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Wendo JK, Mbaria JM, Nyariki JN, Isaac AO. Ginkgo biloba attenuated detrimental inflammatory and oxidative events due to Trypanosoma brucei rhodesiense in mice treated with melarsoprol. PLoS Negl Trop Dis 2024; 18:e0012103. [PMID: 38620045 PMCID: PMC11045140 DOI: 10.1371/journal.pntd.0012103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 04/25/2024] [Accepted: 03/25/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe brain inflammation, oxidative stress and organ damage. Melarsoprol (MelB) is currently the only treatment available for this disease. MelB use is limited by its lethal neurotoxicity due to post-treatment reactive encephalopathy. This study sought to assess the potential of Ginkgo biloba (GB), a potent anti-inflammatory and antioxidant, to protect the integrity of the blood brain barrier and ameliorate detrimental inflammatory and oxidative events due to T.b.r in mice treated with MelB. METHODOLOGY Group one constituted the control; group two was infected with T.b.r; group three was infected with T.b.r and treated with 2.2 mg/kg melarsoprol for 10 days; group four was infected with T.b.r and administered with GB 80 mg/kg for 30 days; group five was given GB 80mg/kg for two weeks before infection with T.b.r, and continued thereafter and group six was infected with T.b.r, administered with GB and treated with MelB. RESULTS Co-administration of MelB and GB improved the survival rate of infected mice. When administered separately, MelB and GB protected the integrity of the blood brain barrier and improved neurological function in infected mice. Furthermore, the administration of MelB and GB prevented T.b.r-induced microcytic hypochromic anaemia and thrombocytopenia, as well as T.b.r-driven downregulation of total WBCs. Glutathione analysis showed that co-administration of MelB and GB prevented T.b.r-induced oxidative stress in the brain, spleen, heart and lungs. Notably, GB averted peroxidation and oxidant damage by ameliorating T.b.r and MelB-driven elevation of malondialdehyde (MDA) in the brain, kidney and liver. In fact, the co-administered group for the liver, registered the lowest MDA levels for infected mice. T.b.r-driven elevation of serum TNF-α, IFN-γ, uric acid and urea was abrogated by MelB and GB. Co-administration of MelB and GB was most effective in stabilizing TNFα levels. GB attenuated T.b.r and MelB-driven up-regulation of nitrite. CONCLUSION Utilization of GB as an adjuvant therapy may ameliorate detrimental effects caused by T.b.r infection and MelB toxicity during late stage HAT.
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Affiliation(s)
- Janet Khatenje Wendo
- The University of Nairobi, Department of Public Health, Pharmacology and Toxicology, Kangemi (Nairobi), Kenya
- The Technical University of Kenya, Department of Pharmaceutical Sciences and Technology, Nairobi, Kenya
| | - James Mucunu Mbaria
- The University of Nairobi, Department of Public Health, Pharmacology and Toxicology, Kangemi (Nairobi), Kenya
| | - James Nyabuga Nyariki
- The Technical University of Kenya, Department of Biochemistry and Biotechnology, Nairobi, Kenya
| | - Alfred Orina Isaac
- The Technical University of Kenya, Department of Pharmaceutical Sciences and Technology, Nairobi, Kenya
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Di Meo F, Cuciniello R, Margarucci S, Bergamo P, Petillo O, Peluso G, Filosa S, Crispi S. Ginkgo biloba Prevents Oxidative Stress-Induced Apoptosis Blocking p53 Activation in Neuroblastoma Cells. Antioxidants (Basel) 2020; 9:antiox9040279. [PMID: 32224984 PMCID: PMC7222193 DOI: 10.3390/antiox9040279] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/20/2020] [Accepted: 03/25/2020] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress has been associated to neuronal cell loss in neurodegenerative diseases. Neurons are post-mitotic cells that are very sensitive to oxidative stress—especially considering their limited capacity to be replaced. Therefore, reduction of oxidative stress, and inhibiting apoptosis, will potentially prevent neurodegeneration. In this study, we investigated the neuroprotective effect of Ginkgo biloba extract (EGb 761) against H2O2 induced apoptosis in SK-N-BE neuroblastoma cells. We analysed the molecular signalling pathway involved in the apoptotic cell death. H2O2 induced an increased acetylation of p53 lysine 382, a reduction in mitochondrial membrane potential, an increased BAX/Bcl-2 ratio and consequently increased Poly (ADP-ribose) polymerase (PARP) cleavage. All these effects were blocked by EGb 761 treatment. Thus, EGb 761, acting as intracellular antioxidant, protects neuroblastoma cells against activation of p53 mediated pathway and intrinsic mitochondrial apoptosis. Our results suggest that EGb 761, protecting against oxidative-stress induced apoptotic cell death, could potentially be used as nutraceutical for the prevention and treatment of neurodegenerative diseases.
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Affiliation(s)
- Francesco Di Meo
- Institute of Biosciences and BioResources-UOS Naples CNR, Via P. Castellino 111, 80131 Naples, Italy; (F.D.M.); (R.C.)
- Department of Biology, University of Naples Federico II, Complesso Universitario Monte Sant’Angelo Via Cinthia, 80126 Naples, Italy
| | - Rossana Cuciniello
- Institute of Biosciences and BioResources-UOS Naples CNR, Via P. Castellino 111, 80131 Naples, Italy; (F.D.M.); (R.C.)
| | - Sabrina Margarucci
- Institute on Terrestrial Ecosystems (IRET) CNR, Via P. Castellino 111, 80131 Naples, Italy; (S.M.); (O.P.); (G.P.)
| | - Paolo Bergamo
- Institute of Food Science CNR, Via Roma, 64, 83100 Avellino, Italy;
| | - Orsolina Petillo
- Institute on Terrestrial Ecosystems (IRET) CNR, Via P. Castellino 111, 80131 Naples, Italy; (S.M.); (O.P.); (G.P.)
| | - Gianfranco Peluso
- Institute on Terrestrial Ecosystems (IRET) CNR, Via P. Castellino 111, 80131 Naples, Italy; (S.M.); (O.P.); (G.P.)
| | - Stefania Filosa
- Institute of Biosciences and BioResources-UOS Naples CNR, Via P. Castellino 111, 80131 Naples, Italy; (F.D.M.); (R.C.)
- IRCCS Neuromed, Localitá Camerelle, 86077 Pozzilli (IS), Italy
- Correspondence: (S.F.); (S.C.)
| | - Stefania Crispi
- Institute of Biosciences and BioResources-UOS Naples CNR, Via P. Castellino 111, 80131 Naples, Italy; (F.D.M.); (R.C.)
- Correspondence: (S.F.); (S.C.)
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Zuo W, Yan F, Zhang B, Li J, Mei D. Advances in the Studies of Ginkgo Biloba Leaves Extract on Aging-Related Diseases. Aging Dis 2017; 8:812-826. [PMID: 29344418 PMCID: PMC5758353 DOI: 10.14336/ad.2017.0615] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 06/15/2017] [Indexed: 12/17/2022] Open
Abstract
The prevalence of degenerative disorders in public health has promoted in-depth investigations of the underlying pathogenesis and the development of new treatment drugs. Ginkgo biloba leaves extract (EGb) is obtained from Ginkgo biloba leaves and has been used for thousands of years. In recent decades, both basic and clinical studies have established the effects of EGb. It is widely used in various degenerative diseases such as cerebrovascular disease, Alzheimer's disease, macroangiopathy and more. Here, we reviewed several pharmacological mechanisms of EGb, including its antioxidant properties, prevention of mitochondrial dysfunctions, and effect on apoptosis. We also described some clinical applications of EGb, such as its effect on neuro and cardiovascular protection, and anticancer properties. The above biological functions of EGb are mainly focused on aging-related disorders, but its effect on other diseases remains unclear. Thus, through this review, we aim to encourage further studies on EGb and discover more potential applications.
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Affiliation(s)
- Wei Zuo
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Feng Yan
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
- Department of Neurobiology, Capital Medical University, Beijing, China
| | - Bo Zhang
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiantao Li
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dan Mei
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Mohamed NES, Abd El-Moneim AE. Ginkgo biloba extract alleviates oxidative stress and some neurotransmitters changes induced by aluminum chloride in rats. Nutrition 2017; 35:93-99. [DOI: 10.1016/j.nut.2016.10.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 10/16/2016] [Accepted: 10/17/2016] [Indexed: 12/26/2022]
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Hepatoprotective and antioxidant activity of linden (Tilia platyphyllos L.) infusion against ethanol-induced oxidative stress in rats. J Membr Biol 2013; 247:181-8. [PMID: 24337514 DOI: 10.1007/s00232-013-9622-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 12/05/2013] [Indexed: 10/25/2022]
Abstract
The present study was carried out to evaluate the hepatoprotective effect and antioxidant role of infusion prepared from linden flowers (LF) against ethanol-induced oxidative stress. The hepatoprotective and antioxidant role of the plant's infusion against ethanol-induced oxidative stress was evaluated by measuring liver damage serum biomarkers, aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase (LDH), total protein, total albumin, and total cholesterol level; ADS such as GSH, GR, SOD, GST, CAT and GPx, and MDA contents in various tissues of rats. Rats were divided into four experimental groups: I (control), II (20 % ethanol), III (2 % LF), and IV (20 % ethanol + 2 % LF). According to the results, the level of serum marker enzymes, AST and LDH, was significantly increased in group alcohol and group LF as compared to control group, whereas decreased in group IV as compared to ethanol group. With regard to MDA content and ADS constituents, MDA contents of alcohol group in all tissues, except for erythrocytes and heart, and in brain, kidney, and spleen of LF group significantly increased compared to control group, whereas LF beverage extract supplementation did not restore the increased MDA towards close the control level. In addition, while ethanol caused fluctuation in antioxidant defense system constituents level as a result of oxidative stress condition in the rats, it could have not been determined the healing effects of the LF against these fluctuations. The results indicated that LF beverage extract could not be as important as diet-derived antioxidants in preventing oxidative damage in the tissues by reducing the lipid oxidation or inhibiting the production of ethanol-induced free radicals in rats.
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Stavniichuk R, Drel VR, Shevalye H, Maksimchyk Y, Kuchmerovska TM, Nadler JL, Obrosova IG. Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation. Exp Neurol 2011; 230:106-13. [PMID: 21515260 DOI: 10.1016/j.expneurol.2011.04.002] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 03/29/2011] [Accepted: 04/07/2011] [Indexed: 01/12/2023]
Abstract
With the consideration of the multifactorial etiology of diabetic peripheral neuropathy, an ideal drug or drug combination should target at least several key pathogenetic mechanisms. The flavonoid baicalein (5,6,7-trihydroxyflavone) has been reported to counteract sorbitol accumulation, activation of 12/15-lipoxygenase, oxidative-nitrosative stress, inflammation, and impaired signaling in models of chronic disease. This study evaluated baicalein on diabetic peripheral neuropathy. Control and streptozotocin-diabetic C57Bl6/J mice were maintained with or without baicalein treatment (30 mg kg(-1) d(-1), i.p., for 4 weeks after 12 weeks without treatment). Neuropathy was evaluated by sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia (Hargreaves test), tactile response threshold (flexible von Frey filament test), and intraepidermal nerve fiber density (fluorescent immunohistochemistry with confocal microscopy). Sciatic nerve and spinal cord 12/15-lipoxygenase and total and phosphorylated p38 mitogen-activated protein kinase expression and nitrated protein levels were evaluated by Western blot analysis, 12(S)hydroxyeicosatetraenoic acid concentration (a measure of 12/15-lipoxygenase activity) by ELISA, and glucose and sorbitol pathway intermediate concentrations by enzymatic spectrofluorometric assays. Baicalein did not affect diabetic hyperglycemia, and alleviated nerve conduction deficit and small sensory nerve fiber dysfunction, but not intraepidermal nerve fiber loss. It counteracted diabetes-associated p38 mitogen-activated protein kinase phosphorylation, oxidative-nitrosative stress, and 12/15-lipoxygenase overexpression and activation, but not glucose or sorbitol pathway intermediate accumulation. In conclusion, baicalein targets several mechanisms implicated in diabetic peripheral neuropathy. The findings provide rationale for studying hydroxyflavones with an improved pharmacological profile as potential treatments for diabetic neuropathy and other diabetic complications.
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Affiliation(s)
- Roman Stavniichuk
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
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Obulesu M, Rao DM. Effect of plant extracts on Alzheimer's disease: An insight into therapeutic avenues. J Neurosci Rural Pract 2011; 2:56-61. [PMID: 21716802 PMCID: PMC3122981 DOI: 10.4103/0976-3147.80102] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Alzheimer's disease (AD) is a devastative neurodegenerative disorder which needs adequate studies on effective treatment options. The extracts of plants and their effect on the amelioration of AD symptoms have been extensively studied. This paper summarizes the mechanisms like acetylcholinesterase (AChE) inhibition, modification of monoamines, antiamyloid aggregation effect, and antioxidant activity which are actively entailed in the process of amelioration of AD symptoms. These effects are induced by extracts of a few plants of different origin like Yizhi Jiannao, Moringa oleifera (Drumstick tree), Ginkgo Biloba (Ginkgo/Maidenhair tree), Cassia obtisufolia (Sicklepod), Desmodium gangeticum (Sal Leaved Desmodium), Melissa officinalis (Lemon Balm), and Salvia officinalis (Garden sage, common sage).
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Affiliation(s)
- M Obulesu
- Capital College, Garden City Group of Institutions, Bangalore, India
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Müller WE, Eckert A, Kurz C, Eckert GP, Leuner K. Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease--therapeutic aspects. Mol Neurobiol 2010; 41:159-71. [PMID: 20461558 DOI: 10.1007/s12035-010-8141-5] [Citation(s) in RCA: 179] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Accepted: 04/15/2010] [Indexed: 12/21/2022]
Abstract
As a fully differentiated organ, our brain is very sensitive to cumulative oxidative damage of proteins, lipids, and DNA occurring during normal aging because of its high energy metabolism and the relative low activity of antioxidative defense mechanisms. As a major consequence, perturbations of energy metabolism including mitochondrial dysfunction, alterations of signaling mechanisms and of gene expression culminate in functional deficits. With the increasing average life span of humans, age-related cognitive disorders such as Alzheimer's disease (AD) are a major health concern in our society. Age-related mitochondrial dysfunction underlies most neurodegenerative diseases, where it is potentiated by disease-specific factors. AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. In this review, we focus on findings in AD animal and cell models indicating that these histopathological alterations induce functional deficits of the respiratory chain complexes and therefore consecutively result in mitochondrial dysfunction and oxidative stress. These parameters lead synergistically with the alterations of the brain aging process to typical signs of neurodegeneration in the later state of the disease, including synaptic dysfunction, loss of synapses and neurites, and finally neuronal loss. We suggest that mitochondrial protection and subsequent reduction of oxidative stress are important targets for prevention and long-term treatment of early stages of AD.
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Affiliation(s)
- Walter E Müller
- Department of Pharmacology, Biocenter, University of Frankfurt, Max-von Laue-Strasse 9, 60438, Frankfurt, Germany.
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Treutter D. Managing phenol contents in crop plants by phytochemical farming and breeding-visions and constraints. Int J Mol Sci 2010; 11:807-57. [PMID: 20479987 PMCID: PMC2868352 DOI: 10.3390/ijms11030807] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 02/02/2010] [Accepted: 02/03/2010] [Indexed: 01/24/2023] Open
Abstract
Two main fields of interest form the background of actual demand for optimized levels of phenolic compounds in crop plants. These are human health and plant resistance to pathogens and to biotic and abiotic stress factors. A survey of agricultural technologies influencing the biosynthesis and accumulation of phenolic compounds in crop plants is presented, including observations on the effects of light, temperature, mineral nutrition, water management, grafting, elevated atmospheric CO(2), growth and differentiation of the plant and application of elicitors, stimulating agents and plant activators. The underlying mechanisms are discussed with respect to carbohydrate availability, trade-offs to competing demands as well as to regulatory elements. Outlines are given for genetic engineering and plant breeding. Constraints and possible physiological feedbacks are considered for successful and sustainable application of agricultural techniques with respect to management of plant phenol profiles and concentrations.
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Affiliation(s)
- Dieter Treutter
- Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany.
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Lee JW, Ahn JY, Hasegawa SI, Cha BY, Yonezawa T, Nagai K, Seo HJ, Jeon WB, Woo JT. Inhibitory effect of luteolin on osteoclast differentiation and function. Cytotechnology 2010; 61:125-34. [PMID: 20162352 DOI: 10.1007/s10616-010-9253-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2009] [Accepted: 01/18/2010] [Indexed: 01/09/2023] Open
Abstract
Osteoclasts are multinucleated cells that play a crucial role in bone resorption, and are formed by the fusion of mononuclear osteoclasts derived from osteoclast precursors of the macrophage lineage. Compounds that specifically target functional osteoclasts would be ideal candidates for anti-resorptive agents for clinical applications. In the present study, we investigated the effects of luteolin, a flavonoid, on the regulation of receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis, functions and signaling pathway. Addition of luteolin to a coculture system of mouse bone marrow cells and ST2 cells in the presence of 10(-8) M 1alpha,25(OH)(2)D(3) caused significant inhibition of osteoclastogenesis. Luteolin had no effects on the 1alpha,25(OH)(2)D(3)-induced expressions of RANKL, osteoprotegerin and macrophage colony-stimulating factor mRNAs. Next, we examined the direct effects of luteolin on osteoclast precursors using bone marrow macrophages and RAW264.7 cells. Luteolin completely inhibited RANKL-induced osteoclast formation. Moreover, luteolin inhibited the bone resorption by mature osteoclasts accompanied by the disruption of their actin rings, and these effects were reversely induced by the disruption of the actin rings in mature osteoclasts. Finally, we found that luteolin inhibited RANKL-induced osteoclastogenesis through the suppression of ATF2, downstream of p38 MAPK and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) expression, respectively. Taken together, the present results indicate that naturally occurring luteolin has inhibitory activities toward both osteoclast differentiation and functions through inhibition of RANKL-induced signaling pathway as well as actin ring disruption, respectively.
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Affiliation(s)
- Ji-Won Lee
- Department of Biological Chemistry, Chubu University, 1200 Matsumoto, Kasugai, Aichi, 487-8501, Japan
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Li R, Chen B, Wu W, Bao L, Li J, Qi R. Ginkgolide B suppresses intercellular adhesion molecule-1 expression via blocking nuclear factor-kappaB activation in human vascular endothelial cells stimulated by oxidized low-density lipoprotein. J Pharmacol Sci 2009; 110:362-9. [PMID: 19609067 DOI: 10.1254/jphs.08275fp] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Atherosclerosis is a complex inflammatory arterial disease. Oxidized low-density lipoprotein (ox-LDL) is directly associated with chronic vascular inflammation. In the current study, we tested the hypothesis that ginkgolide B, a component of traditional Chinese herbal medicine for heart disorder, may affect ox-LDL-induced inflammatory responses in human umbilical vein endothelial cells (HUVECs). The results showed that the ox-LDL treatment caused a significantly increase in the expression of intercellular adhesion molecule-1 (ICAM-1) in HUVECs, which was associated with a dramatic augmentation in phosphorylation of IkappaB and relocation of nuclear factor-kappaB (NF-kappaB) into the nuclei. Interestingly, the ox-LDL-induced ICAM-1 expression and NF-kappaB relocation could be attenuated by addition of ginkgolide B. Moreover, ginkgolide B significantly reduces ox-LDL-induced generation of reactive oxygen species (ROS). In conclusion, ginkgolide B may decrease inflammatory responses induced by ox-LDL via blocking NF-kappaB signaling and inhibiting ROS generation in HUVECs.
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Affiliation(s)
- Rui Li
- Beijing Institute of Geriatrics, Beijing Hospital and Key Laboratory of Geriatrics Ministry of Health, Beijing, China
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Leuner K, Hauptmann S, Abdel-Kader R, Scherping I, Keil U, Strosznajder JB, Eckert A, Müller WE. Mitochondrial dysfunction: the first domino in brain aging and Alzheimer's disease? Antioxid Redox Signal 2007; 9:1659-75. [PMID: 17867931 DOI: 10.1089/ars.2007.1763] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
With the increasing average life span of humans and with decreasing cognitive function in elderly individuals, age-related cognitive disorders including dementia have become a major health problem in society. Aging-related mitochondrial dysfunction underlies many common neurodegenerative disorders diseases, including Alzheimer's disease (AD). AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein. In this review, the authors focus on the latest findings in AD animal models indicating that these histopathological alterations induce deficits in the function of the complexes of the respiratory chain and therefore consecutively result in mitochondrial dysfunction. This parameter is intrinsically tied to oxidative stress. Both are early events in aging and especially in the pathogenesis of aging-related severe neurodegeneration. Ginkgo biloba extract seems to be of therapeutic benefit in the treatment of mild to moderate dementia of different etiology, although the data are quite heterogeneous. Herein, the authors suggest that mitochondrial protection and subsequent reduction of oxidative stress are important components of the neuroprotective activity of Ginkgo biloba extract.
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Affiliation(s)
- Kristina Leuner
- Department of Pharmacology, Zafes, Biocenter, University of Frankfurt, Germany.
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Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J 2007; 21:2400-8. [PMID: 17356006 DOI: 10.1096/fj.06-7649com] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Standardized Ginkgo biloba extract EGb 761 exhibits beneficial effects to patients with Alzheimer's disease (AD). It was previously demonstrated that EGb 761 inhibits amyloid beta (Abeta) oligomerization in vitro, protects neuronal cells against Abeta toxicity, and improves cognitive defects in a mouse model of AD (Tg 2576). In this study, the neurogenic potential of EGb 761 and its effect on cAMP response element binding protein (CREB) were examined in a double transgenic mouse model (TgAPP/PS1). EGb 761 significantly increases cell proliferation in the hippocampus of both young (6 months) and old (22 months) TgAPP/PS1 mice, and the total number of neuronal precursor cells in vitro in a dose-dependent manner. Furthermore, Abeta oligomers inhibit phosphorylation of CREB and cell proliferation in the hippocampus of TgAPP/PS1 mice. Administration of EGb 761 reduces Abeta oligomers and restores CREB phosphorylation in the hippocampus of these mice. The present findings suggest that 1) enhanced neurogenesis by EGb 761 may be mediated by activation of CREB, 2) stimulation of neurogenesis by EGb 761 may contribute to its beneficial effects in AD patients and improved cognitive functions in the mouse model of AD, and 3) EGb 761 has therapeutic potential for the prevention and improved treatment of AD.
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Affiliation(s)
- Flaubert Tchantchou
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA
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Kim JS, Jobin C. The flavonoid luteolin prevents lipopolysaccharide-induced NF-kappaB signalling and gene expression by blocking IkappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells. Immunology 2005; 115:375-87. [PMID: 15946255 PMCID: PMC1782165 DOI: 10.1111/j.1365-2567.2005.02156.x] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The nuclear factor (NF)-kappaB transcriptional system is a major effector pathway involved in inflammation and innate immune responses. The flavonoid luteolin is found in various herbal extracts and has shown anti-inflammatory properties. However, the mechanism of action and impact of luteolin on innate immunity is still unknown. We report that luteolin significantly blocks lipopolysaccharide (LPS)-induced IkappaB phosphorylation/degradation, NF-kappaB transcriptional activity and intercellular adhesion molecule-1 (ICAM-1) gene expression in rat IEC-18 cells. Using chromatin immunoprecipitation, we demonstrate that LPS-induced RelA recruitment to the ICAM-1 gene promoter is significantly reduced in luteolin-treated cells. Moreover, in vitro kinase assays show that luteolin directly inhibits LPS-induced IkappaB kinase (IKK) activity in IEC-18 cells. Using bone-marrow derived dendritic cells (BMDCs) isolated from interleukin (IL)-10(-/-) mice or from recently engineered transgenic mice expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-kappaB cis-elements (cis-NF-kappaB(EGFP)), we found that luteolin blocks LPS-induced IkappaB phosphorylation and IKK activity, and decreases EGFP, IL-12 and tumour necrosis factor-alpha gene expression. Moreover, intraperitoneal administration of luteolin significantly inhibited LPS-induced EGFP expression in both peripheral blood mononuclear cells and splenocytes isolated from cis-NF-kappaB(EGFP) mice. These results indicate that luteolin blocks LPS-induced NF-kappaB signalling and proinflammatory gene expression in intestinal epithelial cells and dendritic cells. Modulation of innate immunity by natural plant products may represent an attractive strategy to prevent intestinal inflammation associated with dysregulated innate immune responses.
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Affiliation(s)
- Joo Sung Kim
- Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
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Abstract
AIM: To investigate the protective effect of ginkgo biloba extract (GBE) on livers of aged rats and the associated mechanisms.
METHODS: Two-mo- and 20-mo-old rats were treated with GBE/saline for 3 mo. Liver tissue samples from 5-mo-old rats treated with saline (group Y) and 23-mo-old rats treated with GBE (group E) or saline (group N) were used for histopathological examinations (hematoxylin-eosin and Masson staining, Lipofuscin staining-Schmorl staining) and determination of expression of tissue inhibitor-1 of metalloproteinase (TIMP-1) and the level of malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD). Blood samples were collected for determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin.
RESULTS: Microscopic studies with Masson staining revealed mild liver fibrosis in aged rats (group N), while the livers of aged rats receiving GBE (group E) showed amelioration in fibrosis (2.2±0.1 vs 2.8±0.1, P<0.01) and deposition of lipofuscin (33.7±5.3 vs 62.8±5.7, P<0.01). The expression of TIMP-1 and the level of liver MDA (1.0±0.1 vs 1.2±0.2, P<0.05) also decreased but the activity of GPx (97.1±15.3 vs 61.8±14.5, P<0.01) increased in group E. Compared with group Y, the level of liver MDA (0.8±0.1 vs 1.2±0.2, P<0.01), lipofuscin (32.4±6.0 vs 62.8±5.7, P<0.01) and TIMP-1 expression were increased, while the activity of GPx (103.2±17.6 vs 61.8±14.5, P<0.01) and SOD (16.7±4.4 vs 11.8±3.9, P<0.05) was decreased in group N. There was no difference in liver function among these three groups.
CONCLUSION: GBE has protective effects on aging liver. The possible mechanisms might be its antioxidant activity and inhibition of TIMP-1 expression.
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Affiliation(s)
- Shang-Zhen Huang
- Department of Geriatrics, Wuhan General Hospital, Guangzhou Command of PLA, Wuhan, Hubei Province, China
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Hu W, Shi ZH, Ma TF, Yu JP. Effects of Ginkgo biloba extract on liver fibrosis induced by carbon tetrachloride in rats. Shijie Huaren Xiaohua Zazhi 2004; 12:886-891. [DOI: 10.11569/wcjd.v12.i4.886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effects of Ginko biloba extract (EGb) on hepato-fibrosis induced by carbon tetrachloride (Cl4) in rat model.
METHODS: Rat liver fibrosis model was induced by Cl4 administration. Wistar rats were randomly divided into 5 groups: normal control group, a model group, a interven-tional group, a therapeutic group, and a EGb group. The EGb interventional group, apart from administration of Cl4, was treated concurrently with EGb 0.3 g/kg, ig once a day; the EGb therapeutic group was treated with EGb 0.3 g/kg, ig once a day after cirrhosis was induced successfully, and the EGb group was treated only with EGb 0.3 g/kg, ig once a day. At the end of wk 8 and 16, all the rats were sacrificed. The pathological changes of liver were observed by H-E and Von-Gieson staining.The expression of mRNA and proteins of collagen I/TGF1 in liver were determined by RT-PCR and immunohistochemistry.
RESULTS: The degree of liver fibrosis and level of mRNA and proteins of collagen I/TGF1 in liver were significantly reduced in the EGb interventional and therapeutic groups compared with those in the model group (type I collagen mRNA: 0.0 778±0.054 vs 0.2 361±0.113, 0.1 075±0.007 vs 0.2 361±0.113, P < 0.01; type I collagen proteins: 0.2 563±0.0 009 vs 0.2 885±0.0 025, 0.2 541±0.0 076 vs 0.2 885±0.0 025 , P < 0.01; TGF1 mRNA: 0.523±0.015 vs 0.956±0.049 , 0.524±0.009 vs 0.956±0.049, P < 0.01; TGF1 proteins: 0.2 785±0.0 012 vs 0.3 015±0.0 012, 0.2 791±0.0 016 vs 0.3 015±0.0 012, P < 0.01).The EGb group had the same results as the normal control group.
CONCLUSION: EGb has prophylactic and therapeutic effects on CCl4-induced rat liver fibrosis, probably through its anti-lipoperoxidation, suppressing the activation of hepatic stellate cells and transition and reducing the synthesis of hepatic type I collagen and TGF1.
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Bastos EL, Romoff P, Eckert CR, Baader WJ. Evaluation of antiradical capacity by H2O2-hemin-induced luminol chemiluminescence. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2003; 51:7481-7488. [PMID: 14640603 DOI: 10.1021/jf0345189] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
This paper describes a screening method for antioxidant potential determination based on luminol/hemin/hydrogen peroxide chemiluminescence. The emission depletion, caused by an antiradical compound added during the chemiluminescence decay, is proportional to the number of reactive species trapped. Therefore, the difference between the areas of the emission decay curves, obtained in the absence and in the presence of the potential antioxidant, is a measure for the antiradical capacity of the sample. The technique has been applied to measure the antiradical capacity of pure compounds and complex mixtures from natural origin, providing reliable results that indicate the method's feasibility.
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Affiliation(s)
- Erick L Bastos
- Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 S, São Paulo, SP, 05508-900, Brazil
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Abstract
This is an exciting time for biological scientists as the "omics" era continues to evolve and shape the way science is understood and conducted. As genome sequencing of the human comes to a close, other mammals are in line to be sequenced. Along with pigs and cows, dogs are now on the high priority list for sequencing, and cats may soon follow suit. Until sequence data are available, genetic maps may be used to reveal important physical characteristics of a genome. Genome mapping is important in identifying gene placement, but gives little information regarding function. Therefore, functional genomics, including the global analysis of RNA and protein expression, protein localization and protein-protein interactions will emerge as important areas of study. The major use of the dog and cat genome maps hitherto has been for the study of human and veterinary medicine. These powerful resources also can be applied to the field of nutritional genomics and proteomics, enhancing our understanding of metabolism and optimizing companion animal nutritional and health status. Genomics has begun to be applied to nutritional research, but issues specifically relevant to companion animals have not been elucidated thus far. The study of genomics and proteomics will be crucial in areas such as nutrient requirement determination, disease prevention and treatment, functional ingredient testing and others. Nutritional genomics and proteomics will definitely play a vital role in the future of pet foods.
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Affiliation(s)
- Kelly S Swanson
- Department of Animal Sciences, University of Illinois, Urbana 61801, USA
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Spaide RF, Armstrong D, Browne R. CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION—WHAT IS THE CAUSE? Retina 2003; 23:595-614. [PMID: 14574243 DOI: 10.1097/00006982-200310000-00001] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Richard F Spaide
- Vitreous Retina Macula Consultants, New York, New York 10021, USA.
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DeFeudis FV. Effects ofGinkgo biloba extract (EGb 761) on gene expression: Possible relevance to neurological disorders and age-associated cognitive impairment. Drug Dev Res 2003. [DOI: 10.1002/ddr.10151] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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