Ginsenoside Compound K Assisted G-Quadruplex Folding and Regulated G-Quadruplex-Containing Transcription.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8659241 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundFour-stranded G-quadruplexes (G4s) are DNA secondary structures in the human genome that are primarily found in active promoters associated with elevated transcription. Here, we explore the relationship between the folding of promoter G4s, transcription and chromatin state.ResultsTranscriptional inhibition by DRB or by triptolide reveals that promoter G4 formation, as assessed by G4 ChIP-seq, does not depend on transcriptional activity. We then show that chromatin compaction can lead to loss of promoter G4s and is accompanied by a corresponding loss of RNA polymerase II (Pol II), thus establishing a link between G4 formation and chromatin accessibility. Furthermore, pre-treatment of cells with a G4-stabilising ligand mitigates the loss of Pol II at promoters induced by chromatin compaction.ConclusionsOverall, our findings show that G4 folding is coupled to the establishment of accessible chromatin and does not require active transcription.
| S-EPMC8103603 | biostudies-literature
Project description:Four stranded DNA G-quadruplex (G4) structures are common features of the human genome that are primarily found in active promoters associated with elevated transcription. Here, we explore the relationship between the folding of G4s in promoters, transcription and chromatin state. Transcriptional inhibition by DRB or by triptolide reveals that promoter G4 formation, as assessed G4 ChIP-seq, is not reliant on transcriptional activity. Establishing a link between G4 formation and chromatin accessibility, we demonstrate that chromatin compaction leads to loss of promoter G4s accompanied by a corresponding loss of RNA polymerase II (Pol II). Furthermore, pre-treatment of cells with a G4-stabilising ligand can mitigate Pol II loss at promoters induced by chromatin compaction. Overall, our findings show that G4 formation is fostered in accessible chromatin and does not require active transcription. Furthermore, our findings suggest that G4s have a role to recruit Pol II to promote transcription.
2021-03-31 | GSE162299 | GEO
Project description:Ginsenoside Rb1is the main component in ginsenosides. It is a protopanaxadiol-type ginsenoside that has a dammarane-type triterpenoid as an aglycone. In this study, ginsenoside Rb1 was transformed into gypenoside XVII, ginsenoside Rd, ginsenoside F2 and compound K by glycosidase from Leuconostoc mesenteroides DC102. The optimum time for the conversion was about 72 h at a constant pH of 6.0 to 8.0 and the optimum temperature was about 30?. Under optimal conditions, ginsenoside Rb1 was decomposed and converted into compound K by 72 h post-reaction (99%). The enzymatic reaction was analyzed by highperformance liquid chromatography, suggesting the transformation pathway: ginsenoside Rb1? gypenoside XVII and ginsenoside Rd?ginsenoside F2?compound K.
| S-EPMC3659545 | biostudies-literature
Project description:Nucleic acids can form noncanonical four-stranded structures called G-quadruplexes. G-quadruplex-forming sequences are found in several genomes including human and viruses. Previous studies showed that the G-rich sequence located in the U3 promoter region of the HIV-1 long terminal repeat (LTR) folds into a set of dynamically interchangeable G-quadruplex structures. G-quadruplexes formed in the LTR could act as silencer elements to regulate viral transcription. Stabilization of LTR G-quadruplexes by G-quadruplex-specific ligands resulted in decreased viral production, suggesting the possibility of targeting viral G-quadruplex structures for antiviral purposes. Among all the G-quadruplexes formed in the LTR sequence, LTR-III was shown to be the major G-quadruplex conformation in vitro. Here we report the NMR structure of LTR-III in K+ solution, revealing the formation of a unique quadruplex-duplex hybrid consisting of a three-layer (3 + 1) G-quadruplex scaffold, a 12-nt diagonal loop containing a conserved duplex-stem, a 3-nt lateral loop, a 1-nt propeller loop, and a V-shaped loop. Our structure showed several distinct features including a quadruplex-duplex junction, representing an attractive motif for drug targeting. The structure solved in this study may be used as a promising target to selectively impair the viral cycle.
| S-EPMC6202629 | biostudies-literature
Project description:Circular dichroism and stopped-flow UV spectroscopies were used to investigate the thermodynamic stability and the folding pathway of d[TGAG3TG3TAG3TG3TA2] at 25 °C in solutions containing 25 mM KCl. Under these conditions the oligonucleotide adopts a thermally stable, all-parallel G-quadruplex topography containing three stacked quartets. K+-induced folding shows three resolved relaxation times, each with distinctive spectral changes. Folding is complete within 200 s. These data indicate a folding pathway that involves at least two populated intermediates, one of which seems to be an antiparallel structure that rearranges to the final all-parallel conformation. Molecular dynamics reveals a stereochemically plausible folding pathway that does not involve complete unfolding of the intermediate. The rate of unfolding was determined using complementary DNA to trap transiently unfolded states to form a stable duplex. As assessed by 1D-1H NMR and fluorescence spectroscopy, unfolding is extremely slow with only one observable rate-limiting relaxation time.
| S-EPMC6455816 | biostudies-literature
Project description:Molecular details for DNA damage impact on the folding of potential G-quadruplex sequences (PQS) to non-canonical DNA structures that are involved in gene regulation are poorly understood. Here, the effects of DNA base damage and strand breaks on PQS folding kinetics were studied in the context of the VEGF promoter sequence embedded between two DNA duplex anchors, referred to as a duplex-G-quadruplex-duplex (DGD) motif. This DGD scaffold imposes constraints on the PQS folding process that more closely mimic those found in genomic DNA. Folding kinetics were monitored by circular dichroism (CD) to find folding half-lives ranging from 2 s to 12 min depending on the DNA damage type and sequence position. The presence of Mg2+ ions and the G-quadruplex (G4)-binding protein APE1 facilitated the folding reactions. A strand break placing all four G runs required for G4 formation on one side of the break accelerated the folding rate by >150-fold compared to the undamaged sequence. Combined 1D 1H-NMR and CD analyses confirmed that isothermal folding of the VEGF-DGD constructs yielded spectral signatures that suggest formation of G4 motifs, and demonstrated a folding dependency with the nature and location of DNA damage. Importantly, the PQS folding half-lives measured are relevant to replication, transcription, and DNA repair time frames.
| S-EPMC10827223 | biostudies-literature
Project description:Biomaterial-based drug delivery systems have been developed to expedite cartilage regeneration; however, challenges related to drug recovery, validation, and efficient drug delivery remain. For instance, compound K (CK) is a major metabolite of ginsenosides that is known to protect against joint degeneration by inhibiting the production of inflammatory cytokines and the activation of immune cells. However, its effects on cartilage degradation and tissue regeneration remain unclear. Additionally, tissue-adhesive drug delivery depots that stably adhere to cartilage defects are required for CK delivery. In this study, CK-loaded adhesive patches were reported to seal cartilage defects and deliver CK to defect sites, preventing cartilage degradation and accelerating cartilage tissue regeneration. Adhesive patches are stable and suitable for application in surgical procedures under physiological conditions and show excellent adhesiveness to cartilage surfaces. In addition, there were no significant differences in the adhesive polymeric networks before and after CK loading. CK-loaded hydrocaffeic acid-conjugated chitosan patches significantly inhibited the stimulation of cartilage-degrading enzymes and apoptosis in osteoarthritic cartilage by releasing CK in cartilage defects. Additionally, the NFkB signaling pathway of released CK from the adhesive patches in the treatment of osteoarthritis is revealed. Thus, the CK-loaded adhesive patches are expected to significantly contribute to cartilage regeneration.
| S-EPMC10518074 | biostudies-literature
Project description:G-quadruplexes adopt various folding topologies, but information on their folding pathways remains scarce. Here, we used electrospray mass spectrometry to detect and quantify the specifically bound potassium ions, and circular dichroism to characterize the stacking topology of each ensemble. For human telomeric (hTel) sequences containing the d((GGGTTA)3GGG) core, K+ binding affinity and cooperativity strongly depends on the chosen construct. The shortest sequences bind only one K+ at low KCl concentration, and this 2-quartet G-quadruplex is antiparallel. Flanking bases increase the K+ binding cooperativity. To decipher the folding pathways, we investigated the kinetics of K+ binding to telomeric (hybrid) and c-myc (parallel) G-quadruplexes. G-quadruplexes fold via branched pathways with multiple parallel reactions. Up to six states (one ensemble without K+, two ensembles with 1-K+ and three ensembles with 2-K+) are separated based on their formation rates and ion mobility spectrometry. All G-quadruplexes first form long-lived misfolded structures (off-pathway compared to the most stable structures) containing one K+ and two quartets in an antiparallel stacking arrangement. The results highlight the particular ruggedness of G-quadruplex nucleic acid folding landscapes. Misfolded structures can play important roles for designing artificial G-quadruplex based structures, and for conformational selection by ligands or proteins in a biological context.
| S-EPMC5159560 | biostudies-literature
Project description:This review is focused on the structural and physicochemical aspects of metal cation coordination to G-Quadruplexes (GQ) and their effects on GQ stability and conformation. G-quadruplex structures are non-canonical secondary structures formed by both DNA and RNA. G-quadruplexes regulate a wide range of important biochemical processes. Besides the sequence requirements, the coordination of monovalent cations in the GQ is essential for its formation and determines the stability and polymorphism of GQ structures. The nature, location, and dynamics of the cation coordination and their impact on the overall GQ stability are dependent on several factors such as the ionic radii, hydration energy, and the bonding strength to the O6 of guanines. The intracellular monovalent cation concentration and the localized ion concentrations determine the formation of GQs and can potentially dictate their regulatory roles. A wide range of biochemical and biophysical studies on an array of GQ enabling sequences have generated at a minimum the knowledge base that allows us to often predict the stability of GQs in the presence of the physiologically relevant metal ions, however, prediction of conformation of such GQs is still out of the realm.
| S-EPMC5016522 | biostudies-literature
Project description:Background and objectiveThe ginsenoside compound K [20-o-beta-dglucopyranosyl-20 (S)-protopanaxadiol; CK] is the main deglycosylated metabolite of ginsenoside. As a rare ginsenoside converted from the active substance of ginseng by intestinal bacteria, CK has higher biological activity than other ginsenosides. It has demonstrated diverse and intriguing biological activities, including anti-carcinogenic, anti-diabetic, anti-inflammation, anti-allergy, anti-angiogenesis, anti-aging, neuroprotective, and hepatoprotective effects. The purpose of this review was to elucidate the rich pharmacological activities and related mechanisms of ginsenoside CK in vivo and in vitro, as well as the potential therapeutic value of CK as a drug in a variety of systemically related diseases.MethodsThe PubMed database was searched for articles published in English from February 2008 to December 2021 using related keywords such as "Ginsenoside compound K", "compound K", and "CK". About 140 research papers and reports written in English were identified. These papers mainly concentrated on the pharmacological activities of CK in cancer prevention, immune regulation, diabetic improvement, central nervous system (CNS) protection, cardiovascular protection, skin improvement, and hepatoprotection.Key content and findingsThis paper describes the synthesis, pharmacokinetics, and adverse reactions of CK, as well as great detailed summarized of the relevant pharmacological activities. Such diverse intriguing biological properties of CK have been found.ConclusionsOn account of CK's numerous pharmacological activities and anti-carcinogenic, anti-inflammation, antiallergic, anti-diabetic, anti-angiogenesis, anti-aging, neuroprotective, and hepatoprotective effects, strong evidence is available for CK as a preventive or therapeutic agent for various diseases. However, further studies are needed to evaluate the safety and effectiveness of CK as a drug and its application in the medical field.
| S-EPMC8908159 | biostudies-literature