Uniport, Not Proton-Symport, in a Non-Mammalian SLC23 Transporter

Holzhüter, Katharina; Geertsma, Eric R.

doi:10.1016/j.jmb.2021.167393

Cited by 6 publications

(3 citation statements)

References 65 publications

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“…To predict potential targets based on their spatial configuration, the compounds generated in the previous step were imported into the SwissTargetPrediction ( Daina et al, 2019 ) ( http://www.swisstargetprediction.ch/ ) and PharmMapper databases ( Liu et al, 2010 ) ( http://www.lilab-ecust.cn/pharmmapper/ ). The UniProt ID of the target was converted into a standardized gene name using the UniProt database ( Holzhüter and Geertsma, 2022 ) ( https://www.uniprot.org ). The keyword “osteoporosis” was searched in the GeneCards ( Barshir et al, 2021 ) ( https://www.genecards.org/ ), DisGeNET ( Piñero et al, 2020 ) ( https://www.disgenet.org ), and Online Mendelian Inheritance in Man ( Li et al, 2012 ) (OMIM, https://omim.org ) databases to obtain relevant targets.…”

Section: Methodsmentioning

confidence: 99%

Unraveling the potential mechanisms of the anti-osteoporotic effects of the Achyranthes bidentata–Dipsacus asper herb pair: a network pharmacology and experimental study

Li,

Guo

et al. 2023

Front. Pharmacol.

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Background: Osteoporosis is a prevalent bone metabolism disease characterized by a reduction in bone density, leading to several complications that significantly affect patients’ quality of life. The Achyranthes bidentata–Dipsacus asper (AB–DA) herb pair is commonly used in Traditional Chinese Medicine (TCM) to treat osteoporosis. This study aimed to investigate the therapeutic compounds and potential mechanisms of AB–DA using network pharmacology, molecular docking, molecular dynamics simulation, and experimental verification.Methods: Identified compounds of AB–DA were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicine Information Database (TCM-ID), TCM@Taiwan Database, BATMAN-TCM, and relevant literature. The main bioactive ingredients were screened based on the criteria of “OB (oral bioavailability) ≥ 30, DL (drug-likeness) ≥ 0.18.” Potential targets were predicted using the PharmMapper and SwissTargetPrediction websites, while disease (osteoporosis)-related targets were obtained from the GeneCards, DisGeNET, and OMIM databases. The PPI network and KEGG/GO enrichment analysis were utilized for core targets and pathway screening in the STRING and Metascape databases, respectively. A drug–compound–target–pathway–disease network was constructed using Cytoscape software to display core regulatory mechanisms. Molecular docking and dynamics simulation techniques explored the binding reliability and stability between core compounds and targets. In vitro and in vivo validation experiments were utilized to explore the anti-osteoporosis efficiency and mechanism of sitogluside.Results: A total of 31 compounds with 83 potential targets for AB–DA against osteoporosis were obtained. The PPI analysis revealed several hub targets, including AKT1, CASP3, EGFR, IGF1, MAPK1, MAPK8, and MAPK14. GO/KEGG analysis indicated that the MAPK cascade (ERK/JNK/p38) is the main pathway involved in treating osteoporosis. The D–C–T–P–T network demonstrated therapeutic compounds that mainly consisted of iridoids, steroids, and flavonoids, such as sitogluside, loganic acid, and β-ecdysterone. Molecular docking and dynamics simulation analyses confirmed strong binding affinity and stability between core compounds and targets. Additionally, the validation experiments showed preliminary evidence of antiosteoporosis effects.Conclusion: This study identified iridoids, steroids, and flavonoids as the main therapeutic compounds of AB–DA in treating osteoporosis. The underlying mechanisms may involve targeting core MAPK cascade (ERK/JNK/p38) targets, such as MAPK1, MAPK8, and MAPK14. In vivo experiments preliminarily validated the anti-osteoporosis effect of sitogluside. Further in-depth experimental studies are required to validate the therapeutic value of AB–DA for treating osteoporosis in clinical practice.

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Section: Methodsmentioning

confidence: 99%

Unraveling the potential mechanisms of the anti-osteoporotic effects of the Achyranthes bidentata–Dipsacus asper herb pair: a network pharmacology and experimental study

Li,

Guo

et al. 2023

Front. Pharmacol.

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“…The structural formulas of therapeutic and toxic compounds obtained in the previous step were input into the PharmMapper ( Liu et al, 2010 ) ( http://www.lilab-ecust.cn/pharmmapper/ ) and SwissTargetPrediction database ( Daina et al, 2019 ) ( http://www.swisstargetprediction.ch/ ) to predict the possible targets based on the spatial conformation. The uniport ID of the target was converted to the standardized gene name by Uniport ( Holzhüter and Geertsma, 2022 ) ( https://www.uniprot.org/ ) database. MeSH database ( https://www.ncbi.nlm.nih.gov/mesh ) was utilized to verify the standard name of the disease as “Pregnancy-induced Hypertension” “drug-induced liver injury” (DILI) and “drug-induced kidney injury” (DIKI) ( Zouhal et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…swisstargetprediction.ch/) to predict the possible targets based on the spatial conformation. The uniport ID of the target was converted to the standardized gene name by Uniport (Holzhüter and Geertsma, 2022) (https://www.uniprot.org/) database. MeSH database (https://www.ncbi.nlm.nih.gov/mesh) was utilized to verify the standard name of the disease as "Pregnancy-induced Hypertension" "drug-induced liver injury" (DILI) and "drug-induced kidney injury" (DIKI) (Zouhal et al, 2021).…”

Section: Potential Targets Related To Ao Compounds Pih Liver and Kidn...mentioning

confidence: 99%

Exploring the mechanism of Alisma orientale for the treatment of pregnancy induced hypertension and potential hepato-nephrotoxicity by using network pharmacology, network toxicology, molecular docking and molecular dynamics simulation

Liao

Ding

et al. 2022

Front. Pharmacol.

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Background: Pregnancy-induced Hypertension (PIH) is a disease that causes serious maternal and fetal morbidity and mortality. Alisma Orientale (AO) has a long history of use as traditional Chinese medicine therapy for PIH. This study explores its potential mechanism and biosafety based on network pharmacology, network toxicology, molecular docking and molecular dynamics simulation.Methods: Compounds of AO were screened in TCMSP, TCM-ID, TCM@Taiwan, BATMAN, TOXNET and CTD database; PharmMapper and SwissTargetPrediction, GeneCards, DisGeNET and OMIM databases were used to predict the targets of AO anti-PIH. The protein-protein interaction analysis and the KEGG/GO enrichment analysis were applied by STRING and Metascape databases, respectively. Then, we constructed the “herb-compound-target-pathway-disease” map in Cytoscape software to show the core regulatory network. Finally, molecular docking and molecular dynamics simulation were applied to analyze binding affinity and reliability. The same procedure was conducted for network toxicology to illustrate the mechanisms of AO hepatotoxicity and nephrotoxicity.Results: 29 compounds with 78 potential targets associated with the therapeutic effect of AO on PIH, 10 compounds with 117 and 111 targets associated with AO induced hepatotoxicity and nephrotoxicity were obtained, respectively. The PPI network analysis showed that core therapeutic targets were IGF, MAPK1, AKT1 and EGFR, while PPARG and TNF were toxicity-related targets. Besides, GO/KEGG enrichment analysis showed that AO might modulate the PI3K-AKT and MAPK pathways in treating PIH and mainly interfere with the lipid and atherosclerosis pathways to induce liver and kidney injury. The “herb-compound-target-pathway-disease” network showed that triterpenoids were the main therapeutic compounds, such as Alisol B 23-Acetate and Alisol C, while emodin was the main toxic compounds. The results of molecular docking and molecular dynamics simulation also showed good binding affinity between core compounds and targets.Conclusion: This research illustrated the mechanism underlying the therapeutic effects of AO against PIH and AO induced hepato-nephrotoxicity. However, further experimental verification is warranted for optimal use of AO during clinical practice.

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Boron‐sensing mechanisms involved in boron transport regulation in plants

Takano¹,

Tanaka²

2023

J. Plant Nutr. Soil Sci.

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Boron (B) is an essential micronutrient for plants. B deficiency and toxicity are widespread agricultural problems worldwide. To maintain appropriate B levels in tissues, plants require B‐sensing mechanisms to regulate its transport. In Arabidopsis thaliana, the boric channel NIP5;1, the borate transporter BOR1, and their homologs in the plasma membrane are responsible for efficient uptake and translocation of B when its supply is limited. Importantly, these transport systems are downregulated under high‐B conditions at multiple post‐transcriptional levels. NIP5;1 is downregulated by mRNA degradation following the B‐dependent ribosome stalling at the minimum upstream open reading frame (uORFs, AUGUAA) in the 5′ untranslated region (5′ UTR). Upon high B supply, BOR1 is ubiquitinated and transported to the vacuole via the endocytic pathway for degradation. Under higher B supply, BOR1 is further downregulated by translational suppression dependent on multiple uORFs in the 5′ UTR. These responses are important for preventing B toxicity. High‐B‐induced ubiquitination of BOR1 was shown to be dependent on its transport activity, suggesting that conformation transition during the borate transport cycle in the plasma membrane controls the rate of ubiquitination. The ribosome stalling that leads to mRNA degradation of NIP5;1 and translational suppression of BOR1 is presumably dependent on B binding to factors involved in translation in the cytosol. This review summarizes recent studies on B sensing and proposes future directions for research.

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Uniport, Not Proton-Symport, in a Non-Mammalian SLC23 Transporter

Cited by 6 publications

References 65 publications

Unraveling the potential mechanisms of the anti-osteoporotic effects of the Achyranthes bidentata–Dipsacus asper herb pair: a network pharmacology and experimental study

Unraveling the potential mechanisms of the anti-osteoporotic effects of the Achyranthes bidentata–Dipsacus asper herb pair: a network pharmacology and experimental study

Exploring the mechanism of Alisma orientale for the treatment of pregnancy induced hypertension and potential hepato-nephrotoxicity by using network pharmacology, network toxicology, molecular docking and molecular dynamics simulation

Boron‐sensing mechanisms involved in boron transport regulation in plants

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