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Effects of phosphorylase kinase or glycogen phosphorylase inhibitor on gintonin (GT) or LPA-mediated astrocytic glycogenolysis and effects of gintonin on glycogen synthase in normoxia for 0.5 h. a, b K252a (0.5 μM), an inhibitor of phosphorylase kinase, and isofagomine (300 μM), an inhibitor of glycogen phosphorylase, attenuated GT (1 μg/mL) and LPA (1 μM)-mediated astrocytic glycogenolysis. *p < 0.01 and **p < 0.001 compared with GT-untreated or control cells (Con); #p < 0.05 compared with GT or LPA alone treatment. c Concentration- and time-dependent effects of GT on the phosphorylation of glycogen phosphorylase. Inset, the representative immunoblotting bands after immunoprecipitation show GT-mediated elevations in glycogen phosphorylase phosphorylation, brain form (GPBB). Inset also shows 10% input lysate (Input). #p < 0.05, compared with GT-untreated cells. d Immunoblotting on effect of GT on the phosphorylation of glycogen synthase. GS, glycogen synthase, pGS, phosphorylated glycogen synthase. *p < 0.01 compared with the absence of GT. Data are presented as the mean ± SEM (n = 4–5)
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Astrocytes are a unique brain cell-storing glycogen and express lysophosphatidic acid (LPA) receptors. Gintonin is a ginseng-derived exogenous G protein-coupled LPA receptor ligand. Accumulating evidence shows that astrocytes serve as an energy supplier to neurons through astrocytic glycogenolysis under physiological and pathophysiological conditio...
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Glycogen phosphorylase kinase β-subunit (PHKB) is a regulatory subunit of phosphorylase kinase (PHK), involving in the activation of glycogen phosphorylase (GP) and the regulation of glycogen breakdown. Emerging evidence suggests that PHKB plays a role in tumor progression. However, the function of PHKB in HCC progression remains elusive. Here, our...
Citations
... The gintonin-enriched extract (GEF) is comprised of a large proportion of gintonin, linoleic acid, phosphatidic acid (Pa), and other bio-reactive lysophospholipids. The unique feature of gintonin is that it uses G-protein-coupled LPA receptor signaling pathways by which gintonin induces a broad spectrum of hormetic dose responses that affect (1) human dermal fibroblast cell proliferation [123,124], (2) human/rabbit corneal cell repair [125], (3) modulation of the mouse blood brain barrier [126], (4) angiogenesis and wound healing using HUVEC models [127], (5) glycogenolysis and astrocyte preconditioning [128], and (6) beta-amyloid-induced dysfunction in mouse models via cholinergic stimulation of ACH release [129]. ...
... Ginseng has been linked to this astrocyte-neuron interaction, since gintonin is an exogenous protein-coupled LPA receptor ligand. As a result of this biological framework, Choi et al. [128] assessed the capacity of gintonin to affect astrocyte glycogenolysis, ATP production, glutamate uptake, and cell viability under a range of biological conditions, including hypoxia and re-oxygenation stress states. The gintonin treatment increased astrocyte glycogenolysis via LPA receptors under both stress and non-stress-related conditions in an hormetic dose-response fashion. ...
This paper demonstrates that ginseng mixtures and individual ginseng chemical constituents commonly induce hormetic dose responses in numerous biological models for endpoints of biomedical and clinical relevance, typically providing a mechanistic framework. The principal focus of ginseng hormesis-related research has been directed toward enhancing neuroprotection against conditions such as Alzheimer’s and Parkinson’s Diseases, stroke damage, as well as enhancing spinal cord and peripheral neuronal damage repair and reducing pain. Ginseng was also shown to reduce symptoms of diabetes, prevent cardiovascular system damage, protect the kidney from toxicities due to immune suppressant drugs, and prevent corneal damage, amongst other examples. These findings complement similar hormetic-based chemoprotective reports for other widely used dietary-type supplements such as curcumin, ginkgo biloba, and green tea. These findings, which provide further support for the generality of the hormetic dose response in the biomedical literature, have potentially important public health and clinical implications.
... It can increase the sensitivity of hypoxic cells to RT, reversing or reducing the hypoxic state of solid tumors [28]. Therefore, during the RT, if hypoxic cells have the opportunity to achieve reoxygenation, this will reduces the negative effects of hypoxic cells, which will increase the killing effect of RT on the initial hypoxic cells [29,30]. ...
As known, radiation therapy (RT) can exacerbate the degree of hypoxia of tumor cells, which induces serious resistance to RT and in turn, is the greatest obstacle to RT. Reoxygenation can restore the hypoxic state of tumor cells, which plays an important role in reshaping tumor microenviroment for achieving optimal therapeutic efficacy. Herein, we report for the first time that microwave (MW)-triggered IL-Quercetin-CuO-SiO2@ZrO2-PEG nanosuperparticles (IQuCS@Zr-PEG NSPs) have been used to achieve an optimal RT therapeutic outcomes by the strategy of upregulating tumor reoxygenation, i.e. hypoxic cells acquire oxygen and return to normal state.
Methods: We prepared a promising multifunctional nanosuperparticle to upregulate tumor reoxygenation by utilizing CuO nanoparticle to generate oxygen under MW irradiation in the tumor microenvironment. The IQuCS@Zr-PEG NSPs were obtained by introducing CuO nanoparticles, MW sensitizer of 1-butyl-3-methylimidazolium hexafluorophosphate (IL), radiosensitizer of Quercetin (Qu) and surface modifier of monomethoxy polyethylene glycol sulfhyl (mPEG-SH, 5k Da) into mesoporous sandwich SiO2@ZrO2 nanosuperparticles (SiO2@ZrO2 NSPs). The release oxygen by IQuCS@Zr-PEG NSPs under MW irradiation was investigated by a microcomputer dissolved oxygen-biochemical oxygen demand detector (DO-BOD) test. Finally, we used the 99mTc-HL91 labeled reoxygenation imaging, Cellular immunofluorescence, immunohistochemistry, and TUNEL experiments to verify that this unique MW-responsive reoxygenation enhancer can be used to stimulate reshaping of the tumor microenvironment.
Results: Through experiments we found that the IQuCS@Zr-PEG NSPs can persistently release oxygen under the MW irradiation, which upregulates tumor reoxygenation and improve the combined tumor treatment effect of RT and microwave thermal therapy (MWTT). Cellular immunofluorescence and immunohistochemistry experiments demonstrated that the IQuCS@Zr-PEG NSPs can downregulate the expression of hypoxia-inducible factor 1α (HIF-1α) under MW irradiation. The 99mTc-HL91 labeled reoxygenation imaging experiment also showed that the oxygen generated by IQuCS@Zr-PEG NSPs under MW irradiation can significantly increase the reoxygenation capacity of tumor cells, thus reshaping the tumor microenvironment. The high inhibition rate of 98.62% was achieved in the antitumor experiments in vivo. In addition, the IQuCS@Zr-PEG NSPs also had good computed tomography (CT) imaging effects, which can be used to monitor the treatment of tumors in real-time.
Conclusions: The proof-of-concept strategy of upregulating tumor reoxygenation is achieved by MW triggered IQuCS@Zr-PEG NSPs, which has exhibited optimal therapeutic outcomes of combination of RT and MWTT tumor. Such unique MW-responsive reoxygenation enhancer may stimulate the research of reshaping tumor microenvironment for enhancing versatile tumor treatment.
... We later demonstrated that lysophosphatidic acids (LPAs) were a major functional component of gintonin [4] and showed that gintonin could activate LPA receptors, a kind of G-protein coupled receptor (GPCR), in animal cells. We reported that gintonin exerted diverse cellular effects in vitro through LPA receptor activation, including transient intracellular calcium mobilization, morphological changes, enhancement of proliferation and migration, vascular development, and neurite retraction [5][6][7][8][9]. Gintonin has also consistently shown memory improvement, hippocampal cell proliferation, and neurodegenerative disease antagonism in animal models [5,6,[9][10][11]. ...
... Its main functional ingredients are LPAs. We have also shown that gintonin LPAs function as an LPA receptor-ligand exhibiting diverse biological effects in vitro and in vivo [4][5][6][7][8][9]. In a subsequent study, we showed that gintonin contains other bioactive lipids besides LPAs, listed in order of prevalence: linoleic acid > phosphatidic acids > LPAs > LPIs [12]. ...
... Co-treatment with the GPR40 antagonist, GW1100, also partially inhibited gintonin-stimulated insulin secretion (Figure 4a). Gintonin-induced insulin secretion was inhibited by GW1100 only under hyperglycemic conditions (16.7 mM glucose), indicating that gintonin-mediated augmentation of insulin secretion was glucose-dependent, as previously reported for long-chain fatty acid-stimulation of insulin secretion via GPR40 [7]. However, the LPA 1/3 antagonist Ki16425 did not influence gintonin-mediated insulin secretion ( Figure S2a), consistent with a previous report on GEF [12]. ...
Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.
... In brief, LPA can induce several of the hallmarks of reactive astrogliosis such as cytoskeletal re-organization [31][32][33], proliferation [34] and axonal outgrowth [35,36]. Moreover, LPA has been reported to modulate astrocytic glucose uptake [37] and glycogenolysis [38], suggesting that LPA is involved in metabolic regulation of astrocytes and hence to the overall CNS energy metabolism, due to the central role of astrocytes in it. Other possible secondary, indirect effects of astrocytic ATX/LPA include neuronal differentiation [39] and possibly synaptic transmission [40] that require further exploration. ...
Autotaxin (ATX) is secreted by various type of cells in health and disease and catalyzes the extracellular production of lysophosphatidic acid (LPA). In turn, LPA is a bioactive lysophospholipid promoting a wide array of cellular functions through its multiple G-protein coupled receptors, differentially expressed in almost all cell types. ATX expression has been shown necessary for embryonic development and has been suggested to participate in the pathogenesis of different chronic inflammatory diseases and cancer. Deregulated ATX and LPA levels have been reported in multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE). ATX genetic deletion from macrophages and microglia (CD11b+ cells) attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in MS/EAE. In this report, increased ATX staining was localized to glial fibrillary acidic protein positive (GFAP+) cells, mostly astrocytes, in spinal cord sections from EAE mice at the peak of the disease. However, genetic deletion of ATX from GFAP+ cells resulted in embryonic lethality, suggesting a major role for ΑΤΧ expression from GFAP+ cells in embryonic development, that urges further dissection. Moreover, the re-expression of ATX from GFAP+ cells during the pathogenesis of EAE, reinforces the concept that ATX/LPA is a developmental program aberrantly reactivated upon chronic inflammation.
... Previous studies have shown that gintonin containing LPAs acts through LPA receptors (Hwang et al., 2012;Choi et al., 2019). As LPA1 and LPA3 expression on oligodendrocytes has been reported (Allard et al., 1998;Weiner et al., 1998;Yu et al., 2004), we made use of Ki16425, an antagonist of LPA1 and LPA3 receptors to investigate whether the increase of cell number was mediated by LPA1/3 receptors. ...
Although evidence on myelin diseases is steadily accumulating, effective preventive or therapeutic strategies against them have not been established so far. Ginseng is well known for its beneficial effects on health and diseases; however, detailed studies on ginseng’s effects on myelin-producing oligodendrocytes have not been performed yet. In this study, we investigated the function of gintonin—an active component of ginseng—on the proliferation, differentiation, and survival of oligodendrocyte lineage cells. We performed real-time percutaneous coronary intervention, Western blot, and immunocytochemistry on primary oligodendrocyte precursor cell cultures and in vitro myelinating co-cultures. Our results show that gintonin stimulates oligodendrocyte precursor cell proliferation. Gintonin’s effect was inhibited by Ki16425, an antagonist of lysophosphatidic acid 1/3 receptors. Interestingly, with regard to cell differentiation, gintonin facilitated late differentiation of oligodendrocyte development, but not early differentiation. Moreover, it showed protective effects on oligodendrocyte lineage cells against endoplasmic reticulum stress-induced cell death, potentially by modulating unfolded protein responses. Our results suggest that gintonin is a potential therapeutic candidate in the treatment of myelin diseases.
... RNase with antieHIV-reverse transcription, ribonuclease, and cell-free translation-inhibitory activities has been reported [40e44]; however, GMP does not exhibit RNase activity. Gintonin, a novel ginseng-derived exogenous G proteinecoupled lysobisphosphatidic acids (LPA) receptor ligand [45], was extracted from PQ and P. ginseng, containing major latex-like protein 151 and GMP [46]. Glycosylation is one of the most significant and widespread posttranslational activities, which not only affects the biological activity but also plays a role in signal transduction [47]. ...
Background
Peptides have diverse and important physiological roles in plants and are ideal markers for species identification. It is unclear whether there are specific peptides in Panax quinquefolius L. (PQ). The aims of this study were to identify Quinetides, a series of diverse posttranslational modified native peptides of the ribonuclease-like storage protein (ginseng major protein), from PQ to explore novel peptide markers and develop a new method to distinguish PQ from Panax ginseng.
Methods
We used different fragmentation modes in the LTQ Orbitrap analysis to identify the enriched Quinetide targets of PQ, and we discovered Quinetide markers of PQ and P. ginseng using ultrahigh-performance liquid chromatography–quadrupole time-of-flight mass spectrometry analysis. These “peptide markers” were validated by simultaneously monitoring Rf and F11 as standard ginsenosides.
Results
We discovered 100 Quinetides of PQ with various post-translational modifications (PTMs), including a series of glycopeptides, all of which originated from the protein ginseng major protein. We effectively distinguished PQ from P. ginseng using new “peptide markers.” Four unique peptides (Quinetides TP6 and TP7 as markers of PQ and Quinetides TP8 and TP9 as markers of P. ginseng) and their associated glycosylation products were discovered in PQ and P. ginseng.
Conclusion
We provide specific information on PQ peptides and propose the clinical application of peptide markers to distinguish PQ from P. ginseng.
Aging is a cellular state characterized by a permanent cessation of cell division and evasion of apoptosis. DNA damage, metabolic dysfunction, telomere damage, and mitochondrial dysfunction are the main factors associated with senescence. Aging increases β-galactosidase activity, enhances cell spreading, and induces Lamin B1 loss, which further accelerate the aging process. It is associated with a variety of diseases, such as Alzheimer's disease, Parkinson's, type 2 diabetes, and chronic inflammation. Ginseng is a traditional Chinese medicine with anti-aging effects. The active components of ginseng, including saponins, polysaccharides, and active peptides, have antioxidant, anti-apoptotic, neuroprotective, and age-delaying effects. DNA damage is the main factor associated with aging, and the mechanism through which the active ingredients of ginseng reduce DNA damage and delay aging has not been comprehensively described. This review focuses on the anti-aging mechanisms of the active ingredients of ginseng. Furthermore, it broadens the scope of ideas for further research on natural products and aging.
Most diseases are preventable, and they are related to what we eat. Moreover, most doctor visits are for lifestyle-based diseases, which means they can be prevented by adopting a healthy lifestyle. Treating the causes of illness rather than symptoms of the disease is not only safer and cheaper, but it can work better. In this context, the Special Issue on “Nutraceuticals in Immune System” for the journal Molecules was launched in January 2020. Soon after that, the world was ravaged by the COVID-19 pandemic causing a grave health threat. Paradoxically, the immune system can be both friend and foe of COVID-19. The COVID-19 manifests only mild to moderate symptoms for most infected people who recover without hospitalisation, demonstrating the proper functioning of the immune system in fighting such an infection. For some, however, the overactivation of the immune response causing “cytokine storm” has dire consequences, with severe respiratory failure leading to multiple organ failure, which could be fatal. In fact, most deaths from COVID-19 came from organ inflammation due to undesirable immune system responses. As such, the COVID-19 is a good case in point, demonstrating the importance of a healthy immune system.
Nutraceuticals are products derived from food sources with health benefits in addition to the basic nutritional values. Many of them can positively affect and enhance the immune system, which is particularly pertinent in the current turbulent times of COVID-19. Not surprisingly, nutraceutical sales rose dramatically during the pandemic period. However, much research is still needed to understand how natural products interact with the immune system to clarify their chemical compositions, mechanisms of action and effects on health and illnesses.
This Special Issue provided an open forum for researchers to share their research findings in the growing interest of nutraceuticals. We received an overwhelming response with a total of 33 submissions, of which only nine original research papers and ten reviews were accepted after rigorous peer-review. The included articles research into natural substances of interest in nutraceuticals ranging from herbal medicine to vitamins to microbiota-derived metabolites. The investigated immune-related responses include cancer, neurological diseases, gastroenterological disorders, inflammatory conditions, and infections.
We thank the publisher for this excellent opportunity to serve the research community. As academic editors for this Special Issue, it is our pleasure to review these insightful manuscripts first-hand. We thank all the authors for their contributions. The collected works represent our current understanding and latest findings of nutraceuticals in immune system, which we hope will continue to inspire knowledge quests into the field of nutraceuticals.
Ginseng (Panax ginseng C.A. Meyer) is a traditional Oriental herbal drug widely used in East Asia. Its main active ingredients are ginsenosides whose constituents are known to have various pharmacological activities such as anticancer, antinociception, and neuroprotection. The analgesic effects of ginsenosides, such as Rg1, Rg2, and Rb1, as well as compound K, are well known and the analgesic mechanism of action in inflammatory pain models is thought to be the down regulation of pro-inflammatory cytokine expression (TNF-α IL-1β, and IL-6). Several studies have also demonstrated that ginsenosides regulate neuropathic pain through the modulation of estrogen receptors. Recently, an increasing number of pathways have emerged in relation to the antinociceptive effect of ginseng and ginsenosides. Therefore, this review presents our current understanding of the effectiveness of ginseng in chronic pain and how its active constituents regulate nociceptive responses and their mechanisms of action.
