Panax notoginseng Saponin Protects Against Diabetic Cardiomyopathy Through Lipid Metabolism Modulation.
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ABSTRACT:
SUBMITTER: Zhang C
PROVIDER: S-EPMC9245810 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Previous studies demonstrated that Bailcalin (BAI) prevented cardiac injuries under different disease models. Whether BAI protected against type 2 diabetes mellitus- (T2DM-) associated cardiomyopathy was investigated in this study. T2DM was established by the combination of streptozotocin injection and high-fat diet in mice. BAI was administered daily for 6 months. After evaluating cardiac functions, mice hearts were removed and processed for morphological, biochemical, and molecular mechanism analyses. Neonatal rat cardiomyocytes (NRCM) were isolated and treated with high glucose and palmitate (HG/Pal) for in vitro investigation. BAI significantly ameliorated T2DM-induced cardiomyocyte hypertrophy, interstitial fibrosis, and lipid accumulation accompanied by markedly improved cardiac functions in diabetic mice. Mechanically, BAI restored decreased phosphorylation of AMPK and enhanced expression and nuclei translocation of Nrf2. In in vitro experiments, BAI also prevented NRCM from HG/Pal-induced apoptosis and oxidative stress injuries by increasing p-AMPK and Nrf2 accumulation. The means by which BAI restored p-AMPK seemed to be related to the antioxidative effects of Nrf2 after silencing AMPK or Nrf2 in NRCM. Furthermore, BAI regulated Nrf2 by inhibiting Nrf2 ubiquitination and consequent degradation mediated by Keap1. This study showed that BAI alleviated diabetes-associated cardiac dysfunction and cardiomyocyte injuries in vivo and in vitro via Keap1/Nrf2/AMPK-mediated antioxidation and lipid-lowering effects. BAI might be a potential adjuvant drug for diabetes cardiomyopathy treatment.
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Project description:BackgroundPanax quinquefolius and Panax notoginseng are widely used and well known for their pharmacological effects. As main pharmacological components, saponins have different distribution patterns in the root tissues of Panax plants.MethodsIn this study, the representative ginsenosides were detected and quantified by desorption electrospray ionization mass spectrometry and high-performance liquid chromatography analysis to demonstrate saponin distribution in the root tissues of P. quinquefolius and P. notoginseng, and saponin metabolite profiles were analyzed by metabolomes to obtain the biomarkers of different root tissues. Finally, the transcriptome analysis was performed to demonstrate the molecular mechanisms of saponin distribution by gene profiles.ResultsThere was saponin distribution in the root tissues differed between P. quinquefolius and P. notoginseng. Eight-eight and 24 potential biomarkers were detected by metabolome analysis, and a total of 340 and 122 transcripts involved in saponin synthesis that were positively correlated with the saponin contents (R > 0.6, P < 0.05) in the root tissues of P. quinquefolius and P. notoginseng, respectively. Among them, GDPS1, CYP51, CYP64, and UGT11 were significantly correlated with the contents of Rg1, Re, Rc, Rb2, and Rd in P. quinquefolius. UGT255 was markedly related to the content of R1; CYP74, CYP89, CYP100, CYP103, CYP109, and UGT190 were markedly correlated with the Rd content in P. notoginseng.ConclusionsThese results provided the visual and quantitative profiles of and confirmed the pivotal transcripts of CYPs and UGTs regulating the saponin distribution in the root tissues of P. quinquefolius and P. notoginseng.
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Project description:Panax notoginseng is a highly valued perennial medicinal herb plant in Yunnan Province, China, and the taproots are the main medicinal parts that are rich in active substances of P. notoginseng saponins. The main purpose of this study is to uncover the physiological and molecular mechanism of Panax notoginseng saponin accumulation triggered by methyl jasmonate (MeJA) under arbuscular mycorrhizal fungi (AMF) by determining physiological indices, high-throughput sequencing and correlation analysis. Physiological results showed that the biomass and saponin contents of P. notoginseng, the concentrations of jasmonic acids (JAs) and the key enzyme activities involved in notoginsenoside biosynthesis significantly increased under AMF or MeJA, but the interactive treatment of AMF and MeJA weakened the effect of AMF, suggesting that a high concentration of endogenous JA have inhibitory effect. Transcriptome sequencing results indicated that differential expressed genes (DEGs) involved in notoginsenoside and JA biosynthesis were significantly enriched in response to AMF induction, e.g., upregulated genes of diphosphocytidyl-2-C-methyl-d-erythritol kinases (ISPEs), cytochrome P450 monooxygenases (CYP450s)_and glycosyltransferases (GTs), while treatments AMF-MeJA and salicylhydroxamic acid (SHAM) decreased the abundance of these DEGs. Interestingly, a high correlation presented between any two of saponin contents, key enzyme activities and expression levels of DEGs. Taken together, the inoculation of AMF can improve the growth and saponin accumulation of P. notoginseng by strengthening the activities of key enzymes and the expression levels of encoding genes, in which the JA regulatory pathway is a key link. This study provides references for implementing ecological planting of P. notoginseng, improving saponin accumulation and illustrating the biosynthesis mechanism.
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Project description:Panax notoginseng saponins (PNS), the main bioactive constituents of a traditional Chinese herb Panax notoginseng, were commonly used for ischemic stroke in China. However, the associated cellular and molecular mechanisms of PNS have not been well examined. This study aimed to decipher the underlying molecular target of PNS in the treatment of cerebral ischemia. The oxygen-glucose-deprived (OGD) model of rat brain microvascular endothelial cells (BMECs) was used in this study. The alteration of gene expression in rat BMECs after PNS treatment was measured by microarray and indicated that there were 38 signaling pathways regulated by PNS. Among them, RIG-I receptor and related signaling molecules TNF receptor-associated factor 2 (Traf2) and nuclear factor-kappa B (NF-κB) were significantly suppressed by PNS, which was verified again in OGD-induced BMECs measured by FQ-PCR and western blotting and in middle cerebral artery occlusion (MCAO) rats measured by immunohistochemistry. The levels of TNF-α, IL-8, and the downstream cytokines regulated by RIG-I receptor pathway were also decreased by PNS. Meanwhile, the neurological evaluation, hematoxylin and eosin (HE) staining, and Evans blue staining were conducted to evaluate the effect of PNS in MCAO rats. Results showed PNS significantly improved functional outcome and cerebral vascular leakage. Flow cytometry showed the number of the inflammatory cells infiltrated in brain tissue was decreased in PNS treatment. Our results identified that RIG-I signaling pathway mediated anti-inflammatory properties of PNS in cerebral ischemia, which provided the novel insights of PNS application in clinics.
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Project description:BackgroundPanax notoginseng (Burk) F.H. Chen is important medicinal plant of the Araliacease family. Triterpene saponins are the bioactive constituents in P. notoginseng. However, available genomic information regarding this plant is limited. Moreover, details of triterpene saponin biosynthesis in the Panax species are largely unknown.ResultsUsing the 454 pyrosequencing technology, a one-quarter GS FLX titanium run resulted in 188,185 reads with an average length of 410 bases for P. notoginseng root. These reads were processed and assembled by 454 GS De Novo Assembler software into 30,852 unique sequences. A total of 70.2% of unique sequences were annotated by Basic Local Alignment Search Tool (BLAST) similarity searches against public sequence databases. The Kyoto Encyclopedia of Genes and Genomes (KEGG) assignment discovered 41 unique sequences representing 11 genes involved in triterpene saponin backbone biosynthesis in the 454-EST dataset. In particular, the transcript encoding dammarenediol synthase (DS), which is the first committed enzyme in the biosynthetic pathway of major triterpene saponins, is highly expressed in the root of four-year-old P. notoginseng. It is worth emphasizing that the candidate cytochrome P450 (Pn02132 and Pn00158) and UDP-glycosyltransferase (Pn00082) gene most likely to be involved in hydroxylation or glycosylation of aglycones for triterpene saponin biosynthesis were discovered from 174 cytochrome P450s and 242 glycosyltransferases by phylogenetic analysis, respectively. Putative transcription factors were detected in 906 unique sequences, including Myb, homeobox, WRKY, basic helix-loop-helix (bHLH), and other family proteins. Additionally, a total of 2,772 simple sequence repeat (SSR) were identified from 2,361 unique sequences, of which, di-nucleotide motifs were the most abundant motif.ConclusionThis study is the first to present a large-scale EST dataset for P. notoginseng root acquired by next-generation sequencing (NGS) technology. The candidate genes involved in triterpene saponin biosynthesis, including the putative CYP450s and UGTs, were obtained in this study. Additionally, the identification of SSRs provided plenty of genetic makers for molecular breeding and genetics applications in this species. These data will provide information on gene discovery, transcriptional regulation and marker-assisted selection for P. notoginseng. The dataset establishes an important foundation for the study with the purpose of ensuring adequate drug resources for this species.
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Project description:Treatment with Panax notoginseng saponin (PNS) can prevent neurological damage in middle cerebral artery occlusion model rats to promote recovery after a stroke. However, the exact molecular mechanisms are unknown and require further study. In the present study, mRNA sequencing was employed to investigate differential gene expression between model and sham groups, and between model and PNS‑treated groups. Enrichment of gene data was performed using Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes database. Hub genes were identified and networks were constructed using Cytoscape that were further verified by reverse transcription‑quantitative PCR. A total of 1,104 genes of interest were found, which included 690 upregulated and 414 downregulated genes that were identified when the model was compared with the sham group. Additionally, 817 genes of interest, which included 390 upregulated and 427 downregulated genes, were identified when the PNS‑treated group was compared with the model group. There were 303 overlapping genes of interest between the analysis of model to sham groups, and the analysis of model to PNS‑treated groups. The top 10 genes from the 303 aberrantly expressed genes of interest included ubiquitin conjugating enzyme E2 variant 2, small ubiquitin‑related modifier 1, small RNA binding exonuclease protection factor La, Finkel‑Biskis‑Reilly murine sarcoma virus (FBR‑MuSV) ubiquitously expressed, centrosomal protein 290 kDa, DNA‑directed RNA polymerase II subunit K, cullin‑4B, matrin‑3 and vascular endothelial growth factor receptor 2. In conclusion, these genes may be important in the underlying mechanism of PNS treatment in ischemic stroke. Additionally, the present data provided novel insight into the pathogenesis of ischemic stroke.
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Project description:BackgroundMetabolic abnormalities have been implicated as a causal event in diabetic cardiomyopathy (DCM). However, the mechanisms underlying cardiac metabolic disorder in DCM were not fully understood.ResultsDb/db mice, palmitate treated H9c2 cells and primary neonatal rat cardiomyocytes were employed in the current study. Microarray data analysis revealed that PGC-1β may play an important role in DCM. Downregulation of PGC-1β relieved palmitate induced cardiac metabolism shift to fatty acids use and relevant lipotoxicity in vitro. Bioinformatics coupled with biochemical validation was used to confirm that PGC-1β was one of the direct targets of miR-30c. Remarkably, overexpression of miR-30c by rAAV system improved glucose utilization, reduced excessive reactive oxygen species production and myocardial lipid accumulation, and subsequently attenuated cardiomyocyte apoptosis and cardiac dysfunction in db/db mice. Similar effects were also observed in cultured cells. More importantly, miR-30c overexpression as well as PGC-1β knockdown reduced the transcriptional activity of PPARα, and the effects of miR-30c on PPARα was almost abated by PGC-1β knockdown.ConclusionsOur data demonstrated a protective role of miR-30c in cardiac metabolism in diabetes via targeting PGC-1β, and suggested that modulation of PGC-1β by miR-30c may provide a therapeutic approach for DCM.
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Project description:Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular Ago2, a core microRNA, remain elusive. We elucidated the function and mechanism of subcellular localized Ago2 on mouse models for diabetes mellitus and diabetic cardiomyopathy. Ago2 decreased in cardiomyocyte mitochondria in both models. Overexpression of mitochondrial Ago2 attenuated diabetes-induced cardiac dysfunction. Ago2 recruited TUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain (ETC) subunits and decrease reactive oxygen species. Malonylation, a post-translational modification of Ago2, reduced the importing of Ago2 into mitochondria in diabetic cardiomyopathy. Ago2 malonylation was regulated by a cytoplasmic-localized short isoform of SIRT3 through a previously unknown demalonylase function. Our results reveal that the SIRT3–Ago2–CYTB axis links glucotoxicity to cardiac ETC imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.
2024-09-27 | GSE242088 | GEO