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Takako Yokozawa - One of the best experts on this subject based on the ideXlab platform.
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Kinetics and molecular docking studies of Loganin, morroniside and 7-O-galloyl-d-sedoheptulose derived from Corni fructus as cholinesterase and β-secretase 1 inhibitors
Archives of Pharmacal Research, 2016Co-Authors: Himanshu Kumar Bhakta, Chan Hum Park, Takako Yokozawa, Hyun Ah Jung, Jae Sue ChoiAbstract:We evaluated the major active components isolated from Corni Fructus: Loganin, morroniside, and 7- O -galloyl- d -sedoheptulose as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) for use in Alzheimer’s disease treatment. These compounds exhibited predominant cholinesterase (ChEs) inhibitory effects with IC_50 values of 0.33, 3.95, and 10.50 ± 1.16 µM, respectively, for AChE, and 33.02, 37.78, and 87.94 ± 4.66 µM, respectively, for BChE. Kinetics studies revealed that Loganin and 7- O -galloyl- d -sedoheptulose inhibited AChE with characteristics typical of mixed inhibitors, while morroniside was found to be a noncompetitive inhibitor against AChE and also exerted mixed BChE inhibitory activities. For BACE1, Loganin showed noncompetitive type inhibitory effects, while morroniside and 7- O -galloyl- d -sedoheptulose were found to be mixed inhibitors. Furthermore, these compounds exhibited dose-dependent inhibitory activity with ONOO^−-mediated protein tyrosine nitration. Molecular docking simulation of these compounds demonstrated negative binding energies for ChEs, and BACE1, indicating high affinity and tighter binding capacity for the active site of the enzyme. Loganin was the most potent inhibitor against both ChEs and BACE1. The data suggest that these compounds together can act as a triple inhibitor of AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for Alzheimer’s disease treatment.
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Kinetic and molecular docking studies of Loganin and 7-O-galloyl-d-sedoheptulose from Corni Fructus as therapeutic agents for diabetic complications through inhibition of aldose reductase
Archives of Pharmacal Research, 2015Co-Authors: Hyun Ah Jung, Chan Hum Park, Takako Yokozawa, Takashi Tanaka, Sang Ho Oh, Jae Sue ChoiAbstract:Aldose reductase (AR) is a key enzyme in the polyol pathway that is strongly implicated in the pathogenesis of diabetic complications. AR inhibitors have been proposed as therapeutic agents for diabetic complications through suppression of sorbitol formation and accumulation. In this study, we evaluated whether two major compounds of Corni Fructus, Loganin and 7- O -galloyl- d -sedoheptulose, had an inhibitory effect on diabetic complications through AR inhibition. Because the iridoid glycoside Loganin and the low-molecular-weight polyphenol 7- O -galloyl- d -sedoheptulose showed marginal inhibitory activities against rat lens AR (RLAR) and human recombinant AR (HRAR) in inhibition assays, we performed enzyme kinetic analyses and molecular simulation of the interaction of these two compounds with AR to further investigate their potential as inhibitors of diabetic complications. In kinetic analysis using Lineweaver–Burk plots and Dixon plots, Loganin and 7- O -galloyl- d -sedoheptulose were both mixed inhibitors of RLAR with inhibition constants ( K _i) of 27.99 and 128.68 μΜ, respectively. Moreover, molecular docking simulation of both compounds demonstrated negative binding energies (Autodock 4.0 = −6.7; −7.5 kcal/mol; Fred 2.0 = −59.4; −63.2 kcal/mol) indicating a high affinity and tight binding capacity for the active site of the enzyme. Iridoid nucleus and aromatic ring systems and glycoside and sedoheptulose moieties were found to bind tightly to the specificity pocket and the anion binding pocket in RLAR through Phe123, His111, Trp21, Tyr49, His111, and Trp112 residues. Our results clearly indicate that Loganin and 7- O -galloyl- d -sedoheptulose have great promise for the treatment of diabetic complications through inhibition of AR.
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hepato protective effects of Loganin iridoid glycoside from corni fructus against hyperglycemia activated signaling pathway in liver of type 2 diabetic db db mice
Toxicology, 2011Co-Authors: Chan Hum Park, Takashi Tanaka, Ji Hyun Kim, Eun Ju Cho, Jong Cheol Park, Naotoshi Shibahara, Takako YokozawaAbstract:Accumulating evidence indicates that uncontrolled diabetes leads to the progression of diabetic complications such as liver disorder. The present study was carried out to elucidate the protective role of Loganin extracted from Corni Fructus against hepatic oxidative stress caused by type 2 diabetes. Loganin (20 or 100mg/kg body weight/day, p.o.) was administered every day for 8 weeks to db/db mice, and its effect was assessed on comparison with vehicle-treated db/db and m/m mice. The administration of Loganin led to a decrease in glucose and elevation of leptin in serum. The diabetic oxidative stress was attenuated by Loganin through inhibitions of reactive oxygen species production and lipid peroxidation in the serum and liver. The expression of proteins induced by oxidative stress was significantly up-regulated in the liver of diabetic db/db mice; however, the expressions of both Nox-4 and p22(phox) were decreased significantly by Loganin administration. Loganin showed a crucial effect in the inflammation-activated signaling pathway through the regulation of NF-κB, COX-2, and iNOS. It was also found to regulate the anti-inflammatory factors Nrf-2 and HO-1 in hepatic tissue. Moreover, expression of MCP-1 was significantly down-regulated in the Loganin-treated db/db mice. Furthermore, Loganin administration showed a protective effect against apoptosis by the regulation of Bcl-2 and cytochrome c. The present study demonstrated that the administration of Loganin isolated from Corni Fructus had a protective effect against hepatic oxidative stress under type 2 diabetes through regulations of protein expressions related to oxidative stress, inflammation, and apoptosis.
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evaluation of Loganin iridoid glycoside from corni fructus on hepatic and renal glucolipotoxicity and inflammation in type 2 diabetic db db mice
European Journal of Pharmacology, 2010Co-Authors: Noriko Yamabe, Chan Hum Park, Takashi Tanaka, Naotoshi Shibahara, Jeong Sook Noh, Ki Sung Kang, Takako YokozawaAbstract:Previously, we have reported that Corni Fructus possessed hypoglycemic and hypocholesterolemic effects in streptozotocin-induced type 1 diabetic rats and diet-induced hypercholesterolemic rats. Herein, we have focused on the effect and mechanism of Loganin, a major iridoid glycoside of Corni Fructus, on the type 2 diabetic db/db mice. Loganin was orally administered to db/db mice at a dose of 20 or 100 mg/kg body weight daily for 8 weeks. The biochemical factors and expressions of protein and mRNA related to lipid metabolism, inflammation, advanced glycation endproducts, and its receptor were measured. In Loganin-treated db/db mice, hyperglycemia and dyslipidemia were ameliorated in both the serum and hepatic tissue; however, in the kidney, only triglyceride was reduced. The enhanced oxidative stress was alleviated by Loganin through a decrease in thiobarbituric acid-reactive substances (liver and kidney) and reactive oxygen species (serum, liver, and kidney), as well as augmentation of the oxidized to reduced glutathione ratio (liver and kidney). The marked lipid-regulatory effect of Loganin was exerted in the liver of type 2 diabetic mice via suppressing mRNA expressions related to lipid synthesis and adjusting the abnormal expression of peroxisome proliferator-activated receptor α and sterol regulatory-element binding protein in the nucleus. Furthermore, Loganin inhibited advanced glycation endproduct formation and the expression of its receptor, and nuclear factor-kappa B-induced inflammation in the hepatic tissue of db/db mice. Loganin exhibits protective effects against hepatic injury and other diabetic complications associated with abnormal metabolic states and inflammation caused by oxidative stress and advanced glycation endproduct formation.
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bioactive constituents of corni fructus the therapeutic use of morroniside Loganin and 7 o galloyl d sedoheptulose as renoprotective agents in type 2 diabetes
Drug discoveries and therapeutics, 2010Co-Authors: Takako Yokozawa, Chan Hum Park, Naotoshi Shibahara, Jeong Sook Noh, K S Kang, N Yamabe, T TanakaAbstract:Corni Fructus, the fruit of Cornus officinalis Sieb. et Zucc. (Cornaceae), is an important crude herb used in Chinese medicine to exhibit several biological activities, including hypoglycemic, antineoplastic, and antimicrobial effects, and to improve liver and kidney functions. We have been investigating the mechanism and bioactive constituents of Corni Fructus using diabetic animal models. Morroniside, Loganin, and 7-O-galloyl-D-sedoheptulose, the main active compounds of Corni Fructus, exhibit the same lowering effects of elevated triglyceride, oxidative stress and advanced glycation endproduct (AGE) formation in the kidney of db/db mice. The effects of morroniside and 7-O-galloyl-D-sedoheptulose were mediated through modulation by renal sterol regulatory element binding proteins and nuclear factor-kappa B expression, but the effect of Loganin was presumably mediated by hypoglycemic and antioxidant effects in the kidney, and also indirectly by the amelioration of metabolic disorders in other organs such as the liver. These findings led us to conclude that morroniside, Loganin, and 7-O-galloyl-D-sedoheptulose would synergistically contribute to the inhibition of metabolic disorders (hyperglycemia and dyslipidemia), oxidative stress, inflammation, as well as AGE formation in the diabetic kidney.
Chan Hum Park - One of the best experts on this subject based on the ideXlab platform.
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Kinetics and molecular docking studies of Loganin, morroniside and 7-O-galloyl-d-sedoheptulose derived from Corni fructus as cholinesterase and β-secretase 1 inhibitors
Archives of Pharmacal Research, 2016Co-Authors: Himanshu Kumar Bhakta, Chan Hum Park, Takako Yokozawa, Hyun Ah Jung, Jae Sue ChoiAbstract:We evaluated the major active components isolated from Corni Fructus: Loganin, morroniside, and 7- O -galloyl- d -sedoheptulose as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) for use in Alzheimer’s disease treatment. These compounds exhibited predominant cholinesterase (ChEs) inhibitory effects with IC_50 values of 0.33, 3.95, and 10.50 ± 1.16 µM, respectively, for AChE, and 33.02, 37.78, and 87.94 ± 4.66 µM, respectively, for BChE. Kinetics studies revealed that Loganin and 7- O -galloyl- d -sedoheptulose inhibited AChE with characteristics typical of mixed inhibitors, while morroniside was found to be a noncompetitive inhibitor against AChE and also exerted mixed BChE inhibitory activities. For BACE1, Loganin showed noncompetitive type inhibitory effects, while morroniside and 7- O -galloyl- d -sedoheptulose were found to be mixed inhibitors. Furthermore, these compounds exhibited dose-dependent inhibitory activity with ONOO^−-mediated protein tyrosine nitration. Molecular docking simulation of these compounds demonstrated negative binding energies for ChEs, and BACE1, indicating high affinity and tighter binding capacity for the active site of the enzyme. Loganin was the most potent inhibitor against both ChEs and BACE1. The data suggest that these compounds together can act as a triple inhibitor of AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for Alzheimer’s disease treatment.
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Kinetic and molecular docking studies of Loganin and 7-O-galloyl-d-sedoheptulose from Corni Fructus as therapeutic agents for diabetic complications through inhibition of aldose reductase
Archives of Pharmacal Research, 2015Co-Authors: Hyun Ah Jung, Chan Hum Park, Takako Yokozawa, Takashi Tanaka, Sang Ho Oh, Jae Sue ChoiAbstract:Aldose reductase (AR) is a key enzyme in the polyol pathway that is strongly implicated in the pathogenesis of diabetic complications. AR inhibitors have been proposed as therapeutic agents for diabetic complications through suppression of sorbitol formation and accumulation. In this study, we evaluated whether two major compounds of Corni Fructus, Loganin and 7- O -galloyl- d -sedoheptulose, had an inhibitory effect on diabetic complications through AR inhibition. Because the iridoid glycoside Loganin and the low-molecular-weight polyphenol 7- O -galloyl- d -sedoheptulose showed marginal inhibitory activities against rat lens AR (RLAR) and human recombinant AR (HRAR) in inhibition assays, we performed enzyme kinetic analyses and molecular simulation of the interaction of these two compounds with AR to further investigate their potential as inhibitors of diabetic complications. In kinetic analysis using Lineweaver–Burk plots and Dixon plots, Loganin and 7- O -galloyl- d -sedoheptulose were both mixed inhibitors of RLAR with inhibition constants ( K _i) of 27.99 and 128.68 μΜ, respectively. Moreover, molecular docking simulation of both compounds demonstrated negative binding energies (Autodock 4.0 = −6.7; −7.5 kcal/mol; Fred 2.0 = −59.4; −63.2 kcal/mol) indicating a high affinity and tight binding capacity for the active site of the enzyme. Iridoid nucleus and aromatic ring systems and glycoside and sedoheptulose moieties were found to bind tightly to the specificity pocket and the anion binding pocket in RLAR through Phe123, His111, Trp21, Tyr49, His111, and Trp112 residues. Our results clearly indicate that Loganin and 7- O -galloyl- d -sedoheptulose have great promise for the treatment of diabetic complications through inhibition of AR.
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hepato protective effects of Loganin iridoid glycoside from corni fructus against hyperglycemia activated signaling pathway in liver of type 2 diabetic db db mice
Toxicology, 2011Co-Authors: Chan Hum Park, Takashi Tanaka, Ji Hyun Kim, Eun Ju Cho, Jong Cheol Park, Naotoshi Shibahara, Takako YokozawaAbstract:Accumulating evidence indicates that uncontrolled diabetes leads to the progression of diabetic complications such as liver disorder. The present study was carried out to elucidate the protective role of Loganin extracted from Corni Fructus against hepatic oxidative stress caused by type 2 diabetes. Loganin (20 or 100mg/kg body weight/day, p.o.) was administered every day for 8 weeks to db/db mice, and its effect was assessed on comparison with vehicle-treated db/db and m/m mice. The administration of Loganin led to a decrease in glucose and elevation of leptin in serum. The diabetic oxidative stress was attenuated by Loganin through inhibitions of reactive oxygen species production and lipid peroxidation in the serum and liver. The expression of proteins induced by oxidative stress was significantly up-regulated in the liver of diabetic db/db mice; however, the expressions of both Nox-4 and p22(phox) were decreased significantly by Loganin administration. Loganin showed a crucial effect in the inflammation-activated signaling pathway through the regulation of NF-κB, COX-2, and iNOS. It was also found to regulate the anti-inflammatory factors Nrf-2 and HO-1 in hepatic tissue. Moreover, expression of MCP-1 was significantly down-regulated in the Loganin-treated db/db mice. Furthermore, Loganin administration showed a protective effect against apoptosis by the regulation of Bcl-2 and cytochrome c. The present study demonstrated that the administration of Loganin isolated from Corni Fructus had a protective effect against hepatic oxidative stress under type 2 diabetes through regulations of protein expressions related to oxidative stress, inflammation, and apoptosis.
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evaluation of Loganin iridoid glycoside from corni fructus on hepatic and renal glucolipotoxicity and inflammation in type 2 diabetic db db mice
European Journal of Pharmacology, 2010Co-Authors: Noriko Yamabe, Chan Hum Park, Takashi Tanaka, Naotoshi Shibahara, Jeong Sook Noh, Ki Sung Kang, Takako YokozawaAbstract:Previously, we have reported that Corni Fructus possessed hypoglycemic and hypocholesterolemic effects in streptozotocin-induced type 1 diabetic rats and diet-induced hypercholesterolemic rats. Herein, we have focused on the effect and mechanism of Loganin, a major iridoid glycoside of Corni Fructus, on the type 2 diabetic db/db mice. Loganin was orally administered to db/db mice at a dose of 20 or 100 mg/kg body weight daily for 8 weeks. The biochemical factors and expressions of protein and mRNA related to lipid metabolism, inflammation, advanced glycation endproducts, and its receptor were measured. In Loganin-treated db/db mice, hyperglycemia and dyslipidemia were ameliorated in both the serum and hepatic tissue; however, in the kidney, only triglyceride was reduced. The enhanced oxidative stress was alleviated by Loganin through a decrease in thiobarbituric acid-reactive substances (liver and kidney) and reactive oxygen species (serum, liver, and kidney), as well as augmentation of the oxidized to reduced glutathione ratio (liver and kidney). The marked lipid-regulatory effect of Loganin was exerted in the liver of type 2 diabetic mice via suppressing mRNA expressions related to lipid synthesis and adjusting the abnormal expression of peroxisome proliferator-activated receptor α and sterol regulatory-element binding protein in the nucleus. Furthermore, Loganin inhibited advanced glycation endproduct formation and the expression of its receptor, and nuclear factor-kappa B-induced inflammation in the hepatic tissue of db/db mice. Loganin exhibits protective effects against hepatic injury and other diabetic complications associated with abnormal metabolic states and inflammation caused by oxidative stress and advanced glycation endproduct formation.
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bioactive constituents of corni fructus the therapeutic use of morroniside Loganin and 7 o galloyl d sedoheptulose as renoprotective agents in type 2 diabetes
Drug discoveries and therapeutics, 2010Co-Authors: Takako Yokozawa, Chan Hum Park, Naotoshi Shibahara, Jeong Sook Noh, K S Kang, N Yamabe, T TanakaAbstract:Corni Fructus, the fruit of Cornus officinalis Sieb. et Zucc. (Cornaceae), is an important crude herb used in Chinese medicine to exhibit several biological activities, including hypoglycemic, antineoplastic, and antimicrobial effects, and to improve liver and kidney functions. We have been investigating the mechanism and bioactive constituents of Corni Fructus using diabetic animal models. Morroniside, Loganin, and 7-O-galloyl-D-sedoheptulose, the main active compounds of Corni Fructus, exhibit the same lowering effects of elevated triglyceride, oxidative stress and advanced glycation endproduct (AGE) formation in the kidney of db/db mice. The effects of morroniside and 7-O-galloyl-D-sedoheptulose were mediated through modulation by renal sterol regulatory element binding proteins and nuclear factor-kappa B expression, but the effect of Loganin was presumably mediated by hypoglycemic and antioxidant effects in the kidney, and also indirectly by the amelioration of metabolic disorders in other organs such as the liver. These findings led us to conclude that morroniside, Loganin, and 7-O-galloyl-D-sedoheptulose would synergistically contribute to the inhibition of metabolic disorders (hyperglycemia and dyslipidemia), oxidative stress, inflammation, as well as AGE formation in the diabetic kidney.
Zenkong Dai - One of the best experts on this subject based on the ideXlab platform.
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Loganin ameliorates painful diabetic neuropathy by modulating oxidative stress inflammation and insulin sensitivity in streptozotocin nicotinamide induced diabetic rats
Cells, 2021Co-Authors: Yuchi Cheng, Yumin Chiu, Zenkong DaiAbstract:Loganin is an iridoid glycoside with antioxidant, anti-inflammatory, glucose-lowering activities which may address the pathological mechanisms of painful diabetic neuropathy (PDN) related to inflammation, oxidative stress, and hyperglycemia. This study investigated the underlying mechanisms of action of Loganin on PDN. The in vivo model of PDN was established by streptozotocin-nicotinamide (STZ-NA) induction in Sprague Dawley (SD) rats. Subsequently, Loganin (5 mg/kg) was administered by daily intraperitoneal injection. High-glucose stimulated human SH-SY5Y cells co-incubated with Loganin were used to mimic the in vitro model of PDN. Loganin improved PDN rats' associated pain behaviors (allodynia and hyperalgesia), insulin resistance index (HOMA-IR), and serum levels of superoxide dismutase (SOD), catalase and glutathione. Loganin also reduced pain-associated channel protein CaV3.2 and calcitonin gene-related peptide (CGRP) in the surficial spinal dorsal horn of PDN rats. Loganin inhibited oxidative stress and NF-κB activation and decreased the levels of mRNA and protein of proinflammatory factors IL-1β and TNF-α. Moreover, Loganin attenuated insulin resistance by modulating the JNK-IRS-1 (insulin receptor substrate-1)-Akt-GSK3β signaling pathway in PDN rats. These results suggested that Loganin improved PDN-mediated pain behaviors by inhibiting oxidative stress-provoked inflammation in the spinal cord, resulting in improved neuropathic pain.
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Loganin prevents cxcl12 cxcr4 regulated neuropathic pain via the nlrp3 inflammasome axis in nerve injured rats
Phytomedicine, 2021Co-Authors: Kuangi Cheng, Yuchi Cheng, Yuchin Chang, Jwulai Yeh, Jonghau Hsu, Sinlan Chen, Chienhsing Lee, Zenkong DaiAbstract:Abstract Background Neuropathic pain has been shown to be modulated by the activation of the chemokine C-X-C motif ligand 12 (CXCL12)/chemokine CXC receptor 4 (CXCR4) dependent nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. Loganin, an iridoid glycoside, was proven to prevent neuropathic pain, but its underlying mechanisms related to NLRP3 activation are still unknown. Purpose This study investigated the underlying mechanisms of Loganin's effect on chronic constriction injury (CCI)-induced NLRP3 inflammasome activation in the spinal cord. Methods Sprague-Dawley rats were randomly divided into four groups: sham, CCI, sham + Loganin, and CCI + Loganin. Loganin (5 mg/kg/day) was administered intraperitoneally starting the day after surgery. Paw withdrawal threshold (PWT) and latency (PWL) were assessed before CCI and on days 1, 3, 7 and 14 after CCI. Spinal cords were collected for western blots and immunofluorescence studies. Results Loganin prevented CCI-attenuated PWT and PWL, suggesting improved mechanical allodynia and thermal hyperalgesia. The expression of CXCL12, CXCR4, thioredoxin-interacting protein (TXNIP), NLRP3 inflammasome (NLRP3, ASC, and caspase-1), IL-1β, and IL-18 were enhanced on day 7 after CCI, and all were reduced after Loganin treatment. Dual immunofluorescence also showed that increased CXCL12, CXCR4, and NLRP3 were colocalized with NeuN (neuronal marker), GFAP (astrocyte marker), and Iba1 (microglial marker) on day 7 in the ipsilateral spinal dorsal horn (SDH). These immunoreactivities were attenuated in Loganin-treated rats. Moreover, Loganin decreased the assembly of NLRP3/ASC inflammasome after CCI in the ipsilateral SDH. Loganin appears to attenuate CCI-induced neuropathic pain by suppressing CXCL12/CXCR4-mediated NLRP3 inflammasome. Conclusion Our findings suggest that Loganin might be a suitable candidate for managing CCI-provoked neuropathic pain.
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Loganin attenuates high glucose induced schwann cells pyroptosis by inhibiting ros generation and nlrp3 inflammasome activation
Cells, 2020Co-Authors: Yuchi Cheng, Liwen Chu, Junyih Chen, Yuchin Chang, Suling Hsieh, Zenkong DaiAbstract:Diabetic peripheral neuropathy (DPN) is caused by hyperglycemia, which induces oxidative stress and inflammatory responses that damage nerve tissue. Excessive generation of reactive oxygen species (ROS) and NOD-like receptor protein 3 (NLRP3) inflammasome activation trigger the inflammation and pyroptosis in diabetes. Schwann cell dysfunction further promotes DPN progression. Loganin has been shown to have antioxidant and anti-inflammatory neuroprotective activities. This study evaluated the neuroprotective effect of Loganin on high-glucose (25 mM)-induced rat Schwann cell line RSC96 injury, a recognized in vitro cell model of DPN. RSC96 cells were pretreated with Loganin (0.1, 1, 10, 25, 50 μM) before exposure to high glucose. Loganin’s effects were examined by CCK-8 assay, ROS assay, cell death assay, immunofluorescence staining, quantitative RT–PCR and western blot. High-glucose-treated RSC96 cells sustained cell viability loss, ROS generation, NF-κB nuclear translocation, P2 × 7 purinergic receptor and TXNIP (thioredoxin-interacting protein) expression, NLRP3 inflammasome (NLRP3, ASC, caspase-1) activation, IL-1β and IL-18 maturation and gasdermin D cleavage. Those effects were reduced by Loganin pretreatment. In conclusion, we found that Loganin’s antioxidant effects prevent RSC96 Schwann cell pyroptosis by inhibiting ROS generation and suppressing NLRP3 inflammasome activation.
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Loganin prevents chronic constriction injury provoked neuropathic pain by reducing tnf α il 1β mediated nf κb activation and schwann cell demyelination
Phytomedicine, 2020Co-Authors: Liwen Chu, Yuchi Cheng, Kuangi Cheng, Junyih Chen, Yuchin Chang, Jwulai Yeh, Jonghau Hsu, Zenkong DaiAbstract:Abstract Background Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity. Purpose This study investigated the molecular mechanisms by which Loganin reduced CCI-induced neuropathic pain. Methods Sprague–Dawley rats were randomly divided into four groups: sham, sham+Loganin, CCI and CCI+Loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies. Results Thermal hyperalgesia and mechanical allodynia were reduced in the Loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1β), inflammatory proteins (TNF-α, IL-1β, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by Loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats. Conclusion Our findings indicate that Loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1β-dependent NF-κB activation.
Takashi Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Kinetic and molecular docking studies of Loganin and 7-O-galloyl-d-sedoheptulose from Corni Fructus as therapeutic agents for diabetic complications through inhibition of aldose reductase
Archives of Pharmacal Research, 2015Co-Authors: Hyun Ah Jung, Chan Hum Park, Takako Yokozawa, Takashi Tanaka, Sang Ho Oh, Jae Sue ChoiAbstract:Aldose reductase (AR) is a key enzyme in the polyol pathway that is strongly implicated in the pathogenesis of diabetic complications. AR inhibitors have been proposed as therapeutic agents for diabetic complications through suppression of sorbitol formation and accumulation. In this study, we evaluated whether two major compounds of Corni Fructus, Loganin and 7- O -galloyl- d -sedoheptulose, had an inhibitory effect on diabetic complications through AR inhibition. Because the iridoid glycoside Loganin and the low-molecular-weight polyphenol 7- O -galloyl- d -sedoheptulose showed marginal inhibitory activities against rat lens AR (RLAR) and human recombinant AR (HRAR) in inhibition assays, we performed enzyme kinetic analyses and molecular simulation of the interaction of these two compounds with AR to further investigate their potential as inhibitors of diabetic complications. In kinetic analysis using Lineweaver–Burk plots and Dixon plots, Loganin and 7- O -galloyl- d -sedoheptulose were both mixed inhibitors of RLAR with inhibition constants ( K _i) of 27.99 and 128.68 μΜ, respectively. Moreover, molecular docking simulation of both compounds demonstrated negative binding energies (Autodock 4.0 = −6.7; −7.5 kcal/mol; Fred 2.0 = −59.4; −63.2 kcal/mol) indicating a high affinity and tight binding capacity for the active site of the enzyme. Iridoid nucleus and aromatic ring systems and glycoside and sedoheptulose moieties were found to bind tightly to the specificity pocket and the anion binding pocket in RLAR through Phe123, His111, Trp21, Tyr49, His111, and Trp112 residues. Our results clearly indicate that Loganin and 7- O -galloyl- d -sedoheptulose have great promise for the treatment of diabetic complications through inhibition of AR.
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hepato protective effects of Loganin iridoid glycoside from corni fructus against hyperglycemia activated signaling pathway in liver of type 2 diabetic db db mice
Toxicology, 2011Co-Authors: Chan Hum Park, Takashi Tanaka, Ji Hyun Kim, Eun Ju Cho, Jong Cheol Park, Naotoshi Shibahara, Takako YokozawaAbstract:Accumulating evidence indicates that uncontrolled diabetes leads to the progression of diabetic complications such as liver disorder. The present study was carried out to elucidate the protective role of Loganin extracted from Corni Fructus against hepatic oxidative stress caused by type 2 diabetes. Loganin (20 or 100mg/kg body weight/day, p.o.) was administered every day for 8 weeks to db/db mice, and its effect was assessed on comparison with vehicle-treated db/db and m/m mice. The administration of Loganin led to a decrease in glucose and elevation of leptin in serum. The diabetic oxidative stress was attenuated by Loganin through inhibitions of reactive oxygen species production and lipid peroxidation in the serum and liver. The expression of proteins induced by oxidative stress was significantly up-regulated in the liver of diabetic db/db mice; however, the expressions of both Nox-4 and p22(phox) were decreased significantly by Loganin administration. Loganin showed a crucial effect in the inflammation-activated signaling pathway through the regulation of NF-κB, COX-2, and iNOS. It was also found to regulate the anti-inflammatory factors Nrf-2 and HO-1 in hepatic tissue. Moreover, expression of MCP-1 was significantly down-regulated in the Loganin-treated db/db mice. Furthermore, Loganin administration showed a protective effect against apoptosis by the regulation of Bcl-2 and cytochrome c. The present study demonstrated that the administration of Loganin isolated from Corni Fructus had a protective effect against hepatic oxidative stress under type 2 diabetes through regulations of protein expressions related to oxidative stress, inflammation, and apoptosis.
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evaluation of Loganin iridoid glycoside from corni fructus on hepatic and renal glucolipotoxicity and inflammation in type 2 diabetic db db mice
European Journal of Pharmacology, 2010Co-Authors: Noriko Yamabe, Chan Hum Park, Takashi Tanaka, Naotoshi Shibahara, Jeong Sook Noh, Ki Sung Kang, Takako YokozawaAbstract:Previously, we have reported that Corni Fructus possessed hypoglycemic and hypocholesterolemic effects in streptozotocin-induced type 1 diabetic rats and diet-induced hypercholesterolemic rats. Herein, we have focused on the effect and mechanism of Loganin, a major iridoid glycoside of Corni Fructus, on the type 2 diabetic db/db mice. Loganin was orally administered to db/db mice at a dose of 20 or 100 mg/kg body weight daily for 8 weeks. The biochemical factors and expressions of protein and mRNA related to lipid metabolism, inflammation, advanced glycation endproducts, and its receptor were measured. In Loganin-treated db/db mice, hyperglycemia and dyslipidemia were ameliorated in both the serum and hepatic tissue; however, in the kidney, only triglyceride was reduced. The enhanced oxidative stress was alleviated by Loganin through a decrease in thiobarbituric acid-reactive substances (liver and kidney) and reactive oxygen species (serum, liver, and kidney), as well as augmentation of the oxidized to reduced glutathione ratio (liver and kidney). The marked lipid-regulatory effect of Loganin was exerted in the liver of type 2 diabetic mice via suppressing mRNA expressions related to lipid synthesis and adjusting the abnormal expression of peroxisome proliferator-activated receptor α and sterol regulatory-element binding protein in the nucleus. Furthermore, Loganin inhibited advanced glycation endproduct formation and the expression of its receptor, and nuclear factor-kappa B-induced inflammation in the hepatic tissue of db/db mice. Loganin exhibits protective effects against hepatic injury and other diabetic complications associated with abnormal metabolic states and inflammation caused by oxidative stress and advanced glycation endproduct formation.
Jin Zhang - One of the best experts on this subject based on the ideXlab platform.
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Loganin alleviates sepsis induced acute lung injury by regulating macrophage polarization and inhibiting nlrp3 inflammasome activation
International Immunopharmacology, 2021Co-Authors: Jin Zhang, Changsong Wang, Hongliang WangAbstract:Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Excessive inflammation response plays an important role in sepsis-induced acute lung injury (ALI). Loganin is an iridoid glycoside isolated from Corni fructus and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of Loganin in sepsis-induced ALI remains unknown. In the current study, the cecal ligation and puncture (CLP)-induced murine sepsis model was constructed to investigate the anti-inflammatory property of Loganin in sepsis-induced ALI. Lipopolysaccharide (LPS)-treated Raw 264.7 cells and primary murine peritoneal macrophages were established to further explore underlying mechanism of Loganin. Results showed that intragastrical administration of Loganin significantly increased murine survival, reduced the alveolar structure damage and inflammatory cell infiltration. Loganin suppressed the release of the M1 macrophage-associated pro-inflammatory cytokines and induced the activation of M2-type anti-inflammatory cytokines. Besides, Loganin dramatically inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1β secretion. Further in vitro studies confirmed that Loganin efficiently inhibited M1 macrophage polarization and NLRP3 inflammasome activation by blocking the extra-cellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways. Taken together, the anti-inflammatory effect of Loganin in sepsis-induced ALI was associated with the ERK and NF-κB pathway-mediated macrophage polarization and NLRP3 inflammasome activation. Our study offers a favorable mechanistic basis to support the therapeutic potential of Loganin in anti-inflammatory diseases, such as sepsis-induced ALI.
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Loganin attenuates septic acute renal injury with the participation of akt and nrf2 ho 1 signaling pathways
Drug Design Development and Therapy, 2021Co-Authors: Jin Zhang, Changsong Wang, Kai Kang, Haitao Liu, Xiaowei Liu, Xiaonan JiaAbstract:Purpose Sepsis, a destructive inflammatory response syndrome, is the principal reason to induce death in the intensive care unit. Loganin has been proved to possess the property of anti-inflammation, antioxidant, neuroprotection, and sedation. The primary aim of this study was to evaluate whether Loganin could alleviate acute kidney injury (AKI) during sepsis and investigate the latent mechanisms. Methods Septic AKI models were established by cecal ligation and puncture (CLP) surgery in mice and given Loganin (20, 40, 80 mg/kg) by gavage. Lipopolysaccharides (LPS)-stimulated human kidney proximal tubular (HK2) cells incubated in Loganin (5, 10, 20 μ M) were used to explore the accurate mechanisms. Survival rate, renal function (creatinine and blood urea nitrogen), and renal pathological changes were detected in septic mice. Oxidative stress markers (SOD, GSH-Px, MDA, and SOD), mitochondrial membrane potential, mitochondrial calcium overload, and nuclear factor E2-related factor 2 (Nrf2)/heme-oxygenase 1 (HO-1) pathway activation in vivo and in vitro were determined by commercial kits and Western blot. Cell apoptosis, apoptotic-related protein (cleaved caspase-3, Bcl-2, and Bax) expression and protein kinase B (AKT) phosphorylation in vivo and in vitro were measured by TUNEL staining and Western blot. Finally, AKT blockage by 10 μM LY294002 or Nrf2 inhibition by10 μ M ML385 were utilized to prove the involvement of AKT and Nrf2/HO-1 pathway in AKI during sepsis. Results We found Loganin treatment (20, 40, 80 mg/kg) mitigated septic AKI reflected by elevated renal function and palliative pathological changes. Oxidative stress and apoptosis in the kidney and LPS-treated HK2 cells were also inhibited by Loganin administration, which was accompanied by AKT and Nrf2/HO-1 pathway activation. Besides, the protective effects of Loganin could be diminished by AKT or Nrf2 blockage, indicating the involvement of AKT and Nrf2/HO-1 pathway. Conclusion The results suggested that the protective effects of Loganin on AKI during sepsis might be mediated by AKT and Nrf2/HO-1 pathway signaling activation in kidney proximal tubular cells.
