using response surface methodology (RSM), ginkgotoxins in both raw and boiled ginkgo seed powder was completely degraded at a temperature of 40 °C and a solvent to solid ratio (60 mL/g) of the ginkgo seed powder suspension within 3 h. Furthermore, the main nutritional components of detoxified ginkgo seed powder did not exhibit significant changes, but there was inevitably a decrease in the content of bioactive compounds. Finally, an acute oral toxicity assessment demonstrated that the detoxified ginkgo seed powder was virtually non-toxic. Therefore, enzymatic degradation using the laccase-syringaldehyde system has the potential to be a simple and effective approach for removing ginkgotoxins from ginkgo seed powder, thereby meeting the safety requirements for ginkgo products.
研究领域:
食品科学
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毒理学
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酶学
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营养学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）