Lee JE

References (11)

Title : SGLT2 and DPP4 inhibitors improve Alzheimer's disease-like pathology and cognitive function through distinct mechanisms in a T2D-AD mouse model - Sim_2023_Biomed.Pharmacother_168_115755
Author(s) : Sim AY , Choi DH , Kim JY , Kim ER , Goh AR , Lee YH , Lee JE
Ref : Biomed Pharmacother , 168 :115755 , 2023
Abstract : Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium-glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D-AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D-AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D-AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid beta (Abeta) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1-7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Abeta accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms.
ESTHER : Sim_2023_Biomed.Pharmacother_168_115755
PubMedSearch : Sim_2023_Biomed.Pharmacother_168_115755
PubMedID: 37871560

Title : A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice - Min_2021_Life.(Basel)_11_
Author(s) : Min HS , Lee JE , Ghee JY , Kang YS , Cha JJ , Han JY , Han SY , Cha DR
Ref : Life (Basel) , 11 : , 2021
Abstract : Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.
ESTHER : Min_2021_Life.(Basel)_11_
PubMedSearch : Min_2021_Life.(Basel)_11_
PubMedID: 33803842

Title : Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus - Sim_2021_Front.Neurosci_15_708547
Author(s) : Sim AY , Barua S , Kim JY , Lee YH , Lee JE
Ref : Front Neurosci , 15 :708547 , 2021
Abstract : Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid beta hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.
ESTHER : Sim_2021_Front.Neurosci_15_708547
PubMedSearch : Sim_2021_Front.Neurosci_15_708547
PubMedID: 34489627

Title : Ethanol Extract of Oldenlandia diffusa Herba Attenuates Scopolamine-Induced Cognitive Impairments in Mice via Activation of BDNF, P-CREB and Inhibition of Acetylcholinesterase - Lee_2018_Int.J.Mol.Sci_19_363
Author(s) : Lee JE , Song HS , Park MN , Kim SH , Shim BS , Kim B
Ref : Int J Mol Sci , 19 :363 , 2018
Abstract : Though Oldenlandia diffusa Herba (ODH) has been known to exhibit anti-cancer and anti-inflammatory effects, its anti-amnestic effect has never been reported so far. The aim of this present study was to elucidate the anti-amnestic effect of ODH. ODH pretreatment significantly reduced escape latency of scopolamine treated Institute of Cancer Research (ICR) mice compared to untreated control groups in a Morris water maze test. Similarly, the passive avoidance test showed that ODH treatment recovered the scopolamine induced amnesia in the ICR mouse model. Concentration of Ach in brains of ODH treated mice was increased compared to that of scopolamine treated mice. In addition, activity of acetylcholinesterase (AChE) was notably decreased by ODH. The protein expression of brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding protein (p-CREB) (Ser133) was increased in ODH pretreated group compared to control group. Consistently, immunohistochemistry (IHC) revealed the elevated expression of brain-derived neurotrophic factor (BDNF) and p-CREB in brains of ODH treated mice compared to the control group. Overall, these findings suggest that ODH has anti-amnestic potential via activation of BDNF and p-CREB and inhibition of AChE in mice with scopolamine induced amnesia.
ESTHER : Lee_2018_Int.J.Mol.Sci_19_363
PubMedSearch : Lee_2018_Int.J.Mol.Sci_19_363
PubMedID: 29370115

Title : Association Between Timed Up and Go Test and Future Dementia Onset - Lee_2018_J.Gerontol.A.Biol.Sci.Med.Sci_73_1238
Author(s) : Lee JE , Shin DW , Jeong SM , Son KY , Cho B , Yoon JL , Park BJ , Kwon IS , Lee J , Kim S
Ref : J Gerontol A Biol Sci Med Sci , 73 :1238 , 2018
Abstract : Background: This study evaluated whether baseline results of the Timed Up and Go (TUG) test is associated with future dementia occurrence. Methods: Using the Korean National Health Insurance Service-National Health Screening Cohort database, we identified 49,283 subjects without a dementia diagnosis who participated in the National Screening Program for Transitional Ages at 66 years of age during 2007-2012. Gait impairment was defined as taking longer than 10 seconds to perform the TUG test. Dementia occurrence was defined by the first prescription for acetylcholinesterase inhibitors or N-Methyl-D-Aspartate receptor antagonist with an International Classification of Diseases 10th Revision (ICD-10) code for dementia (F00, F01, F02, F03, G30, F051, or G311) during 2007-2013. Cox proportional hazard regression models were used to assess the hazard ratios for dementia occurrence according to baseline TUG test results. Results: Mean follow-up period was 3.8 years. Incidence rates of dementia were 4.6 and 6.8 cases per 1,000 person-years in the normal and impaired TUG groups, respectively. The impaired TUG group showed a higher risk of total dementia incidence (adjusted hazard ratio [aHR], 1.34; 95% confidence interval [95% CI], 1.14-1.57). Subtype analysis showed that the impaired TUG group had a higher risk of Alzheimer's disease (aHR, 1.26; 95% CI, 1.06-1.51) and vascular dementia (aHR, 1.65; 95% CI, 1.19-2.30). Conclusions: The TUG test result was associated with future dementia occurrence. More vigilant follow-up and early intervention to prevent dementia would benefit elderly people with impaired TUG test result.
ESTHER : Lee_2018_J.Gerontol.A.Biol.Sci.Med.Sci_73_1238
PubMedSearch : Lee_2018_J.Gerontol.A.Biol.Sci.Med.Sci_73_1238
PubMedID: 29346523

Title : Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex - Jeong_2016_Yonsei.Med.J_57_165
Author(s) : Jeong da U , Oh JH , Lee JE , Lee J , Cho ZH , Chang JW , Chang WS
Ref : Yonsei Med J , 57 :165 , 2016
Abstract : PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND
METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by (1)(8)F-2-fluoro-2-deoxyglucose positron emission tomography.
RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.
ESTHER : Jeong_2016_Yonsei.Med.J_57_165
PubMedSearch : Jeong_2016_Yonsei.Med.J_57_165
PubMedID: 26632397

Title : SUMO modification regulates the protein stability of NDRG1 - Lee_2015_Biochem.Biophys.Res.Commun_459_161
Author(s) : Lee JE , Kim JH
Ref : Biochemical & Biophysical Research Communications , 459 :161 , 2015
Abstract : N-myc Downstream Regulated Gene 1 (NDRG1) is a metastasis suppressor protein which suppresses metastasis without affecting primary tumorigenesis. There have been many reports about the anti-metastatic function of NDRG1 in various cancers. However, the regulatory mechanism of NDRG1 at the protein level has not been studied widely. Here, we found that NDRG1 is posttranslationally modified by Small Ubiquitin-like Modifier (SUMO), preferentially by SUMO-2, and the major SUMO acceptor site of NDRG1 is Lys 14. Using various SUMO-2 modification status mimicking NDRG1 mutants, we characterized the role of SUMO-2 modification on NDRG1. SUMO-2 modification does not affect the subcellular distribution of NDRG1. However, the protein stability of NDRG1 is influenced by SUMO-2 modification. We found that both the wildtype and the SUMO modification site mutant form of the NDRG1 protein were very stable but the protein stability of SUMO-2 fused NDRG1 K14R had dramatically decreased. In addition, the expression of p21 is downregulated by overexpression of SUMO-2 fused NDRG1 K14R mutants. These results indicate that SUMO-2 modification is implicated in the modulation of NDRG1 protein level and function. This novel link between SUMO modification and regulation of NDRG1 could be a therapeutic target for treatment of various metastatic cancers.
ESTHER : Lee_2015_Biochem.Biophys.Res.Commun_459_161
PubMedSearch : Lee_2015_Biochem.Biophys.Res.Commun_459_161
PubMedID: 25712528

Title : Improvements in memory after medial septum stimulation are associated with changes in hippocampal cholinergic activity and neurogenesis - Jeong_2014_Biomed.Res.Int_2014_568587
Author(s) : Jeong da U , Lee JE , Lee SE , Chang WS , Kim SJ , Chang JW
Ref : Biomed Res Int , 2014 :568587 , 2014
Abstract : Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.
ESTHER : Jeong_2014_Biomed.Res.Int_2014_568587
PubMedSearch : Jeong_2014_Biomed.Res.Int_2014_568587
PubMedID: 25101288

Title : Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction - Min_2014_Lab.Invest_94_598
Author(s) : Min HS , Kim JE , Lee MH , Song HK , Kang YS , Lee MJ , Lee JE , Kim HW , Cha JJ , Chung YY , Hyun YY , Han JY , Cha DR
Ref : Lab Invest , 94 :598 , 2014
Abstract : Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFbeta1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kappaB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.
ESTHER : Min_2014_Lab.Invest_94_598
PubMedSearch : Min_2014_Lab.Invest_94_598
PubMedID: 24687121

Title : 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration - Ferchmin_2014_Neurotoxicol_44C_80
Author(s) : Ferchmin PA , Andino M , Reyes Salaman R , Alves J , Velez-Roman J , Cuadrado B , Carrasco M , Torres-Rivera W , Segarra A , Martins AH , Lee JE , Eterovic VA
Ref : Neurotoxicology , 44C :80 , 2014
Abstract : Many organophosphorous esters synthesized for applications in industry, agriculture, or warfare irreversibly inhibit acetylcholinesterase, and acute poisoning with these compounds causes life-threatening cholinergic overstimulation. Following classical emergency treatment with atropine, an oxime, and a benzodiazepine, surviving victims often suffer brain neurodegeneration. Currently, there is no pharmacological treatment to prevent this brain injury. Here we show that a cyclic diterpenoid, (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R) ameliorates the damage caused by diisopropylfluorophosphate (DFP) in the hippocampal area CA1. DFP has been frequently used as a surrogate for the warfare nerve agent sarin. In rats, DFP is lethal at the dose used to cause brain damage. Therefore, to observe brain damage in survivors, the death rate was reduced by pre-administration of the peripherally acting antidotes pyridostigmine and methyl atropine or its analog ipratropium. Pyridostigmine bromide, methyl atropine nitrate, and ipratropium bromide were dissolved in saline and injected intramuscularly at 0.1mg/kg, 20mg/kg, and 23mg/kg, respectively. DFP (9mg/kg) dissolved in cold water was injected intraperitoneally. 4R (6mg/kg) dissolved in DMSO was injected subcutaneously, either 1h before or 5 or 24h after DFP. Neurodegeneration was assessed with Fluoro-Jade B and amino cupric silver staining; neuroinflammation was measured by the expression of nestin, a marker of activated astrocytes. Forty-eight hours after DFP administration, 4R decreased the number of dead neurons by half when injected before or after DFP. 4R also significantly decreased the number of activated astrocytes. These data suggest that 4R is a promising new drug that could change the therapeutic paradigm for acute poisoning with organophosphorous compounds by the implementation of a second-stage intervention after the classical countermeasure treatment.
ESTHER : Ferchmin_2014_Neurotoxicol_44C_80
PubMedSearch : Ferchmin_2014_Neurotoxicol_44C_80
PubMedID: 24928201

Title : Carriage of the V279F null allele within the gene encoding Lp-PLA(2) is protective from coronary artery disease in South Korean males - Jang_2011_PLoS.One_6_e18208
Author(s) : Jang Y , Waterworth D , Lee JE , Song K , Kim S , Kim HS , Park KW , Cho HJ , Oh IY , Park JE , Lee BS , Ku HJ , Shin DJ , Lee JH , Jee SH , Han BG , Jang HY , Cho EY , Vallance P , Whittaker J , Cardon L , Mooser V
Ref : PLoS ONE , 6 :e18208 , 2011
Abstract : BACKGROUND: The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA(2)) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA(2) in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted. METHODOLOGY/PRINCIPAL FINDINGS: PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA(2) activity and CAD risk.
CONCLUSIONS: Natural deficiency in Lp-PLA(2) activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA(2) and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.
ESTHER : Jang_2011_PLoS.One_6_e18208
PubMedSearch : Jang_2011_PLoS.One_6_e18208
PubMedID: 21490708
Gene_locus related to this paper: human-PLA2G7