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      Evidence of synergistic mechanisms of hepatoprotective botanical herbal preparation of Pueraria montana var. lobata and Schisandra sphenanthera

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          Abstract

          Background

          Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) and Schisandra sphenanthera Rehder & E.H. Wilson are traditional edible and medicinal hepatoprotective botanical drugs. Studies have shown that the combination of two botanical drugs enhanced the effects of treating acute liver injury (ALI), but the synergistic effect and its action mechanisms remain unclear. This study aimed to investigate the synergistic effect and its mechanism of the combination of Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) (PM) and Schisandra sphenanthera Rehder & E.H. Wilson (SS) in the treatment of ALI.

          Methods

          High performance liquid chromatography (HPLC) were utilized to conduct the chemical interaction analysis. Then the synergistic effects of botanical hybrid preparation of PM-SS (BHP PM-SS) against ALI were comprehensively evaluated by the CCl 4 induced ALI mice model. Afterwards, symptom-oriented network pharmacology, transcriptomics and metabolomics were applied to reveal the underlying mechanism of action. Finally, the key target genes were experimentally by RT-qPCR.

          Results

          Chemical analysis and pharmacodynamic experiments revealed that BHP PM-SS was superior to the single botanical drug, especially at 2:3 ratio, with a better dissolution rate of active ingredients and synergistic anti-ALI effect. Integrated symptom-oriented network pharmacology combined with transcriptomics and metabolomics analyses showed that the active ingredients of BHP PM-SS could regulate Glutathione metabolism, Pyrimidine metabolism, Arginine biosynthesis and Amino acid sugar and nucleotide sugar metabolism, by acting on the targets of AKT1, TNF, EGFR, JUN, HSP90AA1 and STAT3, which could be responsible for the PI3K-AKT signaling pathway, MAPK signaling pathway and Pathway in cancer to against ALI.

          Conclusion

          Our study has provided compelling evidence for the synergistic effect and its mechanism of the combination of BHP PM-SS, and has contributed to the development and utilization of BHP PM-SS dietary supplements.

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          Most cited references66

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          Analysis of Schisandra chinensis and Schisandra sphenanthera.

          Wuweizi (Fructus Schisandrae) is classified in traditional Chinese medicine as a superior drug, and has been used for thousands of years. Modern pharmacological research has demonstrated that most of the biological actions and pharmacological effects of Wuweizi can be attributed to its lignan constituents, particularly the dibenzocyclooctadiene-type lignans, which can lower the serum glutamate-pyruvate transaminase (SGPT) level, inhibit platelet aggregation, and show antioxidative, calcium antagonism, antitumor-promoting, and anti-HIV (human immunodeficiency virus) effects. The dried ripe fruits of both Schisandra chinensis and Schisandra sphenanthera have long been used as Wuweizi, although their chemical constituents and contents of the bioactive components are quite different. Since 2000, they have been accepted as two different crude drugs, Bei-Wuweizi and Nan-Wuweizi, respectively, by the Chinese Pharmacopoeia. In order to provide a useful reference for good quality control of Wuweizi, many studies on the chemical constituents, pharmacological effects, identification and quality control methods of the two drugs have been reported in the literature and are summarized herein. Particular attention was given to the different methodologies developed for the qualitative and quantitative analysis of the major bioactive lignans. In our opinion, thin-layer chromatography (TLC) is the most simple and convenient method for identification of these two crude drugs, and high-performance liquid chromatography with UV detection (HPLC-UV) is the preferred method for quantitative analysis based on the bioactive lignans. Some newly developed methods, particularly hyphenated chromatographic-analytical techniques, are effective in determination of the lignans that occur in low content and those difficult to be fully separated with HPLC.
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            PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.

            Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E. coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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              Uridine Metabolism and Its Role in Glucose, Lipid, and Amino Acid Homeostasis

              Pyrimidine nucleoside uridine plays a critical role in maintaining cellular function and energy metabolism. In addition to its role in nucleoside synthesis, uridine and its derivatives contribute to reduction of cytotoxicity and suppression of drug-induced hepatic steatosis. Uridine is mostly present in blood and cerebrospinal fluid, where it contributes to the maintenance of basic cellular functions affected by UPase enzyme activity, feeding habits, and ATP depletion. Uridine metabolism depends on three stages: de novo synthesis, salvage synthesis pathway and catabolism, and homeostasis, which is tightly relating to glucose homeostasis and lipid and amino acid metabolism. This review is devoted to uridine metabolism and its role in glucose, lipid, and amino acid homeostasis.
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                Author and article information

                Contributors
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                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                24 June 2024
                2024
                : 15
                : 1412816
                Affiliations
                State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research , College of Pharmacy , Shaanxi University of Chinese Medicine , Xi’an, China
                Author notes

                Edited by: Alexander George Panossian, Phytomed AB, Sweden

                Reviewed by: Karl Tsim, Hong Kong University of Science and Technology, Hong Kong, SAR China

                Yunbin Jiang, Southwest University, China

                *Correspondence: Dong-Yan Guo, xmc2051080@ 123456163.com
                Article
                1412816
                10.3389/fphar.2024.1412816
                11228302
                38978983
                1db19ca3-317e-44dc-a630-a37f8bce8525
                Copyright © 2024 Lv, Li, Zhai, Sun, Cheng, Zhang and Guo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 April 2024
                : 03 June 2024
                Funding
                The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by the Comprehensive Development and Utilization of Zhashui S. sphenanthera Rehd. et Wils and Gastrodia elata Bi of Central Government Guided Local Special Project (2021ZY2-CG-03); the Comprehensive Utilization and Development of Qin Medicine " S. sphenanthera Rehd. et Wils " Medicinal Herbs of Shaanxi Administration of Traditional Chinese Medicine Project (2021-02-22-014); and the disciplinary innovation team con-struction project of Shaanxi University of Chinese Medicine (2019-YL11).
                Categories
                Pharmacology
                Original Research
                Custom metadata
                Ethnopharmacology

                Pharmacology & Pharmaceutical medicine
                pueraria montana var.var. lobata (willd.) maesen & s.m.almeida ex sanjappa & predeep, schisandra sphenanthera rehder & e.h. wilson,acute liver injury,symptomoriented network pharmacology,multi-omics

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