• Journal of Korean Medicine Rehabilitation
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• v.30 no.3
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• pp.71-87
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• 2020

Objectives Even though the various alternative herbal medicine has applied for osteoarthritis (OA) treatment, its scientific proof remains uncertain. The aim of the present study evaluates the effects of Chulbu-tang on inflammatory responses in a monosodium iodoacetate (MIA)-induced osteoarthritis rat model. Methods OA rat model was established by MIA injection in intra-joint of rats. 7 days after, OA rats except OA control rats were administrated Chulbu-tang (100 or 200 mg/kg) or Indomathacin (5 mg/kg) once a day for 14 days. The weight-bearing ability of hind paws were measured when group isolation 0, 7, and 14 days. Western blotting was performed to examine the knockdown/overexpressing efficiency of Chulbu-tang. In addition, cartilage destruction was measured histologically. Results Chulbu-tang treatment significantly reduced the protein expressions of inflammatory mediators such as inducible nitric oxide synthase and cyclooxygenase 2, and inhibited inflammatory cytokines including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6 through nuclear factor-kappa B (NF-κB) inactivation. Moreover, anti-oxidant enzymes such as superoxide dismutase and glutathione peroxidase-1/2 through nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway significantly increased. Our findings indicate that Chulbu-tang has the potential therapeutic effect on OA through inhibiting the inflammatory responses via inactivating NF-κB signaling pathway. In addition, upregulation of Nrf2 led to anti-oxidant effects. Conclusions Taken together, Chulbu-tang is believed to have antioxidant, anti-inflammatory effects, and cartilage protection for arthritis-causing rats.

• Journal of dental hygiene science
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• v.19 no.3
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• pp.198-204
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• 2019

Background: Oxidative stress is a known to be associated with in the pathogenesis of many inflammatory diseases, including periodontitis. Ursolic acid is a pentacyclic triterpenoid with has antimicrobial, antioxidative, and anticancer properties. However, the role of ursolic acid in the regulating of osteogenesis remains undetermined. This study was aimed to elucidate the crucial osteogenic effects of ursolic acid and its ability to inhibit oxidative stress by targeting the immediate early response 3 (IER3)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Methods: Cell proliferation was determined using water-soluble tetrazolium salt assay, cell differentiation was evaluated by alkaline phosphatase (ALP) activity, and formation of calcium nodules was detected using alizarin red S stain. Generation of reactive oxygen species (ROS) was determined using by DCFH-DA fluorescence dye in hydrogen peroxide ($H_2O_2$)-treated MG-63 cells. Expression levels of IER3, Nrf2, and heme oxygenase-1 (HO-1) were analyzed using western blot analysis. Results: Our results showed that ursolic acid up-regulated the proliferation of osteoblasts without any cytotoxic effects, and promoted ALP activity and mineralization. $H_2O_2$-induced ROS generation was found to be significantly inhibited on treatment with ursolic acid. Furthermore, in $H_2O_2$-treated cells, the expression of the early response genes: IER3, Nrf2, and Nrf2-related phase II enzyme (HO-1) was enhanced in the presence of ursolic acid. Conclusion: The key findings of the present study elucidate the protective effects of ursolic acid against oxidative stress conditions in osteoblasts via the IER3/Nrf2 pathway. Thus, ursolic acid may be developed as a preventative and therapeutic agent for mineral homeostasis and inflammatory diseases caused due to oxidative injury.

• Journal of Ginseng Research
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• v.47 no.4
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• pp.552-560
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• 2023

Background: Ginseng Radix (Panax ginseng Meyer, Araliaceae) has been used medicinally to treat the brain and nervous system problems worldwide. Recent studies have revealed physiological effects that could potentially benefit cognitive performance or mood. The present study aimed to investigate the antidepressant effects of Korean red ginseng water extract (KGE) and its active component in an unpredictable chronic mild stress (UCMS)-induced animal model and elucidate the underlying mechanisms. Methods: The antidepressant potential of the UCMS model was evaluated using the sucrose preference test and open field tests. The behavioral findings were further corroborated by the assessment of neurotransmitters and their metabolites from the prefrontal cortex and hippocampus of rats. Three doses of KGE (50, 100, and 200 mg/kg) were orally administered during the experiment. Furthermore, the mechanism underlying the antidepressant-like action of KGE was examined by measuring the levels of brain-derived neurotrophic factor (BDNF)/CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1) proteins in the prefrontal cortex of UCMS-exposed rats. Results: KGE treatment normalized UCMS-induced depression-related behaviors. Neurotransmitter studies conducted after completing behavioral experiments demonstrated that KGE caused a reduction in the ratio of serotonin and dopamine, indicating a decrease in serotonin and dopamine turnover. Moreover, the expression of BDNF, Nrf2, Keap1 and AKT were markedly increased by KGE in the prefrontal cortex of depressed rats. Conclusion: Our results provide evidence that KGE and its constituents exert antidepressant effects that mediate the dopaminergic and serotonergic systems and expression of BDNF protein in an animal model.

• Herbal Formula Science
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• v.26 no.1
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• pp.1-12
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• 2018

Objectives : Cheongnoimyungshin-hwan (CNMSH) is a Herbal compound prescription that is composed mainly of herbal medicines such as Ginseng Radix Alba, Angelicae Gigantis Radix, Dioscoreae Rhizoma, Longan Arillus and cornus cervi parvum, and for the purpose of improving memory and preventing dementia. Methods : In this study, it was investigated whether CNMSH could suppress inflammatory response and oxidative stress in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. As a result, CNMSH decreased expression of inducible nitric oxide (NO) synthase and cyclooxygenase-2, and also inhibited production of NO, prostaglandin E2. Results : This effect was associated with the suppression of the expression of p65, one of the nuclear factor-kappaB ($NF-{\kappa}B$) subunits, and increased expression of $I{\kappa}B-{\alpha}$, inhibit the $NF-{\kappa}B$ transcription factor. In addition, CNMSH significantly blocked intracellular reactive oxygen species accumulation in response to LPS stimulation. Furthermore, CNMSH increased expression of nuclear factor erythroid 2-related factor (Nrf)-2 activation and heme oxygenase (HO)-1. Conclusions : Therefore, it has been shown anti-inflammatory and antioxidant effects by inhibiting the expression and production of inflammatory mediators in LPS-stimulated macrophages, and is associated with ROS generation and is activated by Nrf2/HO-1 signaling pathway.

• Journal of Ginseng Research
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• v.42 no.3
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• pp.379-388
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• 2018

Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. KRGE (37.5 mg/ kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2-related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood-brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood-brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD.

• The Korean Journal of Pain
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• v.34 no.1
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• pp.35-46
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• 2021

Background: The present investigation explored the therapeutic actions of oleuropein along with the possible signaling pathway involved in attenuating neuropathic pain in chronic constriction injury (CCI) and vincristine-induced neuropathic pain in male rats. Methods: Four loose ligatures were placed around the sciatic nerve to induce CCI, and vincristine (50 ㎍/kg) was injected for 10 days to develop neuropathic pain. The development of cold allodynia, mechanical allodynia, and mechanical hyperalgesia was assessed using different pain-related behavioral tests. The levels of H2S, cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), orexin, and nuclear factor erythroid-2-related factor 2 (Nrf2) were measured in the sciatic nerve. Results: Treatment with oleuropein for 14 days led to significant amelioration of behavioral manifestations of neuropathic pain in two pain models. Moreover, oleuropein restored both CCI and vincristine-induced decreases in H2S, CSE, CBS, orexin, and Nrf2 levels. Co-administration of suvorexant, an orexin receptor antagonist, significantly counteracted the pain-attenuating actions of oleuropein and Nrf2 levels without modulating H2S, CSE and CBS. Conclusions: Oleuropein has therapeutic potential to attenuate the pain manifestations in CCI and vincristine-induced neuropathic pain, possibly by restoring the CSE, CBS, and H2S, which may subsequently increase the expression of orexin and Nrf2 to ameliorate behavioral manifestations of pain.

• Biomolecules & Therapeutics
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• v.30 no.6
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• pp.570-575
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• 2022

Stress breaks body balance, which can cause diverse physiological disorders and worsen preexisting diseases. However, recent studies have reported that controllable stress and overcoming from stress reinforce resilience to resist against more intense stress afterwards. In this study, we investigated the protective effect of corticosterone (CORT), a representative stress hormone against hydrogen peroxide (H₂O₂)-induced neuronal cell death and its underlying molecular mechanism in SH-SY5Y cells, a human neuroblastoma cell line. The decreased cell viability by H₂O₂ was effectively restored by the pretreatment with low concentration of CORT (0.03 μM for 72 h) in the cells. H₂O₂-increased expression of apoptotic markers such as PUMA and Bim was decreased by CORT pretreatment. Furthermore, pretreatment of CORT attenuated H₂O₂-mediated oxidative damages by upregulation of antioxidant enzymes via activation of nuclear factor erythroid 2-related factor 2 (Nrf2). These findings suggest that low concentration of CORT with eustressed condition enhances intracellular self-defense against H₂O₂-mediated oxidative cell death, suggesting a role of low concentration of CORT as one of key molecules for resilience and neuronal cell survival.

• Bulletin of the Korean Chemical Society
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• v.35 no.12
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• pp.3623-3626
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• 2014

Nuclear factor-erythroid 2-related factor 2 (Nrf2) regulates the expression of over 200 genes of antioxidant and phase II drug-metabolizing enzymes, and is highly expressed in non-small cell lung cancer (NSCLC). Nine derivatives of 4-(2-cyclohexylethoxy)aniline were designed. Our previous study demonstrated that IM3829 increases radiosensitivity of several lung cancer cells in vitro and in vivo. Here, biological effects of IM3829 derivatives (2a-2i) were evaluated. Compound 2g derivative effectively inhibits mRNA and protein expression of Nrf2 and HO-1. In addition, we observed over two fold enhancement in IR-induced cell death, from $2.90{\pm}0.22$ to $6.02{\pm}0.87$, in H1299 cancer cell-line. Among the nine derivatives, compound 2g derivative exhibited the highest enhancement of radiosensitizing effect via inhibition of Nrf2 activity.

• BMB Reports
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• v.53 no.5
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• pp.272-277
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• 2020

Protein kinase CK2 downregulation induces premature senescence in various human cell types via activation of the reactive oxygen species (ROS)-p53-p21^Cip1/WAF1 pathway. The transcription factor "nuclear factor erythroid 2-related factor 2" (Nrf2) plays an important role in maintaining intracellular redox homeostasis. In this study, Nrf2 overexpression attenuated CK2 downregulation-induced ROS production and senescence markers including SA-β-gal staining and activation of p53-p21^Cip1/WAF1 in human breast (MCF-7) and colon (HCT116) cancer cells. CK2 downregulation reduced the transcription of Nrf2 target genes, such as glutathione S-transferase, glutathione peroxidase 2, and glutathione reductase 1. Furthermore, CK2 downregulation destabilized Nrf2 protein via inhibiting autophagic degradation of Kelch-like ECH-associated protein 1 (Keap1). Finally, CK2 downregulation decreased the nuclear import of Nrf2 by deactivating AMP-activated protein kinase (AMPK). Collectively, our data suggest that both Keap1 stabilization and AMPK inactivation are associated with decreased activity of Nrf2 in CK2 downregulation-induced cellular senescence.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.3
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• pp.239-249
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• 2021

The present study explored the therapeutic potential of hydrogen sulfide (H2S) in restoring aging-induced loss of cardioprotective effect of remote ischemic preconditioning (RIPC) along with the involvement of signaling pathways. The left hind limb was subjected to four short cycles of ischemia and reperfusion (IR) in young and aged male rats to induce RIPC. The hearts were subjected to IR injury on the Langendorff apparatus after 24 h of RIPC. The measurement of lactate dehydrogenase, creatine kinase and cardiac troponin served to assess the myocardial injury. The levels of H2S, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible factor (HIF-1α) were also measured. There was a decrease in cardioprotection in RIPC-subjected old rats in comparison to young rats along with a reduction in the myocardial levels of H2S, CBS, CSE, HIF-1α, and nuclear: cytoplasmic Nrf2 ratio. Supplementation with sodium hydrogen sulfide (NaHS, an H2S donor) and l-cysteine (H2S precursor) restored the cardioprotective actions of RIPC in old hearts. It increased the levels of H2S, HIF-1α, and Nrf2 ratio without affecting CBS and CSE. YC-1 (HIF-1α antagonist) abolished the effects of NaHS and l-cysteine in RIPC-subjected old rats by decreasing the Nrf2 ratio and HIF-1α levels, without altering H2S. The late phase of cardioprotection of RIPC involves an increase in the activity of H2S biosynthetic enzymes, which increases the levels of H2S to upregulate HIF-1α and Nrf2. H2S has the potential to restore aging-induced loss of cardioprotective effects of RIPC by upregulating HIF-1α/Nrf2 signaling.