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Rb1 modulated the NADPH/NADP + and glutathione (GSH)/GSSG ratios in RCECs exposed to high glucose. (a) NADPH and GSH levels. (b) NADP + and GSSG levels. (c) NADPH/NADP + and GSH/GSSG ratios. Data are expressed as the means ± SD. ## p < 0.01 versus 5.5 mM glucose; * p < 0.05 and ** p < 0.01 versus 30 mM glucose.
Source publication
(1) Aims: The present study aimed to observe the effects of Ginsenoside Rb1 on high glucose-induced endothelial damage in rat retinal capillary endothelial cells (RCECs) and to investigate the underlying mechanism. (2) Methods: Cultured RCECs were treated with normal glucose (5.5 mM), high glucose (30 mM glucose), or high glucose plus Rb1 (20 μM)....
Contexts in source publication
Context 1
... investigate the redox status of the cells, we measured NADPH, NADP + , GSH, and GSSG levels. As shown in Figure 8, high glucose induced a significant decrease in NADPH and GSH concentrations and an increase in NADP + and GSSG levels, causing the NADPH/NADP + and GSH/GSSG ratios to significantly decrease (p < 0.01). RCECs treated with 20 μM Rb1 showed a significant increase in NADPH and GSH levels (p < 0.05), while the NADP + and GSSG levels in these cells were markedly decreased (p < 0.05); consequently, the intracellular NADPH/NADP + and GSH/GSSG ratios were increased (p < 0.01) (Figure 8). ...
Context 2
... shown in Figure 8, high glucose induced a significant decrease in NADPH and GSH concentrations and an increase in NADP + and GSSG levels, causing the NADPH/NADP + and GSH/GSSG ratios to significantly decrease (p < 0.01). RCECs treated with 20 μM Rb1 showed a significant increase in NADPH and GSH levels (p < 0.05), while the NADP + and GSSG levels in these cells were markedly decreased (p < 0.05); consequently, the intracellular NADPH/NADP + and GSH/GSSG ratios were increased (p < 0.01) (Figure 8). These data show that Rb1 maintains the intracellular redox balance by increasing the NADPH and GSH levels and reducing intracellular oxidative stress. ...
Context 3
... investigate the redox status of the cells, we measured NADPH, NADP + , GSH, and GSSG levels. As shown in Figure 8, high glucose induced a significant decrease in NADPH and GSH concentrations and an increase in NADP + and GSSG levels, causing the NADPH/NADP + and GSH/GSSG ratios to significantly decrease (p < 0.01). RCECs treated with 20 µM Rb1 showed a significant increase in NADPH and GSH levels (p < 0.05), while the NADP + and GSSG levels in these cells were markedly decreased (p < 0.05); consequently, the intracellular NADPH/NADP + and GSH/GSSG ratios were increased (p < 0.01) (Figure 8). ...
Context 4
... shown in Figure 8, high glucose induced a significant decrease in NADPH and GSH concentrations and an increase in NADP + and GSSG levels, causing the NADPH/NADP + and GSH/GSSG ratios to significantly decrease (p < 0.01). RCECs treated with 20 µM Rb1 showed a significant increase in NADPH and GSH levels (p < 0.05), while the NADP + and GSSG levels in these cells were markedly decreased (p < 0.05); consequently, the intracellular NADPH/NADP + and GSH/GSSG ratios were increased (p < 0.01) (Figure 8). These data show that Rb1 maintains the intracellular redox balance by increasing the NADPH and GSH levels and reducing intracellular oxidative stress. ...
Citations
... After 15 days of eye drop administration, the db/db mice yielded better visual function [144]. Other ginsenosides, GRe, GRd, and GRb1 also showed strong potential to scavenge ROS and inhibit apoptosis and angiogenesis, attenuating HG-induced cell injury [145][146][147][148]. ...
Diabetic retinopathy (DR) is a major vision-threatening disease among the working-age population worldwide. Present therapeutic strategies such as intravitreal injection of anti-VEGF and laser photocoagulation mainly target proliferative DR. However, there is a need for early effective management in patients with early stage of DR before its progression into the more severe sight-threatening proliferative stage. Nutraceuticals, natural functional foods with few side effects, have been proposed to be beneficial in patients with DR. Over the decades, many studies, either in vitro or in vivo, have demonstrated the advantages of a number of nutraceuticals in DR with their antioxidative, anti-inflammatory, neuroprotective, or vasoprotective effects. However, only a few clinical trials have been conducted, and their outcomes varied. The low bioavailability and instability of many nutraceuticals have indeed hindered their utilization in clinical use. In this context, nanoparticle carriers have been developed to deliver nutraceuticals and to improve their bioavailability. Despite its preclinical nature, research of interventive nutraceuticals for DR may yield promising information in their clinical applications.
... Similar to our results, it has been shown previously that PC shows inhibitory activity on NADPH oxidase (NOX) [39], producing ROS by utilizing NADPH [28]. Fan et al. [40] showed that NOX inhibition augments NADPH and NAD+ levels. Based on Fan et al. [40]'s report, we assumed that the NADPH levels increased following NOX inhibition by PC, and the NAD+ and NAM levels were elevated in parallel depending on the reduced NADPH requirement. ...
... Fan et al. [40] showed that NOX inhibition augments NADPH and NAD+ levels. Based on Fan et al. [40]'s report, we assumed that the NADPH levels increased following NOX inhibition by PC, and the NAD+ and NAM levels were elevated in parallel depending on the reduced NADPH requirement. The elevated NAM level might have stimulated NAMPT upregulation in the group with NR supplemented with a low dose of PC to promote the NAD+ salvage pathway. ...
Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Phycocyanin oligopeptide (PC), a phytonutrient found in blue-green algae, has antioxidant and anti-inflammatory properties. This study explored the effects of NR, PC, and their combination on the telomere length as well as inflammatory and antioxidant status of rats under chronic stress conditions (CS). Forty-nine rats were allocated into seven groups: control, chronic stress (CS), CS with NR (26.44 mg/kg), a low dose of 2.64 mg/kg of PC (PC-LD), or a high dose of 26.44 mg/kg PC (PC-HD), NR + PC-LD, and NR + PC-HF. The rats were given daily corticosterone injections (40 mg/kg) to induce stress conditions, or NR and PC were orally administered for 21 days. NR and PC supplementation, particularly NR plus PC, increased the serum antioxidant enzyme activities, hepatic nicotinamide adenine (NAD+) content, and telomere length (p < 0.001 for all) compared to the CS group. The levels of serum malondialdehyde (MDA), liver interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), IL-1β, and IL-8 were reduced under the CS condition (p < 0.001). In addition, CS decreased the levels of hepatic telomere-related proteins and sirtuins (SIRT1 and 3), whereas administration of NR and PC or their combination to CS-exposed rats increased the levels of telomere-related proteins (e.g., POT1b, TRF1 and TRF2), SIRT3 and NAMPT (p < 0.05). In conclusion, NR and PC, especially their combination, can alleviate metabolic abnormalities by enhancing hepatic cytokines, SIRT3, NAMPT, and NAD+ levels in CS-exposed rats. More research is needed to further elucidate the potential health effects of the combination of NR and PC in humans.
... Other studies have revealed that decreased NMNAT2 expression was markedly correlated with downregulation of SIRT6 expression in DR. It has been reported that high glucose-induced endothelial damage is related to NAD depletion in cells [36]. A study on cardiac hypertrophy showed that SIRT6 participated in the anti-hypertrophic signals of NMNAT2 overexpression, which suggested that upon activation of SIRT6 via intracellular NAD, the protein level and enzymatic activity of NMNAT2 were dramatically reduced [9]. ...
Purpose
To determine the expression levels of SIRT6 and NMNAT2 in diabetic retinopathy (DR).
Methods
We obtained peripheral blood mononuclear cells (PBMCs) and vitreous samples from 77 patients with type 2 diabetes mellitus: 52 with DR and 25 without DR, and 27 healthy control subjects. Western blot analysis and qRT-PCR were performed to evaluate the expression of SIRT6 and NMNAT2 in their PBMCs. The levels of IL-1β, IL-6, and TNF-α in the vitreous fluid were determined by ELISA. Immunohistochemistry was performed to detect the expression of SIRT6 and NMNAT2 in proliferative DR (PDR) and the control subjects.
Results
The expression of SIRT6 and NMNAT2 was markedly downregulated in DR patients, which was negatively correlated with the increased expression of IL-1β, IL-6 and TNF-α. Additionally, we observed decreased expression of SIRT6 and NMNAT2 in the fibrovascular membranes of PDR patients.
Conclusions
The downregulated expression of SIRT6 and NMNAT2 in PDR patients reveals a potential pathogenic association; more extended studies could verify them as potential therapeutic targets.
... Similar to our results, It has been shown that PC has inhibitory activity on NADPH oxidase (NOX) [37], producing ROS by utilizing NADPH [26]. Fan et al. [38] showed that NOX inhibition augments NADPH and NAD+ levels. Based on Fan et al. [38]'s report, we assumed that NADPH levels increased following NOX inhibition by PC, and NAD+ and NAM levels were elevated in parallel depending on the reduced NADPH requirement. ...
... Fan et al. [38] showed that NOX inhibition augments NADPH and NAD+ levels. Based on Fan et al. [38]'s report, we assumed that NADPH levels increased following NOX inhibition by PC, and NAD+ and NAM levels were elevated in parallel depending on the reduced NADPH requirement. The elevated NAM level might have stimulated NAMPT upregulation in the NR plus low-dose PC-supplemented group to promote the NAD+ salvage pathway. ...
Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Phycocyanin oligopeptide (PC), a phytonutrient found in blue-green algae, has antioxidant and anti-inflammatory properties. This study explored the effects of NR, PC, and their combination on telomere length, inflammatory and antioxidant status in rats under chronic stressed conditions (CS). Forty-nine rats were allocated into seven groups: Control, chronic stress (CS), CS with NR (26.44 mg/kg), a low dose of 2.64 mg/kg of PC (PC-LD), or a high dose of 26.44 mg/kg PC (PC-HD), NR+PC-LD and NR+PC-HF. Rats were given daily corticosterone injections (40 mg/kg) to induce stressed conditions, or NR and PC were orally administered for 21 days. NR and PC supplementation, particularly NR plus PC, increased the serum antioxidant enzyme activities, hepatic nicotinamide adenine (NAD+) content, and telomere length (P<0.001 for all) compared with the CS group. The levels of serum malondialdehyde (MDA), liver interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), IL-1β, and IL-8 were reduced under CS condition (P<0.001). In addition, CS decreased the levels of hepatic telomere-related proteins and sirtuin1 (SIRT1-3), while supplementation of NR and PC alone or in combination increased the levels of telomere-related proteins (e.g., POT1b, TRF1, and TRF2), and SIRT3, NAMPT P<0.05. In conclusion, NR and PC, especially their combination, can alleviate metabolic abnormalities by enhancing hepatic cytokines, SIRT3, NAMPT, and NAD+ levels in CS-exposed rats. More research is needed to elucidate further the potential health effects of the combination of NR and PC in humans.
... Ginsenoside Rg1 may increase SIRT3 expression at both the mRNA and protein levels in HSCs/HPCs cells of an aging rat model [38]. In rat retinal capillary endothelial cells, Rb1 recovers the protein expression of SIRT1 and SIRT3 during high glucose-induced endothelial damage [39]. Rb1 also increases SIRT activity, which is decreased by high glucose [39]. ...
... In rat retinal capillary endothelial cells, Rb1 recovers the protein expression of SIRT1 and SIRT3 during high glucose-induced endothelial damage [39]. Rb1 also increases SIRT activity, which is decreased by high glucose [39]. In this study, KRGE contains 0.83 mg/g ginsenoside Rg1 and 5.52 mg/g ginsenoside Rb1. ...
Astrocytes play a key role in brain functioning by providing energy to neurons. Increased astrocytic mitochondrial functions by Korean red ginseng extract (KRGE) have been investigated in previous studies. KRGE administration induces hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in astrocytes in the adult mouse brain cortex. VEGF expression can be controlled by transcription factors, such as the HIF-1α and estrogen-related receptor α (ERRα). However, the expression of ERRα is unchanged by KRGE in astrocytes of the mouse brain cortex. Instead, sirtuin 3 (SIRT3) expression is induced by KRGE in astrocytes. SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that resides in the mitochondria and maintains mitochondrial homeostasis. Mitochondrial maintenance requires oxygen, and active mitochondria enhance oxygen consumption, resulting in hypoxia. The effects of SIRT3 on HIF-1α-mediated mitochondria functions induced by KRGE are not well established. We aimed to investigate the relationship between SIRT3 and HIF-1α in KRGE-treated normoxic astrocyte cells. Without changing the expression of the ERRα, small interfering ribonucleic acid targeted for SIRT3 in astrocytes substantially lowers the amount of KRGE-induced HIF-1α proteins. Reduced proline hydroxylase 2 (PHD2) expression restores HIF-1α protein levels in SIRT3-depleted astrocytes in normoxic cells treated with KRGE. The translocation of outer mitochondrial membranes 22 (Tom22) and Tom20 is controlled by the SIRT3-HIF-1α axis, which is activated by KRGE. KRGE-induced Tom22 increased oxygen consumption and mitochondrial membrane potential, as well as HIF-1α stability through PHD2. Taken together, in normoxic astrocytes, KRGE-induced SIRT3 activated the Tom22–HIF-1α circuit by increasing oxygen consumption in an ERRα-independent manner.
... To compensate for the lack of NAD+ in LPS-stimulated macrophages, CK increased the expression of genes involved in the NAD+ salvage pathway. Ginsenoside Rb1, which can be converted to CK [56], has been reported to be crucial against hyperglycemic oxidative damage by modulating the NAD+-SIRT1 axis [62]. NAD+, a cofactor that activates SIRT1 [63], can also be supported by CK. ...
Inflammation, an innate immune response mediated by macrophages, has been a hallmark leading to the pathophysiology of diseases. In this study, we examined the inhibitory effects of ginsenoside compound K (CK) on lipopolysaccharide (LPS)-induced inflammation and metabolic alteration in RAW 264.7 macrophages by regulating sirtuin 1 (SIRT1) and histone deacetylase 4 (HDAC4). LPS suppressed SIRT1 while promoting HDAC4 expression, accompanied by increases in cellular reactive oxygen species accumulation and pro-inflammatory gene expression; however, the addition of CK elicited the opposite effects. CK ameliorated the LPS-induced increase in glycolytic genes and abrogated the LPS-altered genes engaged in the NAD+ salvage pathway. LPS decreased basal, maximal, and non-mitochondrial respiration, reducing ATP production and proton leak in macrophages, which were abolished by CK. SIRT1 inhibition augmented Hdac4 expression along with increased LPS-induced inflammatory and glycolytic gene expression, while decreasing genes that regulate mitochondrial biogenesis; however, its activation resulted in the opposite effects. Inhibition of HDAC4 enhanced Sirt1 expression and attenuated the LPS-induced inflammatory gene expression. In conclusion, CK exerted anti-inflammatory and antioxidant properties with the potential to counteract the alterations of energy metabolism, including glycolysis and mitochondrial respiration, through activating SIRT1 and repressing HDAC4 in LPS-stimulated macrophages.
... Таким образом, исследование влияния пептида KE на функции стволовых клеток человека имеет важное научнопрактическое значение для понима ния его геро и иммунопротекторного действия. NAD (nicotinamide adenine dinucleotide), PARP и SIRT [14]. Экспрессия SIRT1 снижается при старении, что приводит к митохондриальной дис функции, развитию воспалительных реакций, ней догенеративных и других ассоциированных с воз растом заболеваний. ...
... Важную роль в защите ДНК от повреждения при окислительном стрессе и геропротекции игра ют белки семейства сиртуинов (silent information regulator, SIRT 1-7). Сиртуины представляют собой семейство никотинамидадениндинуклеотид (НАД)зависимых белков, регулирующих транс крипцию и клеточное старение при помощи деаце тилирования гистоновых и негистоновых белков мишеней [10,14,21,45]. Повреждение ДНК при окислительном стрессе приводит к активации сиг нальных каскадов, в которые вовлечены NMNAT (nicotinamide mononucleotide adenylyltransferase 1), но с контрольными по двухстороннему критерию Стьюдента при p<0,05. ...
... Another active compound, ginsenoside Rb1, protected REC viability and mitochondrial DNA copy number and reduced ROS generation via enhanced Sirt activity and Sirt1/Sirt3 expression. The protective mechanism of Rb1 is due to modulation of the NAD-poly (ADP-ribose) polymerase-Sirt signaling pathway and maintenance of the cellular reducing power (Fan et al., 2019). ...
Epigenetics focuses on DNA methylation, histone modification, chromatin remodeling, noncoding RNAs, and other gene regulation mechanisms beyond the DNA sequence. In the past decade, epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels. The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated. The diabetic condition facilitates epigenetic changes and influences target gene expression. In this review, we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.
... Meanwhile, the mediation effects of Rb1 were accompanied by the upregulation of Nrf2/HO-1 and downregulation of NLRP3 inflammasome, as well as the improvement in depressive-like behavior in mice (exposed to CSDS). It has been reported that ginsenoside Rb1 attenuates oxidative damage through the SIRT1 signaling pathways in vitro experiments (60). Ginsenoside Rb1 inhibited the expression of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 in I/R injury rats via activating of TLR4/MyD88 and SIRT1 signaling cascades (61). ...
Ginsenoside Rb1, a diol-type ginseng saponin, has various positive effects on the central nervous system. This study aimed to evaluate the antidepressant effects of Rb1 on chronic social defeat stress (CSDS) induced behavioral deficits and the exact neural cascades linked with inflammatory processes. The results of behavioral tests such as social interaction, tail suspension, and forced swimming revealed that oral treatment of Rb1 (35 and 70 mg/kg) alleviates depression-like behavior. Rb1 treatment increased antioxidant enzyme activity (SOD and CAT) and reduced lipid peroxidation (LPO) content in the hippocampus. Rb1 also suppressed the production of inflammatory cytokines (TNF-α, IL-18, and IL-1β) as well as microglial activation (Iba1) in response to CSDS. Moreover, Rb1 administration considerably reduced the protein expression of NLRP3 (inflammasome) and promoted the protein expressions of Nrf2, HO-1 and Sirtuin1(SIRT1) activation in the hippocampus. Our findings showed that Rb1 effectively restores the depressive-like behavior in CSDS-induced model mice, mediated in part by the normalization of oxidative stress levels. The suppression of neuroinflammation is mediated by the regulation of SIRT1-NLRP3/Nrf2 pathways. Our results asserted that the Rb1 is a novel therapeutic candidate for treating depression.
... Ginsenoside Rb1 is a panaxadiol saponin extracted from ginseng, Panax notoginseng, American ginseng, and other Araliaceae plants. It has been reported that ginsenoside Rb1 exerts multiple pharmacological actions such as cerebral protection, cardiovascular system protection, immunoregulation and anti-leukemia effects (Zymone et al., 2018;Fan et al., 2019;Cao et al., 2020). Although the pharmacological effects of ginsenoside Rb1 have been gradually understood over the years, its potential hepatotoxic effect (especially TP-induced hepatotoxicity), and the mechanism involved, remain unclear. ...
Triptolide (TP) is the major bioactive compound extracted from Tripterygium wilfordii Hook F. It exerts anti-inflammatory, antirheumatic, antineoplastic, and neuroprotective effects. However, the severe hepatotoxicity induced by TP limits its clinical application. Ginsenoside Rb1 has been reported to possess potential hepatoprotective effects, but its mechanism has not been fully investigated. This study was aimed at investigating the effect of ginsenoside Rb1 against TP-induced cytotoxicity in HL-7702 cells, as well as the underlying mechanism. The results revealed that ginsenoside Rb1 effectively reversed TP-induced cytotoxicity in HL-7702 cells. Apoptosis induced by TP was suppressed by ginsenoside Rb1 via inhibition of death receptor-mediated apoptotic pathway and mitochondrial-dependent apoptotic pathway. Pretreatment with ginsenoside Rb1 significantly reduced Bax/Bcl-2 ratio and down-regulated the expression of Fas, cleaved poly ADP-ribose polymerase (PARP), cleaved caspase-3, and -9. Furthermore, ginsenoside Rb1 reversed TP-induced cell cycle arrest in HL-7702 cells at S and G2/M phase, via upregulation of the expressions of cyclin-dependent kinase 2 (CDK2), cyclin E, cyclin A, and downregulation of the expressions of p53, p21, and p-p53. Ginsenoside Rb1 increased glutathione (GSH) and superoxide dismutase (SOD) levels, but decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Pretreatment with ginsenoside Rb1 enhanced the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), total Nrf2, NAD(P)H: quinone oxidoreductases-1 (NQO-1), heme oxygenase-1 (HO-1), and Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 complex. Therefore, ginsenoside Rb1 effectively alleviates TP-induced cytotoxicity in HL-7702 cells through activation of the Keap1/Nrf2/ARE antioxidant pathway.
