A deep clustering-based mass spectral data visualization strategy for anti-renal fibrotic lead compound identification from natural products

Lai, Jieying; Huang, Lichuang; Bao, Yini; Wang, Lu; Lyu, Qiang; Kuang, Haodan; Wang, Kuilong; Sang, Xianan; Yang, Qiao; Shan, Qiyuan; Cao, Gang

doi:10.1039/d2an01185a

Cited by 2 publications

(2 citation statements)

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“…Thus, reducing excess levels of glutamate in the synaptic cleft is a potential strategy for preventing and treating neurologic diseases [ 35 , 36 ]. Since oxidative stress and neuroinflammation are common pathologic signatures of neurodegeneration, PD might possess neuroprotective effects, as PD exhibits a series of promising therapeutic potential, such as anti-inflammatory and antioxidative activity [ 13 , 14 , 15 , 16 , 17 ]. In this work, we observed that PD inhibited the 4-AP-evoked release of glutamate in association with Ca 2+ -dependent synaptic vesicular exocytosis and VDCCs rather than by modulating the plasma membrane potential.…”

Section: Discussionmentioning

confidence: 99%

“…hongyao and Lagotis integra W. W. Smith [ 8 , 9 , 10 , 11 , 12 ]. Previous studies have shown that PD exhibits a series of impressive pharmacological effects, such as inhibitory activity against angiotensin-converting enzyme, an anti-renal fibrosis effect, cardioprotection, anti-inflammatory activity, and antioxidative activity [ 13 , 14 , 15 , 16 , 17 ]. Compounds with anti-inflammatory and antioxidative properties might confer neuroprotective effects, considering that oxidative stress and neuroinflammation are essential elements of neuronal death in various neurodegenerative disorders [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Plantainoside D Reduces Depolarization-Evoked Glutamate Release from Rat Cerebral Cortical Synaptosomes

Chiu

Lee

et al. 2023

Molecules

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Inhibiting the excessive release of glutamate in the brain is emerging as a promising therapeutic option and is efficient for treating neurodegenerative disorders. The aim of this study is to investigate the effect and mechanism of plantainoside D (PD), a phenylenthanoid glycoside isolated from Plantago asiatica L., on glutamate release in rat cerebral cortical nerve terminals (synaptosomes). We observed that PD inhibited the potassium channel blocker 4-aminopyridine (4-AP)-evoked release of glutamate and elevated concentration of cytosolic Ca2+. Using bafilomycin A1 to block glutamate uptake into synaptic vesicles and EDTA to chelate extracellular Ca2+, the inhibitory effect of PD on 4-AP-evoked glutamate release was prevented. In contrast, the action of PD on the 4-AP-evoked release of glutamate in the presence of dl-TBOA, a potent nontransportable inhibitor of glutamate transporters, was unaffected. PD does not alter the 4-AP-mediated depolarization of the synaptosomal membrane potential, suggesting that the inhibitory effect of PD on glutamate release is associated with voltage-dependent Ca2+ channels (VDCCs) but not the modulation of plasma membrane potential. Pretreatment with the Ca2+ channel blocker (N-type) ω-conotoxin GVIA abolished the inhibitory effect of PD on the evoked glutamate release, as did pretreatment with the protein kinase C inhibitor GF109203x. However, the PD-mediated inhibition of glutamate release was eliminated by applying the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157 or dantrolene, which inhibits Ca2+ release through ryanodine receptor channels. These data suggest that PD mediates the inhibition of evoked glutamate release from synaptosomes primarily by reducing the influx of Ca2+ through N-type Ca2+ channels, subsequently reducing the protein kinase C cascade.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plantainoside D Reduces Depolarization-Evoked Glutamate Release from Rat Cerebral Cortical Synaptosomes

Chiu

Lee

et al. 2023

Molecules

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Small molecule metabolites: discovery of biomarkers and therapeutic targets

Qiu

Cai

et al. 2023

Sig Transduct Target Ther

168

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Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks of diseases. Metabolite signatures that have close proximity to subject’s phenotypic informative dimension, are useful for predicting diagnosis and prognosis of diseases as well as monitoring treatments. The lack of early biomarkers could lead to poor diagnosis and serious outcomes. Therefore, noninvasive diagnosis and monitoring methods with high specificity and selectivity are desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool for metabolic biomarker and pathway analysis, for revealing possible mechanisms of human various diseases and deciphering therapeutic potentials. It could help identify functional biomarkers related to phenotypic variation and delineate biochemical pathways changes as early indicators of pathological dysfunction and damage prior to disease development. Recently, scientists have established a large number of metabolic profiles to reveal the underlying mechanisms and metabolic networks for therapeutic target exploration in biomedicine. This review summarized the metabolic analysis on the potential value of small-molecule candidate metabolites as biomarkers with clinical events, which may lead to better diagnosis, prognosis, drug screening and treatment. We also discuss challenges that need to be addressed to fuel the next wave of breakthroughs.

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A deep clustering-based mass spectral data visualization strategy for anti-renal fibrotic lead compound identification from natural products

Abstract: We present a deep clustering-based MS data visualization strategy (MCnebula), integrated with the influential open-source automatic MS annotation platform SIRIUS and in vivo and in vitro methods, to screen and validate potential lead compounds from natural products.

Cited by 2 publications

References 32 publications

Plantainoside D Reduces Depolarization-Evoked Glutamate Release from Rat Cerebral Cortical Synaptosomes

Plantainoside D Reduces Depolarization-Evoked Glutamate Release from Rat Cerebral Cortical Synaptosomes

Small molecule metabolites: discovery of biomarkers and therapeutic targets

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