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1
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Rębas E. Role of Flavonoids in Protecting Against Neurodegenerative Diseases-Possible Mechanisms of Action. Int J Mol Sci 2025; 26:4763. [PMID: 40429904 PMCID: PMC12112047 DOI: 10.3390/ijms26104763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 05/10/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Neurodegenerative and mood disorders represent growing medical and social problems, many of which are produced by oxidative stress, neuroinflammation, disruption in the metabolism of various neurotransmitters, and some disturbances in lipid/carbohydrate homeostasis. Biologically active plant compounds, including flavonoids, have been shown to exert a positive impact on central nervous system function. This review assesses the studies of naturally occurring flavonoids belonging to various polyphenol subclasses and their mechanisms of neuroprotective action, especially against neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Most of the studied phytochemicals possess anti-oxidative, anti-inflammatory, and neuroprotective properties. These phytochemicals have been considered as compounds that reduce the risk of developing Alzheimer's and Parkinson's diseases and can be used in the treatment of neurological diseases. The neuroprotective actions of some flavonoids may entail mechanisms that regulate reactive oxygen species generation and modify inflammatory pathways, and they should be considered as therapeutic agents.
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Affiliation(s)
- Elżbieta Rębas
- Department of Molecular Neurochemistry, Medical University of Lodz, 90-419 Lodz, Poland
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2
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Bishr A, Atwa AM, El-Mokadem BM, El-Din MN. Canagliflozin potentially promotes renal protection against glycerol-induced acute kidney injury by activating the AMPK/SIRT1/FOXO-3a/PGC-1α and Nrf2/HO-1 pathways. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04017-x. [PMID: 40257493 DOI: 10.1007/s00210-025-04017-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 03/04/2025] [Indexed: 04/22/2025]
Abstract
The reno-protective potential of canagliflozin (Cana), an inhibitor of the sodium glucose-linked co-transporter-2 (SGLT-2), has been demonstrated in different models of kidney injury. However, its potential role in preventing glycerol (Gly)-induced acute kidney injury (AKI) remains to be divulged. Therefore, the aim of this study is to investigate the potential reno-protective effect of Cana and its underlying mechanism in a rat model of Gly-induced AKI. Rats were randomly allocated into five groups: normal, Gly, Gly pretreated with 10 mg/kg Cana, Gly pretreated with Cana 25 mg/kg, and normal pretreated with Cana 25 mg/kg for 14 consecutive days. Pretreatment with Cana improved renal structure and enhanced kidney functions manifested by reducing serum creatinine and blood urea nitrogen, as well as renal contents of neutrophil gelatinase-associated lipocalin and kidney injury molecule. Moreover, Cana signified its anti-inflammatory effect by reducing the Gly-induced elevation in renal contents of nuclear factor-κB and interleuκin-6. Additionally, Cana augmented the defense enzymatic antioxidants superoxide dismutase (SOD), manganese-SOD, and heme oxygenase-1, besides increasing the protein expression of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 to point for its ability to correct redox balance. Cana also upregulated the protein expression of the 5' adenosine monophosphate-activated protein kinase (AMPK), Sirtuin1 (SIRT1), Forkhead box protein O3 (FOXO-3a), and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), as well as the transcriptional activity of growth arrest and DNA damage-inducible protein alpha (GAAD45a). In conclusion, Cana demonstrated potentially novel reno-protective mechanisms and mitigated the consequences of AKI through its antioxidant and anti-inflammatory properties, partially by activating the AMPK/SIRT1/FOXO-3a/PGC-1α pathway.
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Affiliation(s)
- Abeer Bishr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
| | - Ahmed M Atwa
- Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
- College of Pharmacy, Al-Ayen Iraqi University, AUIQ, An Nasiriyah, Iraq
| | - Bassant M El-Mokadem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Chinese University, Cairo, Egypt
| | - Mahmoud Nour El-Din
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt
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Corsi F, Galante A, Maggi MA, Mazziotti R, Bisti S, Piano I, Gargini C. The efficacy of Saffron Repron® in counteracting the progression of retinitis pigmentosa: Neuroprotection and resilience. Asia Pac J Ophthalmol (Phila) 2025:100192. [PMID: 40122468 DOI: 10.1016/j.apjo.2025.100192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 03/13/2025] [Accepted: 03/16/2025] [Indexed: 03/25/2025] Open
Abstract
The mutations observed in the various forms of retinitis pigmentosa (RP) affect genes coding for rod-specific proteins and direct the progression of different forms of dystrophy toward total blindness. The present investigation aims to explore the protective effects of Saffron Repron®, in a mouse model of RP. Saffron was administered orally to pregnant females and weaned pups for 120 days. At different time points (P30, P60, P90, and P120), visual function, retinal function, cone lifespan, morphology, gene expression, and protein level were analyzed. The results indicate that chronic saffron treatment effectively slows the progression of long-term damage caused by genetic mutations in both the morphology and function of retinal neurons. Cellular mechanisms responsible for this action appear complex and, probably, due to coordinated and synergistic activities by its chemical components. Here we provide evidence that saffron is able to modulate the epigenetic pathway involved in neuroinflammation. Biochemical and molecular measures suggest that early saffron treatment may induce a form of adaptation known as acquired resilience.
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Affiliation(s)
- Francesca Corsi
- University of Pisa, Department of Pharmacy, Italy; National Institute of Biostructure and Biosystem (INBB), Italy
| | | | - Maria Anna Maggi
- Hortus Novus srl, via Campo Sportivo 2, Italy; Department of Physical and Chemical Sciences, University of L'Aquila, Italy
| | - Raffaele Mazziotti
- Department of Neuroscience, Psychology, Pharmacology, and Child Health, University of Florence, Italy; Institute of Neuroscience, National Research Council (CNR), Italy
| | - Silvia Bisti
- National Institute of Biostructure and Biosystem (INBB), Italy
| | - Ilaria Piano
- University of Pisa, Department of Pharmacy, Italy; National Institute of Biostructure and Biosystem (INBB), Italy.
| | - Claudia Gargini
- University of Pisa, Department of Pharmacy, Italy; National Institute of Biostructure and Biosystem (INBB), Italy
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Wang Y, Fan D, Zhang Y, Wang J, Dong L, Hu Y, Wang S. Long-term exposure to advanced lipid peroxidation end products impairs cognitive function through microbiota-gut-brain axis. Food Chem 2024; 461:140864. [PMID: 39173255 DOI: 10.1016/j.foodchem.2024.140864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/17/2024] [Accepted: 08/11/2024] [Indexed: 08/24/2024]
Abstract
The frequent intake of ultra-processed, heat-processed, and fat-enriched foods rich in dietary advanced lipoxidation end-products (ALEs) has been correlated with cognitive decline; however, the underlying mechanisms of action remain unexplored. This study investigated the impact of a 12-month dietary exposure to ALEs on learning, memory, and Aβ1-42 accumulation in mice, with a focus on the AMPK/SIRT1 signaling pathway and ADAM10 expression. The gut microbiota and metabolomic profiles revealed ALEs-induced gut dysbiosis and cognitive impairment, highlighting modulation through the microbiota-gut-brain axis. Key findings include increased pathogenic bacteria and decreased beneficial bacteria, linked to metabolite profile changes that affect neurotoxic Aβ1-42 peptide accumulation. This long-term comprehensive study underscores the need for dietary guidelines to reduce ALE intake and mitigate neurodegenerative disease risk, highlighting the intricate interplay between diet, gut microbiota, and cognitive health.
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Affiliation(s)
- Yaya Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Dancai Fan
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yan Zhang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Junping Wang
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
| | - Lu Dong
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yaozhong Hu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China.
| | - Shuo Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China.
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Ganguly SC, Sangram S, Paul S, Kundu M. Phyto-nanotechnology: A novel beneficial strategy for Alzheimer's disease therapy. Neurochem Int 2024; 180:105868. [PMID: 39326498 DOI: 10.1016/j.neuint.2024.105868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 08/08/2024] [Accepted: 09/24/2024] [Indexed: 09/28/2024]
Abstract
Alzheimer's disease, a neurodegenerative condition, is characterized by the slow and progressive deterioration of the cognitive functions of geriatric patients. It occurs due to exacerbation of neurons in the brain, indicated by loss of memory, mood instability, and even death. The aggregation of amyloid β protein and neurofibrillary tangles-atypical forms of tau protein is the major cause of this disease. Phytoconstituents have been frequently employed in treating Alzheimer's disease. These natural compounds act through different molecular mechanisms to treat the disease. However, their potential in Alzheimer's disease therapy may be limited due to poor blood-brain barrier permeability, off-target effects, low bioavailability, etc. In recent times, nanotechnology has gained attraction to overcome these challenges. This article focuses on the potential phytoconstituents for Alzheimer's disease treatment and the associated limitations. Moreover, it highlights various nanoformulation strategies employed to penetrate the blood-brain barrier effectively, avoid side effects, improve bioavailability, and target specificity in treating Alzheimer's disease. The integration of nanotechnology with plant-derived compounds has the potential to revolutionize the therapeutic landscape for Alzheimer's disease.
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Affiliation(s)
| | - Sk Sangram
- Department of Pharmaceutical Chemistry, Calcutta Institute of Pharmaceutical Technology & Allied Health Sciences, West Bengal, India
| | - Sayani Paul
- Department of Pharmaceutical Chemistry, Calcutta Institute of Pharmaceutical Technology & Allied Health Sciences, West Bengal, India; Bengal School of Technology, Hooghly, West Bengal, India
| | - Moumita Kundu
- Department of Pharmaceutical Technology, Brainware University, West Bengal, India; Center for Multidisciplinary Research & Innovations, Brainware University, West Bengal, India.
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Pauletto M, Giantin M, Tolosi R, Bassan I, Bardhi A, Barbarossa A, Montanucci L, Zaghini A, Dacasto M. Discovering the Protective Effects of Quercetin on Aflatoxin B1-Induced Toxicity in Bovine Foetal Hepatocyte-Derived Cells (BFH12). Toxins (Basel) 2023; 15:555. [PMID: 37755981 PMCID: PMC10534839 DOI: 10.3390/toxins15090555] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/28/2023] Open
Abstract
Aflatoxin B1 (AFB1) induces lipid peroxidation and mortality in bovine foetal hepatocyte-derived cells (BFH12), with underlying transcriptional perturbations associated mainly with cancer, cellular damage, inflammation, bioactivation, and detoxification pathways. In this cell line, curcumin and resveratrol have proven to be effective in mitigating AFB1-induced toxicity. In this paper, we preliminarily assessed the potential anti-AFB1 activity of a natural polyphenol, quercetin (QUE), in BFH12 cells. To this end, we primarily measured QUE cytotoxicity using a WST-1 reagent. Then, we pre-treated the cells with QUE and exposed them to AFB1. The protective role of QUE was evaluated by measuring cytotoxicity, transcriptional changes (RNA-sequencing), lipid peroxidation (malondialdehyde production), and targeted post-transcriptional modifications (NQO1 and CYP3A enzymatic activity). The results demonstrated that QUE, like curcumin and resveratrol, reduced AFB1-induced cytotoxicity and lipid peroxidation and caused larger transcriptional variations than AFB1 alone. Most of the differentially expressed genes were involved in lipid homeostasis, inflammatory and immune processes, and carcinogenesis. As for enzymatic activities, QUE significantly reverted CYP3A variations induced by AFB1, but not those of NQO1. This study provides new knowledge about key molecular mechanisms involved in QUE-mediated protection against AFB1 toxicity and encourages in vivo studies to assess QUE's bioavailability and beneficial effects on aflatoxicosis.
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Affiliation(s)
- Marianna Pauletto
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell’Università 16, I-35020 Legnaro, Italy; (M.G.); (R.T.); (I.B.); (M.D.)
| | - Mery Giantin
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell’Università 16, I-35020 Legnaro, Italy; (M.G.); (R.T.); (I.B.); (M.D.)
| | - Roberta Tolosi
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell’Università 16, I-35020 Legnaro, Italy; (M.G.); (R.T.); (I.B.); (M.D.)
| | - Irene Bassan
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell’Università 16, I-35020 Legnaro, Italy; (M.G.); (R.T.); (I.B.); (M.D.)
| | - Anisa Bardhi
- Department of Veterinary Medical Sciences, Alma Mater Studiorum—University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, I-40064 Bologna, Italy; (A.B.); (A.B.); (A.Z.)
| | - Andrea Barbarossa
- Department of Veterinary Medical Sciences, Alma Mater Studiorum—University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, I-40064 Bologna, Italy; (A.B.); (A.B.); (A.Z.)
| | - Ludovica Montanucci
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA;
| | - Anna Zaghini
- Department of Veterinary Medical Sciences, Alma Mater Studiorum—University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, I-40064 Bologna, Italy; (A.B.); (A.B.); (A.Z.)
| | - Mauro Dacasto
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell’Università 16, I-35020 Legnaro, Italy; (M.G.); (R.T.); (I.B.); (M.D.)
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Ghasemzadeh Rahbardar M, Hosseinzadeh H. A review of how the saffron (Crocus sativus) petal and its main constituents interact with the Nrf2 and NF-κB signaling pathways. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1879-1909. [PMID: 37067583 DOI: 10.1007/s00210-023-02487-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/04/2023] [Indexed: 04/18/2023]
Abstract
The primary by-product of saffron (Crocus sativus) processing is saffron petals, which are produced in large quantities but are discarded. The saffron petals contain a variety of substances, including alkaloids, anthocyanins, flavonoids, glycosides, kaempferol, and minerals. Pharmacological investigations revealed the antibacterial, antidepressant, antidiabetic, antihypertensive, antinociceptive, antispasmodic, antitussive, hepatoprotective, immunomodulatory, and renoprotective properties of saffron petals, which are based on their antioxidant, anti-inflammatory, and antiapoptotic effects. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway protects against oxidative stress, carcinogenesis, and inflammation. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) is a protein complex involved in approximately all animal cells and participates in different biological procedures such as apoptosis, cell growth, development, deoxyribonucleic acid (DNA) transcription, immune response, and inflammation. The pharmacological properties of saffron and its compounds are discussed in this review, along with their associated modes of action, particularly the Nrf2 and NF-ĸB signaling pathways. Without considering a time constraint, our team conducted this review using search engines or electronic databases like PubMed, Scopus, and Web of Science. Saffron petals and their main constituents may have protective effects in numerous organs such as the brain, colon, heart, joints, liver, lung, and pancreas through several mechanisms, including the Nrf2/heme oxygenase-1 (HO-1)/Kelch-like ECH-associated protein 1 (Keap1) signaling cascade, which would then result in its antioxidant, anti-inflammatory, antiapoptotic, and therapeutic effects.
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Affiliation(s)
| | - Hossein Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Bermejo-Bescós P, Jiménez-Aliaga KL, Benedí J, Martín-Aragón S. A Diet Containing Rutin Ameliorates Brain Intracellular Redox Homeostasis in a Mouse Model of Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24054863. [PMID: 36902309 PMCID: PMC10003355 DOI: 10.3390/ijms24054863] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/18/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Quercetin has been studied extensively for its anti-Alzheimer's disease (AD) and anti-aging effects. Our previous studies have found that quercetin and in its glycoside form, rutin, can modulate the proteasome function in neuroblastoma cells. We aimed to explore the effects of quercetin and rutin on intracellular redox homeostasis of the brain (reduced glutathione/oxidized glutathione, GSH/GSSG), its correlation with β-site APP cleaving enzyme 1 (BACE1) activity, and amyloid precursor protein (APP) expression in transgenic TgAPP mice (bearing human Swedish mutation APP transgene, APPswe). On the basis that BACE1 protein and APP processing are regulated by the ubiquitin-proteasome pathway and that supplementation with GSH protects neurons from proteasome inhibition, we investigated whether a diet containing quercetin or rutin (30 mg/kg/day, 4 weeks) diminishes several early signs of AD. Genotyping analyses of animals were carried out by PCR. In order to determine intracellular redox homeostasis, spectrofluorometric methods were adopted to quantify GSH and GSSG levels using o-phthalaldehyde and the GSH/GSSG ratio was ascertained. Levels of TBARS were determined as a marker of lipid peroxidation. Enzyme activities of SOD, CAT, GR, and GPx were determined in the cortex and hippocampus. ΒACE1 activity was measured by a secretase-specific substrate conjugated to two reporter molecules (EDANS and DABCYL). Gene expression of the main antioxidant enzymes: APP, BACE1, a Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), caspase-3, caspase-6, and inflammatory cytokines were determined by RT-PCR. First, overexpression of APPswe in TgAPP mice decreased GSH/GSSG ratio, increased malonaldehyde (MDA) levels, and, overall, decreased the main antioxidant enzyme activities in comparison to wild-type (WT) mice. Treatment of TgAPP mice with quercetin or rutin increased GSH/GSSG, diminished MDA levels, and favored the enzyme antioxidant capacity, particularly with rutin. Secondly, both APP expression and BACE1 activity were diminished with quercetin or rutin in TgAPP mice. Regarding ADAM10, it tended to increase in TgAPP mice with rutin treatment. As for caspase-3 expression, TgAPP displayed an increase which was the opposite with rutin. Finally, the increase in expression of the inflammatory markers IL-1β and IFN-γ in TgAPP mice was lowered by both quercetin and rutin. Collectively, these findings suggest that, of the two flavonoids, rutin may be included in a day-to-day diet as a form of adjuvant therapy in AD.
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Chen XY, Wu ZM, Wang R, Cao YH, Tao YL. Danggui Sini decoction treatment of refractory allergic cutaneous vasculitis: A case report. World J Clin Cases 2022; 10:12422-12429. [PMID: 36483805 PMCID: PMC9724523 DOI: 10.12998/wjcc.v10.i33.12422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/05/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Allergic cutaneous vasculitis (ACV) is a difficult disease to treat. At present, there is no effective treatment for this condition. Traditionally, immunosuppressants and hormones have been primarily used in its management, but the treatment effect is suboptimal, and it has several side effects.
CASE SUMMARY We present the case of a 19-year-old woman who presented at our hospital with a four-year history of symmetric skin lesions mainly affecting her lower extremities. She had previously undergone treatment with prednisolone acetate, cetirizine hydrochloride, and loratadine tablets but had not experienced any relief in her condition. Thereafter, she was treated with oral traditional Chinese medicine. Her skin damage gradually improved within two months of treatment initiation. After six months, the skin ulcers had completely subsided. No evidence of skin ulcer recurrence was observed during the subsequent follow-up. This report presents the first case of a female patient who received oral Danggui Sini decoction for the treatment of ACV.
CONCLUSION Danggui Sini decoction may be a promising oral treatment for ACV patients.
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Affiliation(s)
- Xi-Ya Chen
- The Second Clinical Medical College, Yunnan University of Chinese Traditional Medicine, Kunming 650000, Yunnan Province, China
| | - Zhi-Ming Wu
- School of Basic Medicine, Yunnan University of Chinese Traditional Medicine, Kunming 650000, Yunnan Province, China
| | - Rui Wang
- First Affiliated Hospital, Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Yu-Hong Cao
- The Second Clinical Medical College, Yunnan University of Chinese Traditional Medicine, Kunming 650000, Yunnan Province, China
| | - Yong-Lian Tao
- The Second Clinical Medical College, Yunnan University of Chinese Traditional Medicine, Kunming 650000, Yunnan Province, China
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Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants. JOURNAL OF PROTEINS AND PROTEOMICS 2022; 13:227-245. [PMCID: PMC9667835 DOI: 10.1007/s42485-022-00098-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/27/2022] [Accepted: 09/29/2022] [Indexed: 11/17/2022]
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Cai J, Ye L, Hu Y, Ye Z, Gao L, Wang Y, Sun Q, Tong S, Yang J, Chen Q. Exploring the inverse association of glioblastoma multiforme and Alzheimer's disease via bioinformatics analysis. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:182. [PMID: 36071287 DOI: 10.1007/s12032-022-01786-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 06/28/2022] [Indexed: 11/30/2022]
Abstract
Glioblastoma multiforme (GBM) and Alzheimer's disease (AD) are two major diseases in the nervous system with a similar peak age of onset, which has the typical characteristics of high cost, difficult treatment, and poor prognosis. Epidemiological studies and a few molecular biological studies have hinted at an opposite relationship between AD and GBM. However, there are few studies on their reverse relationship, and the regulatory mechanism is still unclear, indicating that further systematic research is urgently needed. Our study firstly employs advanced bioinformatics methods to explore the inverse relationship between them and find various target drugs. We obtained the gene expression dataset from public databases (GEO, TCGA, and GTEx). Then, we identified 122 differentially expressed genes (DEGs) of AD and GBM. Four significant gene modules were identified through protein-protein interaction (PPI) and module construction, and 13 hub genes were found using cytoHubba. We constructed co-expression networks and found various target drugs through these hub genes. Functional enrichment analysis revealed that the AMPK pathway, cell cycle, and cellular senescence play important roles in AD and GBM. Our study may provide a potential direction for studying the opposite molecular mechanism of AD and GBM in the future.
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Affiliation(s)
- Jiayang Cai
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China
| | - Liguo Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China
| | - Yuanyuan Hu
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhang Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China
| | - Lun Gao
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China
| | - Yixuan Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China
| | - Qian Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China
| | - Shiao Tong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China
| | - Ji'an Yang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. .,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China.
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. .,Central Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Street, Wuhan, 430060, Hubei, China.
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Kong L, Wang Z, Xiao C, Zhu Q, Song Z. Glycerol monolaurate attenuated immunological stress and intestinal mucosal injury by regulating the gut microbiota and activating AMPK/Nrf2 signaling pathway in lipopolysaccharide-challenged broilers. ANIMAL NUTRITION 2022; 10:347-359. [PMID: 35919246 PMCID: PMC9307562 DOI: 10.1016/j.aninu.2022.06.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/29/2022] [Accepted: 06/14/2022] [Indexed: 11/11/2022]
Abstract
This study was conducted to investigate the effects of glycerol monolaurate (GML) on lipopolysaccharide (LPS)-induced immunological stress and intestinal mucosal injury in broilers and its underlying mechanisms. A total of 144 one-d-old Arbor Acres broilers were allocated to a 2 × 2 factorial arrangement involving dietary treatment (0 or 1,200 mg/kg dietary GML) and LPS challenge (injected with saline or Escherichia coli LPS on d 16, 18, and 20). Samples were collected on d 21. The results revealed that dietary GML augmented serum immunoglobulin A (P = 0.009) and immunoglobulin G (P < 0.001) levels in challenged birds. Dietary GML normalized LPS-induced variations in serum interleukin-6, interferon-gamma, and LPS levels (P < 0.05), jejunal villus height (P = 0.030), and gene expression of interleukin-6, macrophage inflammatory protein-3 alpha, Toll-like receptor 4, nuclear factor kappa-B, caspase-1, tight junction proteins, adenosine monophosphate-activated protein kinase alpha 1 (AMPKα1), nuclear factor-erythroid 2-related factor 2 (Nrf2), and superoxide dismutase-1 (P < 0.05). GML supplementation ameliorated LPS-induced peroxidation by reducing malondialdehyde content and increasing antioxidant enzyme activity (P < 0.05). Dietary GML enhanced the abundances of Anaerostipes, Pseudoflavonifractor, and Gordonibacter and reduced the proportion of Phascolarctobacterium in challenged birds. Dietary GML was positively correlated with alterations in antioxidant enzyme activities and AMPKα1, Nrf2, and zonula occludens-1 expressions. The genera Anaerostipes, Lachnospira, Gordonibacter, Lachnospira, Marvinbryantia, Peptococcus, and Pseudoflavonifractor were linked to attenuated inflammation and improved antioxidant capacity of challenged birds. In conclusion, dietary GML alleviated LPS-induced immunological stress and intestinal injury of broilers by suppressing inflammation and oxidative stress. Dietary GML regulated cecal microbiota and activated the AMPK/Nrf2 pathway in LPS-challenged broilers.
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Dutta BJ, Singh S, Seksaria S, Das Gupta G, Singh A. Inside the diabetic brain: Insulin resistance and molecular mechanism associated with cognitive impairment and its possible therapeutic strategies. Pharmacol Res 2022; 182:106358. [PMID: 35863719 DOI: 10.1016/j.phrs.2022.106358] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/02/2022] [Accepted: 07/15/2022] [Indexed: 01/21/2023]
Abstract
Type 2 diabetes mellitus (T2DM) the most prevalent metabolic disease that has evolved into a major public health issue. Concerning about its secondary complications, a growing body of evidence links T2DM to cognitive impairment and neurodegenerative disorders. The underlying pathology behind this secondary complication disease is yet to be fully known. Nonetheless, they are likely to be associated with poor insulin signaling as a result of insulin resistance. We have combed through a rising body of literature on insulin signaling in the normal and diabetic brains along with various factors like insulin resistance, hyperglycemia, obesity, oxidative stress, neuroinflammation and Aβ plaques which can act independently or synergistically to link T2DM with cognitive impairments. Finally, we explored several pharmacological and non-pharmacological methods in the hopes of accelerating the rational development of medications for cognitive impairment in T2DM by better understanding these shared pathways.
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Affiliation(s)
- Bhaskar Jyoti Dutta
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Shamsher Singh
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Sanket Seksaria
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Ghanshyam Das Gupta
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Amrita Singh
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India.
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14
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Wu M, Zhai Y, Liang X, Chen W, Lin R, Ma L, Huang Y, Zhao D, Liang Y, Zhao W, Fang J, Fang S, Chen Y, Wang Q, Li W. Connecting the Dots Between Hypercholesterolemia and Alzheimer’s Disease: A Potential Mechanism Based on 27-Hydroxycholesterol. Front Neurosci 2022; 16:842814. [PMID: 35464321 PMCID: PMC9021879 DOI: 10.3389/fnins.2022.842814] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/01/2022] [Indexed: 12/13/2022] Open
Abstract
Alzheimer’s disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects β-amyloid (Aβ) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.
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Affiliation(s)
- Mingan Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yingying Zhai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoyi Liang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weichun Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ruiyi Lin
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Linlin Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Di Zhao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong Liang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Zhao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuhuan Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yunbo Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Qi Wang,
| | - Weirong Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
- Weirong Li,
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Wang D, Kang L, Chen C, Guo J, Du L, Zhou D, Li G, Zhang Y, Mi X, Zhang M, Liu S, Tan X. Loss of legumain induces premature senescence and mediates aging-related renal fibrosis. Aging Cell 2022; 21:e13574. [PMID: 35195326 PMCID: PMC8920435 DOI: 10.1111/acel.13574] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 01/19/2022] [Accepted: 02/05/2022] [Indexed: 12/14/2022] Open
Abstract
Aging is an independent risk factor for acute kidney injury and subsequent chronic kidney diseases, while the underlying mechanism is still elusive. Here, we found that renal tubules highly express a conserved lysosomal endopeptidase, legumain, which is significantly downregulated with the growing of age. Tubule‐specific legumain‐knockout mice exhibit spontaneous renal interstitial fibrosis from the 3rd month. In the tubule‐specific legumain‐knockout mice and the cultured legumain‐knockdown HK‐2 cells, legumain deficiency induces the activation of tubular senescence and thus increases the secretion of profibrotic senescence‐associated cytokines, which in turn accelerates the activation of fibroblasts. Blockage of senescence mitigates the fibrotic lesion caused by legumain deficiency. Mechanistically, we found that silencing down of legumain leads to the elevated lysosome pH value, enlargement of lysosome size, and increase of lysosomal voltage dependent membrane channel proteins. Either legumain downregulation or aging alone induces the activation of nuclear transcription factors EB (TFEB) while it fails to further upregulate in the elderly legumain‐knockdown tubules, accompanied with impaired mitophagy and increased mitochondrial ROS (mtROS) accumulation. Therapeutically, supplementation of exosomal legumain ameliorated fibronectin and collagen I production in an in vitro coculture system of tubular cells and fibroblasts. Altogether, our data demonstrate that loss of legumain in combined with aging dysregulates lysosomal homeostasis, although either aging or legumain deficiency alone induces lysosome adaptation via stimulating lysosomal biogenesis. Consequently, impaired mitophagy leads to mtROS accumulation and therefore activates tubular senescence and boosts the interstitial fibrosis.
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Affiliation(s)
- Dekun Wang
- Department of Pathology School of Medicine Nankai University Tianjin China
| | - Lichun Kang
- Department of Pathology School of Medicine Nankai University Tianjin China
| | - Chuan'ai Chen
- Department of Pathology School of Medicine Nankai University Tianjin China
| | - Jiasen Guo
- College of Life Science Nankai University Tianjin China
| | - Lingfang Du
- Department of Pathology School of Medicine Nankai University Tianjin China
| | - Donghui Zhou
- Department of Pathology School of Medicine Nankai University Tianjin China
| | - Gang Li
- Nephrology Division The Second Hospital of Tianjin Medical University Tianjin China
| | - Yuying Zhang
- Department of Pathology School of Medicine Nankai University Tianjin China
| | - Xue Mi
- Department of Pathology School of Medicine Nankai University Tianjin China
| | - Mianzhi Zhang
- Dongfang Hospital of Beijing University of Chinese medicine Beijing China
| | - Shuxia Liu
- Hebei Key Laboratory of Nephrology Department of Pathology Hebei Medical University Shijiazhuang China
| | - Xiaoyue Tan
- Department of Pathology School of Medicine Nankai University Tianjin China
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Kim D, Jo YS, Jo HS, Bae S, Kwon YW, Oh YS, Yoon JH. Comparative Phosphoproteomics of Neuro-2a Cells under Insulin Resistance Reveals New Molecular Signatures of Alzheimer's Disease. Int J Mol Sci 2022; 23:ijms23021006. [PMID: 35055191 PMCID: PMC8781554 DOI: 10.3390/ijms23021006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/03/2022] [Accepted: 01/12/2022] [Indexed: 12/29/2022] Open
Abstract
Insulin in the brain is a well-known critical factor in neuro-development and regulation of adult neurogenesis in the hippocampus. The abnormality of brain insulin signaling is associated with the aging process and altered brain plasticity, and could promote neurodegeneration in the late stage of Alzheimer’s disease (AD). The precise molecular mechanism of the relationship between insulin resistance and AD remains unclear. The development of phosphoproteomics has advanced our knowledge of phosphorylation-mediated signaling networks and could elucidate the molecular mechanisms of certain pathological conditions. Here, we applied a reliable phosphoproteomic approach to Neuro2a (N2a) cells to identify their molecular features under two different insulin-resistant conditions with clinical relevance: inflammation and dyslipidemia. Despite significant difference in overall phosphoproteome profiles, we found molecular signatures and biological pathways in common between two insulin-resistant conditions. These include the integrin and adenosine monophosphate-activated protein kinase pathways, and we further verified these molecular targets by subsequent biochemical analysis. Among them, the phosphorylation levels of acetyl-CoA carboxylase and Src were reduced in the brain from rodent AD model 5xFAD mice. This study provides new molecular signatures for insulin resistance in N2a cells and possible links between the molecular features of insulin resistance and AD.
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Affiliation(s)
- Dayea Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Korea;
| | - Yeon Suk Jo
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea; (Y.S.J.); (H.-S.J.); (S.B.); (Y.W.K.)
- Department of Brain-Cognitive Science, Daegu-Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
| | - Han-Seul Jo
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea; (Y.S.J.); (H.-S.J.); (S.B.); (Y.W.K.)
| | - Sungwon Bae
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea; (Y.S.J.); (H.-S.J.); (S.B.); (Y.W.K.)
| | - Yang Woo Kwon
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea; (Y.S.J.); (H.-S.J.); (S.B.); (Y.W.K.)
| | - Yong-Seok Oh
- Department of Brain-Cognitive Science, Daegu-Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
- Correspondence: (Y.-S.O.); (J.H.Y.); Tel.: +82-53-785-6114 (Y.-S.O.); +82-53-980-8341 (J.H.Y.)
| | - Jong Hyuk Yoon
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea; (Y.S.J.); (H.-S.J.); (S.B.); (Y.W.K.)
- Correspondence: (Y.-S.O.); (J.H.Y.); Tel.: +82-53-785-6114 (Y.-S.O.); +82-53-980-8341 (J.H.Y.)
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Xu Y, Yan H, Zhang X, Zhuo J, Han Y, Zhang H, Xie D, Lan X, Cai W, Wang X, Wang S, Li X. Roles of Altered Macrophages and Cytokines: Implications for Pathological Mechanisms of Postmenopausal Osteoporosis, Rheumatoid Arthritis, and Alzheimer's Disease. Front Endocrinol (Lausanne) 2022; 13:876269. [PMID: 35757427 PMCID: PMC9226340 DOI: 10.3389/fendo.2022.876269] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
Postmenopausal osteoporosis (PMOP) is characterized by the uncoupling of bone resorption and bone formation induced by estrogen deficiency, which is a complex outcome related to estrogen and the immune system. The interaction between bone and immune cells is regarded as the context of PMOP. Macrophages act differently on bone cells, depending on their polarization profile and secreted paracrine factors, which may have implications for the development of PMOP. PMOP, rheumatoid arthritis (RA), and Alzheimer's disease (AD) might have pathophysiological links, and the similarity of their pathological mechanisms is partially visible in altered macrophages and cytokines in the immune system. This review focuses on exploring the pathological mechanisms of PMOP, RA, and AD through the roles of altered macrophages and cytokines secretion. First, the multiple effects on cytokines secretion by bone-bone marrow (BM) macrophages in the pathological mechanism of PMOP are reviewed. Then, based on the thought of "different tissue-same cell type-common pathological molecules-disease pathological links-drug targets" and the methodologies of "molecular network" in bioinformatics, highlight that multiple cytokines overlap in the pathological molecules associated with PMOP vs. RA and PMOP vs. AD, and propose that these overlaps may lead to a pathological synergy in PMOP, RA, and AD. It provides a novel strategy for understanding the pathogenesis of PMOP and potential drug targets for the treatment of PMOP.
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Affiliation(s)
- Yunteng Xu
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Hui Yan
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Basic Discipline Laboratory of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xin Zhang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Junkuan Zhuo
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Yidan Han
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Haifeng Zhang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Dingbang Xie
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xin Lan
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Wanping Cai
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xiaoning Wang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Key Laboratory of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Shanshan Wang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Key Laboratory of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xihai Li
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Key Laboratory of Fujian University of Traditional Chinese Medicine, Fuzhou, China
- *Correspondence: Xihai Li,
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Mesenchymal stem cells after the proprocessing of tanshinone IIA attenuate cognitive deficits and oxidative stress injury in an amyloid β-peptide (25-35)-induced rodent model of Alzheimer's disease. Neuroreport 2021; 33:61-71. [PMID: 34954772 DOI: 10.1097/wnr.0000000000001755] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To verify whether mesenchymal stem cells cocultured with tanshinone IIA may ameliorate Alzheimer's disease by inhibiting oxidative stress. METHODS Sixty male Sprague-Dawley rats were randomly divided into 4 groups named Sham, Aβ25-35, mesenchymal stem cells, and mesenchymal stem cells (tanshinone IIA). The rats were treated according to different groups. The neurobehavioral performance of Sprague-Dawley rats was evaluated via Morris water maze test. Histological changes were checked via hematoxylin-eosin staining. The levels of total antioxidant activity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and malondialdehyde in hippocampus were assayed by ELISA kit. The levels of Aβ, p-tau/tau, and p-AMP-activated protein kinase/AMP-activated protein kinase in hippocampus were checked by Western blot. RESULTS Our research showed that the injection of mesenchymal stem cells (tanshinone IIA) into the hippocampus alleviated learning and memory deficits and reduced hippocampal neuronal injury in the Alzheimer's disease rats. Moreover, mesenchymal stem cells (tanshinone IIA) treatment suppressed oxidative stress, attenuated Aβ accumulation reduced Tau hyperphosphorylation, and enhanced the activity of AMP-activated protein kinase in the hippocampus of the Alzheimer's disease rats. However, there were almost no significant difference between the mesenchymal stem cells and Aβ25-35 groups. CONCLUSIONS Mesenchymal stem cells (tanshinone IIA) transplantation may be a potential treatment for curing Alzheimer's disease, which may be related to the inhibition of oxidative stress.
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Pharmacological Mechanism of Danggui-Sini Formula for Intervertebral Disc Degeneration: A Network Pharmacology Study. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5165075. [PMID: 34805401 PMCID: PMC8601842 DOI: 10.1155/2021/5165075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/19/2021] [Indexed: 12/22/2022]
Abstract
Background Intervertebral disc degeneration (IVDD) is the most significant cause of low back pain, the sixth-largest disease burden globally, and the leading cause of disability. This study is aimed at investigating the molecular biological mechanism of Danggui-Sini formula (DSF) mediated IVDD treatment. Methods A potential gene set for DSF treatment of IVDD was identified through TCMSP, UniProt, and five disease gene databases. A protein interaction network of common targets between DSF and IVDD was established by using the STRING database. GO and KEGG enrichment analyses were performed using the R platform to discover the potential mechanism. Moreover, AutoDock Vina was used to verify molecular docking and calculate the binding energy. Results A total of 119 active ingredients and 136 common genes were identified, including 10 core genes (AKT1, IL6, ALB, TNF, VEGFA, TP53, MAPK3, CASP3, JUN, and EGF). Enrichment analysis results showed that the therapeutic targets of DSF for diseases mainly focused on the AGE-RAGE signaling pathway involved in diabetic complications, IL-17 signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, apoptosis, cellular senescence, PI3K-Akt signaling pathway, and FoxO signaling pathway. These biological processes are induced mainly in response to oxidative stress and reactive oxygen species and the regulation of apoptotic signaling pathways. Molecular docking showed that there was a stable affinity between the core genes and the key components. Conclusions The combination of network pharmacology and molecular docking provides a practical way to analyze the molecular biological mechanism of DSF-mediated IVDD treatment, which confirms the “multicomponent, multitarget and multipathway” characteristics of DSF and provides an essential theoretical basis for clinical practice.
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Alshammari GM, Al-Qahtani WH, Alshuniaber MA, Yagoub AEA, Al-Khalifah AS, Al-Harbi LN, Alhussain MH, AlSedairy SA, Yahya MA. Quercetin improves the impairment in memory function and attenuates hippocampal damage in cadmium chloride-intoxicated male rats by suppressing acetylcholinesterase and concomitant activation of SIRT1 signaling. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104675] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Neumann NR, Thompson DC, Vasiliou V. AMPK activators for the prevention and treatment of neurodegenerative diseases. Expert Opin Drug Metab Toxicol 2021; 17:1199-1210. [PMID: 34632898 DOI: 10.1080/17425255.2021.1991308] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION As the global population ages at an unprecedented rate, the burden of neurodegenerative diseases is expected to grow. Given the profound impact illness like dementia exert on individuals and society writ large, researchers, physicians, and scientific organizations have called for increased investigation into their treatment and prevention. Both metformin and aspirin have been associated with improved cognitive outcomes. These agents are related in their ability to stimulate AMP kinase (AMPK). Momordica charantia, another AMPK activator, is a component of traditional medicines and a novel agent for the treatment of cancer. It is also being evaluated as a nootropic agent. AREAS COVERED This article is a comprehensive review which examines the role of AMPK activation in neuroprotection and the role that AMPK activators may have in the management of dementia and cognitive impairment. It evaluates the interaction of metformin, aspirin, and Momordica charantia, with AMPK, and reviews the literature characterizing these agents' impact on neurodegeneration. EXPERT OPINION We suggest that AMPK activators should be considered for the treatment and prevention of neurodegenerative diseases. We identify multiple areas of future investigation which may have a profound impact on patients worldwide.
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Affiliation(s)
- Natalie R Neumann
- Department of Emergency Medicine, Yale School of Medicine, New Haven, CT, USA
| | - David C Thompson
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale School of Medicine, New Haven, CT, USA
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22
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Nishihira J, Nishimura M, Kurimoto M, Kagami-Katsuyama H, Hattori H, Nakagawa T, Muro T, Kobori M. The effect of 24-week continuous intake of quercetin-rich onion on age-related cognitive decline in healthy elderly people: a randomized, double-blind, placebo-controlled, parallel-group comparative clinical trial. J Clin Biochem Nutr 2021; 69:203-215. [PMID: 34616111 PMCID: PMC8482389 DOI: 10.3164/jcbn.21-17] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 02/23/2021] [Indexed: 12/19/2022] Open
Abstract
Quercetin, a type of flavonoid, is believed to reduce age-related cognitive decline. To elucidate its potential function, we carried out a randomized, double-blind, placebo-controlled, parallel-group comparative clinical trial involving 24-week continuous intake of quercetin-rich onion compared to quercetin-free onion as a placebo. Seventy healthy Japanese individuals (aged 60 to 79 years old) were enrolled in this study. We examined the effect of quercetin-rich onion (the active test food) on cognitive function using the Mini-Mental State Examination, Cognitive Assessment for Dementia iPad version, and Neuropsychiatric Inventory Nursing Home version. The Mini-Mental State Examination scores were significantly improved in the active test food group (daily quercetin intake, 50 mg as aglycone equivalent) compared to the placebo food group after 24 weeks. On the Cognitive Assessment for Dementia iPad version for emotional function evaluation, we found that the scores of the active test food group were significantly improved, suggesting that quercetin prevents cognitive decline by improving depressive symptoms and elevating motivation. On the Neuropsychiatric Inventory Nursing Home version, we found significant effects on reducing the burden on study partners. Taking all the data together, we concluded that 24-week continuous intake of quercetin-rich onion reduces age-related cognitive decline, possibly by improving emotional conditions. Clinical trial register and their clinical registration number: This study was registered with UMIN (approval number UMIN000036276, 5 April 2019).
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Affiliation(s)
- Jun Nishihira
- Department of Medical Management and Informatics, Hokkaido Information University, Nishi-Nopporo 59-2, Ebetsu, Hokkaido 069-8585, Japan
| | - Mie Nishimura
- Department of Medical Management and Informatics, Hokkaido Information University, Nishi-Nopporo 59-2, Ebetsu, Hokkaido 069-8585, Japan
| | - Masanori Kurimoto
- Department of Medical Management and Informatics, Hokkaido Information University, Nishi-Nopporo 59-2, Ebetsu, Hokkaido 069-8585, Japan
| | - Hiroyo Kagami-Katsuyama
- Department of Medical Management and Informatics, Hokkaido Information University, Nishi-Nopporo 59-2, Ebetsu, Hokkaido 069-8585, Japan
| | - Hiroki Hattori
- Department of Medical Management and Informatics, Hokkaido Information University, Nishi-Nopporo 59-2, Ebetsu, Hokkaido 069-8585, Japan
| | - Toshiyuki Nakagawa
- Department of Neurobiology, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1194, Japan
| | - Takato Muro
- Tohoku Agricultural Research Center, National Agriculture and Food Research Organization, Akahira 4, Shimokuriyagawa, Morioka, Iwate 020-0198, Japan
| | - Masuko Kobori
- Food Research Institute, National Agriculture and Food Research Organization, 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan
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Rezaee N, Fernando WB, Hone E, Sohrabi HR, Johnson SK, Gunzburg S, Martins RN. Potential of Sorghum Polyphenols to Prevent and Treat Alzheimer's Disease: A Review Article. Front Aging Neurosci 2021; 13:729949. [PMID: 34690742 PMCID: PMC8527926 DOI: 10.3389/fnagi.2021.729949] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/24/2021] [Indexed: 12/06/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by the excessive deposition of extracellular amyloid-beta peptide (Aβ) and the build-up of intracellular neurofibrillary tangles containing hyperphosphorylated tau proteins. This leads to neuronal damage, cell death and consequently results in memory and learning impairments leading to dementia. Although the exact cause of AD is not yet clear, numerous studies indicate that oxidative stress, inflammation, and mitochondrial dysfunction significantly contribute to its onset and progression. There is no effective therapeutic approach to stop the progression of AD and its associated symptoms. Thus, early intervention, preferably, pre-clinically when the brain is not significantly affected, is a better option for effective treatment. Natural polyphenols (PP) target multiple AD-related pathways such as protecting the brain from Aβ and tau neurotoxicity, ameliorating oxidative damage and mitochondrial dysfunction. Among natural products, the cereal crop sorghum has some unique features. It is one of the major global grain crops but in the developed world, it is primarily used as feed for farm animals. A broad range of PP, including phenolic acids, flavonoids, and condensed tannins are present in sorghum grain including some classes such as proanthocyanidins that are rarely found in others plants. Pigmented varieties of sorghum have the highest polyphenolic content and antioxidant activity which potentially makes their consumption beneficial for human health through different pathways such as oxidative stress reduction and thus the prevention and treatment of neurodegenerative diseases. This review summarizes the potential of sorghum PP to beneficially affect the neuropathology of AD.
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Affiliation(s)
- Nasim Rezaee
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - W.M.A.D. Binosha Fernando
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Eugene Hone
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Hamid R. Sohrabi
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
- Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia
- Centre for Healthy Ageing, Health Future Institute, Murdoch University, Murdoch, WA, Australia
| | - Stuart K. Johnson
- School of Molecular and Life Sciences, Faculty of Science and Engineering, Curtin University, Perth, WA, Australia
- Ingredients by Design Pty Ltd., Lesmurdie, WA, Australia
| | | | - Ralph N. Martins
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
- Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia
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Gravandi MM, Fakhri S, Zarneshan SN, Yarmohammadi A, Khan H. Flavonoids modulate AMPK/PGC-1α and interconnected pathways toward potential neuroprotective activities. Metab Brain Dis 2021; 36:1501-1521. [PMID: 33988807 DOI: 10.1007/s11011-021-00750-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 04/30/2021] [Indexed: 01/29/2023]
Abstract
As progressive, chronic, incurable and common reasons for disability and death, neurodegenerative diseases (NDDs) are significant threats to human health. Besides, the increasing prevalence of neuronal gradual degeneration and death during NDDs has made them a global concern. Since yet, no effective treatment has been developed to combat multiple dysregulated pathways/mediators and related complications in NDDs. Therefore, there is an urgent need to create influential and multi-target factors to combat neuronal damages. Accordingly, the plant kingdom has drawn a bright future. Among natural entities, flavonoids are considered a rich source of drug discovery and development with potential biological and medicinal activities. Growing studies have reported multiple dysregulated pathways in NDDs, which among those mediator AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) play critical roles. In this line, critical role of flavonoids in the upregulation of AMPK/PGC-1α pathway seems to pave the road in the treatment of Alzheimer's disease (AD), Parkinson's disease (PD), aging, central nervous system (brain/spinal cord) damages, stroke, and other NDDs. In the present study, the regulatory role of flavonoids in managing various NDDs has been shown to pass through AMPK/PGC-1α signaling pathway.
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Affiliation(s)
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | | | - Akram Yarmohammadi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan.
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25
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Querfurth H, Lee HK. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol Neurodegener 2021; 16:44. [PMID: 34215308 PMCID: PMC8252260 DOI: 10.1186/s13024-021-00428-5] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Novel targets to arrest neurodegeneration in several dementing conditions involving misfolded protein accumulations may be found in the diverse signaling pathways of the Mammalian/mechanistic target of rapamycin (mTOR). As a nutrient sensor, mTOR has important homeostatic functions to regulate energy metabolism and support neuronal growth and plasticity. However, in Alzheimer's disease (AD), mTOR alternately plays important pathogenic roles by inhibiting both insulin signaling and autophagic removal of β-amyloid (Aβ) and phospho-tau (ptau) aggregates. It also plays a role in the cerebrovascular dysfunction of AD. mTOR is a serine/threonine kinase residing at the core in either of two multiprotein complexes termed mTORC1 and mTORC2. Recent data suggest that their balanced actions also have implications for Parkinson's disease (PD) and Huntington's disease (HD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Beyond rapamycin; an mTOR inhibitor, there are rapalogs having greater tolerability and micro delivery modes, that hold promise in arresting these age dependent conditions.
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Affiliation(s)
- Henry Querfurth
- Department of Neurology, Tufts Medical Center, Boston, Massachusetts, USA.
| | - Han-Kyu Lee
- Department of Neurology, Tufts Medical Center, Boston, Massachusetts, USA
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26
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Arbab AAI, Lu X, Abdalla IM, Idris AA, Chen Z, Li M, Mao Y, Xu T, Yang Z. Metformin Inhibits Lipoteichoic Acid-Induced Oxidative Stress and Inflammation Through AMPK/NRF2/NF-κB Signaling Pathway in Bovine Mammary Epithelial Cells. Front Vet Sci 2021; 8:661380. [PMID: 34262962 PMCID: PMC8274905 DOI: 10.3389/fvets.2021.661380] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/20/2021] [Indexed: 12/13/2022] Open
Abstract
The objective of this research was to explore the effect of metformin on the lipoteichoic acid (LTA)–induced mastitis model using isolated primary bovine mammary epithelial cells (PBMECs). The PBMECs were exposed to either 3 mM metformin for 12 h as a metformin group (MET) or 100 μg/mL LTA for 6 h as LTA group (LTA). Cells pretreated with 3 mM metformin for 12 h followed by washing and 100 μg/mL LTA exposure for 6 h served as the MET + LTA group. Phosphate-buffered saline was added to cells as the control group. PBMECs pretreated with different metformin doses were analyzed by a flow cytometry (annexin V–fluorescein isothiocyanate assay) to detect the cell apoptotic rate. We performed quantitative reverse transcriptase–polymerase chain reaction and Western blot analysis to evaluate the inflammatory and oxidative responses to metformin and LTA by measuring cellular cytotoxicity, mRNA expression, and protein expression. Immunofluorescence was used to evaluate nuclear localization. The results showed that the gene expression of COX2, IL-1β, and IL-6 significantly increased in the cells challenged with LTA doses compared to control cells. In inflammatory PBMECs, metformin attenuated LTA-induced expression of inflammatory genes nuclear factor κB (NF-κB) p65, tumor necrosis factor α, cyclooxygenase 2, and interleukin 1β, as well as the nuclear localization and phosphorylation of NF-κBp65 protein, but increased the transcription of nuclear factor erythroid 2–related factor 2 (Nrf2) and Nrf2-targeted antioxidative genes heme oxygenase-1 (HO-1) and Gpx1, as well as the nuclear localization of HO-1 protein. Importantly, metformin-induced activation of Nrf2 is AMP-activated protein kinase (AMPK)–dependent; as metformin-pretreated PBMECs activated AMPK signaling via the upregulation of phosphorylated AMPK levels, cell pretreatment with metformin also reversed the translocation of Nrf2 that was LTA inhibited. This convergence between AMPK and Nrf2 pathways is essential for the anti-inflammatory effect of metformin in LTA-stimulated PBMECs. Altogether, our results indicate that metformin exerts anti-inflammation and oxidative stress through regulation of AMPK/Nrf2/NF-κB signaling pathway, which highlights the role of AMPK as a potential therapeutic strategy for treatment of bovine mastitis.
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Affiliation(s)
- Abdelaziz Adam Idriss Arbab
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Darfur College, Biomedical Research Institute, Niyla, Sudan
| | - Xubin Lu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | | | | | - Zhi Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Mingxun Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Yongjiang Mao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Tianle Xu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Zhangping Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, China
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27
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Islam MS, Quispe C, Hossain R, Islam MT, Al-Harrasi A, Al-Rawahi A, Martorell M, Mamurova A, Seilkhan A, Altybaeva N, Abdullayeva B, Docea AO, Calina D, Sharifi-Rad J. Neuropharmacological Effects of Quercetin: A Literature-Based Review. Front Pharmacol 2021; 12:665031. [PMID: 34220504 PMCID: PMC8248808 DOI: 10.3389/fphar.2021.665031] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 06/07/2021] [Indexed: 12/17/2022] Open
Abstract
Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimer’s disease, Amyloid β peptide, Parkinson’s disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.
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Affiliation(s)
- Md Shahazul Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Cristina Quispe
- Facultad de Ciencias de La Salud, Universidad Arturo Prat, Iquique, Chile
| | - Rajib Hossain
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Ahmed Al-Rawahi
- Natural and Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, Centre for Healthy Living, University of Concepción, Concepción, Chile
| | - Assem Mamurova
- Department of Biodiversity of Bioresources, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Ainur Seilkhan
- Educational program, Geography, Environment and Service sector, Abai Kazakh National Pedagogical University, Kazakhstan, Almaty, Kazakhstan.,Biomedical Research Centre, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Nazgul Altybaeva
- Department of Molecular Biology and Genetics, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Bagila Abdullayeva
- Department of Biodiversity of Bioresources, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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28
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Singh AK, Rai SN, Maurya A, Mishra G, Awasthi R, Shakya A, Chellappan DK, Dua K, Vamanu E, Chaudhary SK, Singh MP. Therapeutic Potential of Phytoconstituents in Management of Alzheimer's Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:5578574. [PMID: 34211570 PMCID: PMC8208882 DOI: 10.1155/2021/5578574] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/28/2021] [Indexed: 01/03/2023]
Abstract
Since primitive times, herbs have been extensively used in conventional remedies for boosting cognitive impairment and age-associated memory loss. It is mentioned that medicinal plants have a variety of dynamic components, and they have become a prominent choice for synthetic medications for the care of cognitive and associated disorders. Herbal remedies have played a major role in the progression of medicine, and many advanced drugs have already been developed. Many studies have endorsed practicing herbal remedies with phytoconstituents, for healing Alzheimer's disease (AD). All the information in this article was collated from selected research papers from online scientific databases, such as PubMed, Web of Science, and Scopus. The aim of this article is to convey the potential of herbal remedies for the prospect management of Alzheimer's and related diseases. Herbal remedies may be useful in the discovery and advancement of drugs, thus extending new leads for neurodegenerative diseases such as AD. Nanocarriers play a significant role in delivering herbal medicaments to a specific target. Therefore, many drugs have been described for the management of age-linked complaints such as dementia, AD, and the like. Several phytochemicals are capable of managing AD, but their therapeutic claims are restricted due to their lower solubility and metabolism. These limitations of natural therapeutics can be overcome by using a targeted nanocarrier system. This article will provide the primitive remedies as well as the development of herbal remedies for AD management.
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Affiliation(s)
- Anurag Kumar Singh
- Centre of Experimental Medicine & Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Sachchida Nand Rai
- Centre of Biotechnology, University of Allahabad, Prayagraj 211002, India
| | - Anand Maurya
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Gaurav Mishra
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Rajendra Awasthi
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida 201303, Uttar Pradesh, India
| | - Anshul Shakya
- Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Assam 786004, Dibrugarh, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University (IMU), Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney (UTS), Ultimo, New South Wales, Australia
| | - Emanuel Vamanu
- Faculty of Biotechnology, University of Agronomic Science and Veterinary Medicine, 59 Marasti Blvd, 1 District, 011464, Bucharest, Romania
| | - Sushil Kumar Chaudhary
- Faculty of Pharmacy, DIT University, Mussoorie-Diversion Road, Makkawala, Dehradun 248 009, Uttarakhand, India
| | - M P Singh
- Centre of Biotechnology, University of Allahabad, Prayagraj 211002, India
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29
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Martins WK, Silva MDND, Pandey K, Maejima I, Ramalho E, Olivon VC, Diniz SN, Grasso D. Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100033. [PMID: 34909664 PMCID: PMC8663935 DOI: 10.1016/j.crphar.2021.100033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 04/15/2021] [Accepted: 05/02/2021] [Indexed: 02/08/2023] Open
Abstract
Autophagy is a critical metabolic process that supports homeostasis at a basal level and is dynamically regulated in response to various physiological and pathological processes. Autophagy has some etiologic implications that support certain pathological processes due to alterations in the lysosomal-degradative pathway. Some of the conditions related to autophagy play key roles in highly relevant human diseases, e.g., cardiovascular diseases (15.5%), malignant and other neoplasms (9.4%), and neurodegenerative conditions (3.7%). Despite advances in the discovery of new strategies to treat these age-related diseases, autophagy has emerged as a therapeutic option after preclinical and clinical studies. Here, we discuss the pitfalls and success in regulating autophagy initiation and its lysosome-dependent pathway to restore its homeostatic role and mediate therapeutic effects for cancer, neurodegenerative, and cardiac diseases. The main challenge for the development of autophagy regulators for clinical application is the lack of specificity of the repurposed drugs, due to the low pharmacological uniqueness of their target, including those that target the PI3K/AKT/mTOR and AMPK pathway. Then, future efforts must be conducted to deal with this scenery, including the disclosure of key components in the autophagy machinery that may intervene in its therapeutic regulation. Among all efforts, those focusing on the development of novel allosteric inhibitors against autophagy inducers, as well as those targeting autolysosomal function, and their integration into therapeutic regimens should remain a priority for the field.
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Affiliation(s)
- Waleska Kerllen Martins
- Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Maryana do Nascimento da Silva
- Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Kiran Pandey
- Center for Neural Science, New York University, Meyer Building, Room 823, 4 Washington Place, New York, NY, 10003, USA
| | - Ikuko Maejima
- Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa Machi, Maebashi, Gunma, 3718512, Japan
| | - Ercília Ramalho
- Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Vania Claudia Olivon
- Laboratory of Pharmacology and Physiology, UNIDERP, Av. Ceará, 333. Vila Miguel Couto, Campo Grande, MS, 79003-010, Brazil
| | - Susana Nogueira Diniz
- Laboratory of Molecular Biology and Functional Genomics, Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Daniel Grasso
- Instituto de Estudios de la Inmunidad Humoral (IDEHU), Universidad de Buenos Aires, CONICET, Junín 954 p4, Buenos Aires, C1113AAD, Argentina
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30
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Nikbakhtzadeh M, Shaerzadeh F, Ashabi G. Highlighting the protective or degenerative role of AMPK activators in dementia experimental models. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 20:786-801. [PMID: 34042039 DOI: 10.2174/1871527320666210526160214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 11/02/2020] [Accepted: 12/21/2020] [Indexed: 11/22/2022]
Abstract
AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a driving or deterrent factor in the development of neurodegenerative diseases and dementia. AMPK affects intracellular proteins like the mammalian target of rapamycin (mTOR). Peroxisome proliferator-activated receptor-γ coactivator 1-α (among others) contributes to a wide range of intracellular activities based on its downstream molecules such as energy balancing (ATP synthesis), extracellular inflammation, cell growth, and neuronal cell death (such as apoptosis, necrosis, and necroptosis). Several studies have looked at the dual role of AMPK in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington disease (HD) but the exact effect of this enzyme on dementia, stroke, and motor neuron dysfunction disorders has not been elucidated yet. In this article, we review current research on the effects of AMPK on the brain to give an overview of the relationship. More specifically, we review the neuroprotective or neurodegenerative effects of AMPK or AMPK activators like metformin, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside on neurological diseases and dementia, which exert through the intracellular molecules involved in neuronal survival or death.
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Affiliation(s)
- Marjan Nikbakhtzadeh
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Shaerzadeh
- Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, United States
| | - Ghorbangol Ashabi
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
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31
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Network Pharmacology and Molecular Docking Analysis on Molecular Targets and Mechanisms of Buyang Huanwu Decoction in the Treatment of Ischemic Stroke. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:8815447. [PMID: 33727944 PMCID: PMC7937485 DOI: 10.1155/2021/8815447] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 02/01/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023]
Abstract
Methods The bioactive components and potential targets of BHD were screened by TCMSP, BATMAN-TCM, ETCM, and SymMap databases. Besides, compounds that failed to find the targets from the above databases were predicted through STITCH, SwissTargetPrediction, and SEA. Moreover, six databases were searched to mine targets of IS. The intersection targets were obtained and analyzed by GO and KEGG enrichment. Furthermore, BHD-IS PPI network, compound-target network, and herb-target-pathway network were constructed by Cytoscape 3.6.0. Finally, AutoDock was used for molecular docking verification. Results A total of 235 putative targets were obtained from 59 active compounds in BHD. Among them, 62 targets were related to IS. PPI network showed that the top ten key targets were IL6, TNF, VEGFA, AKT1, etc. The enrichment analysis demonstrated candidate BHD targets were more frequently involved in TNF, PI3K-Akt, and NF-kappa B signaling pathway. Network topology analysis showed that Radix Astragali was the main herb in BHD, and the key components were quercetin, beta-sitosterol, kaempferol, stigmasterol, etc. The results of molecular docking showed the active components in BHD had a good binding ability with the key targets. Conclusions Our study demonstrated that BHD exerted the effect of treating IS by regulating multitargets and multichannels with multicomponents through the method of network pharmacology and molecular docking.
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32
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Yang L, Jiang Y, Shi L, Zhong D, Li Y, Li J, Jin R. AMPK: Potential Therapeutic Target for Alzheimer's Disease. Curr Protein Pept Sci 2021; 21:66-77. [PMID: 31424367 DOI: 10.2174/1389203720666190819142746] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 06/30/2019] [Accepted: 08/31/2019] [Indexed: 12/19/2022]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder. The pathogenesis of AD is very complicated. For decades, the amyloid hypothesis has influenced and guided research in the field of AD. Meanwhile, researchers gradually realized that AD is caused by multiple concomitant factors, such as autophagy, mitochondrial quality control, insulin resistance and oxidative stress. In current clinical trials, the improvement strategies of AD, such as Aβ antibody immunotherapy and gamma secretase inhibitors, are limited. There is mounting evidence of neurodegenerative disorders indicated that activation of AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. We reviewed the researches on AMPK for AD, the results demonstrated that activation of AMPK is controversial in Aβ deposition and tau phosphorylation, but is positive to promote autophagy, maintain mitochondrial quality control, reduce insulin resistance and relieve oxidative stress. It is concluded that AMPK might be a new target for AD by aggressively treating the risk factors in the future.
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Affiliation(s)
- Luping Yang
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610037, China
| | - Yijing Jiang
- Rehabilitation Hospital affiliated to Fujian University of Traditional Chinese Medicine Fuzhou 350003 Fujian Key Laboratory of Rehabilitation Technology, Fuzhou 350003, China
| | - Lihong Shi
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610037, China
| | - Dongling Zhong
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610037, China
| | - Yuxi Li
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610037, China
| | - Juan Li
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610037, China
| | - Rongjiang Jin
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610037, China
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Moujahed S, Ruiz A, Hallegue D, Sakly M. Quercetin alleviates styrene oxide-induced cytotoxicity in cortical neurons in vitro via modulation of oxidative stress and apoptosis. Drug Chem Toxicol 2020; 45:1634-1643. [PMID: 33297769 DOI: 10.1080/01480545.2020.1851706] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Styrene 7,8-oxide (SO) is the principal metabolite of styrene, an industrial neurotoxic compound which causes various neurodegenerative disorders. The present study aimed to explore the mechanisms of SO cytotoxicity (0.5 - 4 mM) in primary cortical neurons and to evaluate the neuroprotective potential of quercetin (QUER). Our results showed that exposure to SO decreased viability of cortical neurons in a concentration-dependent manner. In the presence of QUER, cell viability was increased significantly. The neuroprotective effects of QUER were associated with the reduction of intracellular Reactive Oxygen Species (ROS), the decrease in calcium overload and the restoration of mitochondrial membrane depolarization caused by SO. Additionally, to evaluate neuronal death mechanisms triggered by SO, cells were incubated with Ac-DEVD-CHO, Calpeptin and Necrostatin-1, pharmacological inhibitors of caspase-3, calpains and necroptosis respectively. The data showed that the three inhibitors reduced cell death induced by SO and suggested the implication of apoptotic, necrotic and necroptotic pathways. However, western blot analysis showed that QUER attenuated the activation of caspase-3 but did not prevent calpain activity. Taken together, these data indicated that the cytotoxicity of SO was mediated by oxidative stress and apoptosis, necrosis and necroptosis mechanisms, while the neuroprotection provided by QUER against SO depended mainly on its anti-apoptotic activity.
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Affiliation(s)
- Sabrine Moujahed
- Faculty of Sciences of Bizerte, Laboratory of Integrative Physiology, University of Carthage, Jarzouna, Tunisia
| | - Asier Ruiz
- Faculty of Medicine and Nursing, Department of Neurosciences, University of the Basque Country, Vizcaya, Spain
| | - Dorsaf Hallegue
- Faculty of Sciences of Bizerte, Laboratory of Integrative Physiology, University of Carthage, Jarzouna, Tunisia
| | - Mohsen Sakly
- Faculty of Sciences of Bizerte, Laboratory of Integrative Physiology, University of Carthage, Jarzouna, Tunisia
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Chen M, Huang N, Liu J, Huang J, Shi J, Jin F. AMPK: A bridge between diabetes mellitus and Alzheimer's disease. Behav Brain Res 2020; 400:113043. [PMID: 33307136 DOI: 10.1016/j.bbr.2020.113043] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/21/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
The pathogenesis and etiology of diabetes mellitus (DM) and Alzheimer's disease (AD) share many common cellular and molecular themes. Recently, a growing body of research has shown that AMP-activated protein kinase (AMPK), a biomolecule that regulates energy balance and glucose and lipid metabolism, plays key roles in DM and AD. In this review, we summarize the relevant research on the roles of AMPK in DM and AD, including its functions in gluconeogenesis and insulin resistance (IR) and its relationships with amyloid β-protein (Aβ), Tau and AMPK activators. In DM, AMPK is involved in the regulation of glucose metabolism and IR. AMPK is closely related to gluconeogenesis, which can not only be activated by the upstream kinases liver kinase B1 (LKB1), transforming growth factor β-activated kinase 1 (TAK1), and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) but also regulate the downstream kinases glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxy kinase (PEPCK), thereby affecting gluconeogenesis and ameliorating DM. Moreover, AMPK can regulate glucose transporter 4 (GLUT4) and free fatty acids to improve IR. In AD, AMPK can ameliorate abnormal brain energy metabolism, not only by reduces Aβ deposition through β-secretase but also reduces tau hyperphosphorylation through sirtuin 1 (SIRT1) and protein phosphatase 2A (PP2A). Therefore, AMPK is a bridge between DM and AD.
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Affiliation(s)
- Meixiang Chen
- Key Laboratory of Basic Pharmacology and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nanqu Huang
- National Drug Clinical Trial Institution, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Ju Liu
- Key Laboratory of Basic Pharmacology and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Juan Huang
- Key Laboratory of Basic Pharmacology and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jingshan Shi
- Key Laboratory of Basic Pharmacology and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Feng Jin
- Key Laboratory of Basic Pharmacology and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.
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Chen Q, Xu B, Huang W, Amrouche AT, Maurizio B, Simal-Gandara J, Tundis R, Xiao J, Zou L, Lu B. Edible flowers as functional raw materials: A review on anti-aging properties. Trends Food Sci Technol 2020; 106:30-47. [DOI: 10.1016/j.tifs.2020.09.023] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Li Y, Yang Q, Yu Y. A Network Pharmacological Approach to Investigate the Mechanism of Action of Active Ingredients of Epimedii Herba and Their Potential Targets in Treatment of Alzheimer's Disease. Med Sci Monit 2020; 26:e926295. [PMID: 32980851 PMCID: PMC7528617 DOI: 10.12659/msm.926295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Epimedii Herba is a traditional Chinese herbal medicine used to treat central nervous system diseases such as Alzheimer’s disease in China. However, the pharmacological mechanism is unclear. To investigate the mechanisms of Epimedii Herba in the treatment of Alzheimer’s disease, we assessed effective compounds, corresponding targets, and related pathways of Epimedii Herba in the treatment of Alzheimer’s disease based on network pharmacology. Material/Methods The active components and targets of Epimedii Herba were obtained through the TCMSP database and the DrugBank database. The DisGeNET database and GeneCards database were used to search for Alzheimer’s disease targets. The common targets of components and disease were obtained by Wayne diagram. Gene ontology (GO) analysis and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed using the DAVID database. The component-target-pathway interaction network model was constructed using Cytoscape software. Auto Duck Vina software was used for molecular docking to analyze the affinity of the key ingredients and the main targets. Results We screened 17 active ingredients and 27 key targets of Epimedii Herba in the treatment of Alzheimer’s disease, which were related to the HIF-1 signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, NF-κB signaling pathway, VEGF signaling pathway, and sphingolipid signaling pathway. Conclusions Based on network pharmacology, the multi-component, multi-target, and multi-pathway characteristics of Epimedii Herba in the treatment of Alzheimer’s disease were explored. Our results provide new ideas for future pharmacological and experimental research on Epimedii Herba in the treatment of Alzheimer’s disease.
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Affiliation(s)
- Yajuan Li
- Department of Histology and Embryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Qin Yang
- Department of Histology and Embryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Yang Yu
- Department of Histology and Embryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China (mainland)
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Ebrahimpour S, Esmaeili A, Dehghanian F, Beheshti S. Effects of quercetin-conjugated with superparamagnetic iron oxide nanoparticles on learning and memory improvement through targeting microRNAs/NF-κB pathway. Sci Rep 2020; 10:15070. [PMID: 32934245 PMCID: PMC7493930 DOI: 10.1038/s41598-020-71678-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 07/06/2020] [Indexed: 12/15/2022] Open
Abstract
Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) have an ameliorative effect on diabetes-induced memory impairment. The current study aimed to compare the effect of quercetin (QC) and QCSPIONs on inflammation-related microRNAs and NF-κB signaling pathways in the hippocampus of diabetic rats. The expression levels of miR-146a, miR-9, NF-κB, and NF-κB-related downstream genes, including TNF-α, BACE1, AβPP, Bax, and Bcl-2 were measured using quantitative real-time PCR. To determine the NF-κB activity, immunohistochemical expression of NF-κB/p65 phosphorylation was employed. Computer simulated docking analysis also performed to find the QC target proteins involved in the NF-κB pathway. Results indicate that diabetes significantly upregulated the expression levels of miR-146a, miR-9, TNF-α, NF-κB, and subsequently AβPP, BACE1, and Bax. Expression analysis shows that QCSPIONs are more effective than pure QC in reducing the expression of miR-9. Interestingly, QCSPIONs reduce the pathological activity of NF-κB and subsequently normalize BACE1, AβPP, and the ratio of Bax/Bcl-2 expression better than pure QC. Comparative docking analyses also show the stronger binding affinity of QC to IKK and BACE1 proteins compared to specific inhibitors of each protein. In conclusion, our study suggests the potent efficacy of QCSPIONs as a promising drug delivery system in memory improvement through targeting the NF-κB pathway.
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Affiliation(s)
- Shiva Ebrahimpour
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, 81746-73441, Isfahan, Iran
| | - Abolghasem Esmaeili
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, 81746-73441, Isfahan, Iran.
| | - Fariba Dehghanian
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, 81746-73441, Isfahan, Iran
| | - Siamak Beheshti
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, HezarJarib Street, 81746-73441, Isfahan, Iran
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Xu C, Xiao Z, Wu H, Zhou G, He D, Chang Y, Li Y, Wang G, Xie M. BDMC protects AD in vitro via AMPK and SIRT1. Transl Neurosci 2020; 11:319-327. [PMID: 33335771 PMCID: PMC7712110 DOI: 10.1515/tnsci-2020-0140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/04/2020] [Accepted: 08/13/2020] [Indexed: 01/02/2023] Open
Abstract
Background Alzheimer’s disease (AD) is a common neurodegenerative disorder without any satisfactory therapeutic approaches. AD is mainly characterized by the deposition of β-amyloid protein (Aβ) and extensive neuronal cell death. Curcumin, with anti-oxidative stress (OS) and cell apoptosis properties, plays essential roles in AD. However, whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, can exert a neuroprotective effect in AD remains to be elucidated. Methods In this study, SK-N-SH cells were used to establish an in vitro model to investigate the effects of BDMC on the Aβ1–42-induced neurotoxicity. SK-N-SH cells were pretreated with BDMC and with or without compound C and EX527 for 30 min after co-incubation with rotenone for 24 h. Subsequently, western blotting, cell viability assay and SOD and GSH activity measurement were performed. Results BDMC increased the cell survival, anti-OS ability, AMPK phosphorylation levels and SIRT1 in SK-N-SH cells treated with Aβ1–42. However, after treatment with compound C, an AMPK inhibitor, and EX527, an SIRT1inhibitor, the neuroprotective roles of BDMC on SK-N-SH cells treated with Aβ1–42 were inhibited. Conclusion These results suggest that BDMC exerts a neuroprotective role on SK-N-SH cells in vitro via AMPK/SIRT1 signaling, laying the foundation for the application of BDMC in the treatment of neurodegenerative diseases related to AMPK/SIRT1 signaling.
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Affiliation(s)
- Chenlin Xu
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China.,Xiangxi Autonomous Prefecture People's Hospital, Jishou, Hunan 416000, People's Republic of China
| | - Zijian Xiao
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Heng Wu
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Guijuan Zhou
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Duanqun He
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Yunqian Chang
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Yihui Li
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Gang Wang
- Department of Rehabilitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, People's Republic of China
| | - Ming Xie
- The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, People's Republic of China
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Wang YY, Chang CY, Lin SY, Wang JD, Wu CC, Chen WY, Kuan YH, Liao SL, Wang WY, Chen CJ. Quercetin protects against cerebral ischemia/reperfusion and oxygen glucose deprivation/reoxygenation neurotoxicity. J Nutr Biochem 2020; 83:108436. [PMID: 32599520 DOI: 10.1016/j.jnutbio.2020.108436] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 03/27/2020] [Accepted: 05/20/2020] [Indexed: 01/01/2023]
Abstract
Beyond nutrition effect, quercetin is applied as a complement or an alternative for promoting human health and treating diseases. However, its complicated neuroprotective mechanisms have not yet been fully elucidated. This study provides evidence of an alternative target for quercetin, and sheds light on the mechanisms of its neuroprotection against cerebral ischemia/reperfusion (I/R) injury in Sprague-Dawley rats. Oral pretreatment using quercetin has alleviated cerebral I/R-induced neurological deficits, brain infarction, blood-brain barrier disruption, oxidative stress, TNF-α and IL-1β mRNA expression, along with apoptotic caspase 3 activity. The neuroprotective, anti-oxidative, anti-inflammatory, and anti-apoptotic effects of quercetin were replicated in rat hippocampal slice cultures and neuron/glia cultures which suffered from oxygen-glucose deprivation and reoxygenation (OGDR). Biochemical studies revealed a reduction of extracellular signal-regulated kinase (ERK) and Akt phosphorylation, along with an increase in protein tyrosine and serine/threonine phosphatase activity in cerebral I/R rat cortical tissues and OGDR hippocampal slice and neuron/glia cultures. Quercetin alleviated the changes in ERK/Akt phosphorylation and protein phosphatase activities. Inhibition of ERK or Akt alone was enough to cause apoptotic cell death and cytotoxicity in hippocampal slice cultures and neuron/glia cultures, while activators of ERK or Akt alleviated OGDR-induced cytotoxicity. Taken together, our results demonstrate that quercetin alleviated the increment of protein tyrosine and serine/threonine phosphatase activity, along with the reduction of ERK and Akt phosphorylation, which may play pivotal roles in the expansion of brain injury after cerebral I/R.
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Affiliation(s)
- Ya-Yu Wang
- Department of Family Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan; Institute of Clinical Medicine, National Yang Ming University, Taipei City, Taiwan.
| | - Cheng-Yi Chang
- Department of Surgery, Feng Yuan Hospital, Taichung City, Taiwan.
| | - Shih-Yi Lin
- Institute of Clinical Medicine, National Yang Ming University, Taipei City, Taiwan; Center for Geriatrics and Gerontology, Taichung Veterans General Hospital, Taichung City, Taiwan.
| | - Jiaan-Der Wang
- Children's Medical Center, Taichung Veterans General Hospital, Taichung City, Taiwan; Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung City, Taiwan.
| | - Chih-Cheng Wu
- Department of Anesthesiology, Taichung Veterans General Hospital, Taichung City, Taiwan; Department of Financial Engineering, Providence University, Taichung City, Taiwan; Department of Data Science and Big Data Analytics, Providence University, Taichung City, Taiwan.
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung-Hsing University, Taichung City, Taiwan.
| | - Yu-Hsiang Kuan
- Department of Pharmacology, Chung Shan Medical University, Taichung City, Taiwan.
| | - Su-Lan Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan.
| | - Wen-Yi Wang
- Department of Nursing, Hung-Kuang University, Taichung City, Taiwan.
| | - Chun-Jung Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, Taiwan.
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Uddin MS, Kabir MT, Rahman MS, Behl T, Jeandet P, Ashraf GM, Najda A, Bin-Jumah MN, El-Seedi HR, Abdel-Daim MM. Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer's Disease. Int J Mol Sci 2020; 21:5858. [PMID: 32824102 PMCID: PMC7461598 DOI: 10.3390/ijms21165858] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/03/2020] [Accepted: 08/12/2020] [Indexed: 12/18/2022] Open
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40-42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.
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Affiliation(s)
- Md. Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka 1213, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka 1207, Bangladesh
| | - Md. Tanvir Kabir
- Department of Pharmacy, BRAC University, Dhaka 1212, Bangladesh;
| | - Md. Sohanur Rahman
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India;
| | - Philippe Jeandet
- Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, PO Box 1039, 51687 Reims CEDEX 2, France;
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Agnieszka Najda
- Laboratory of Quality of Vegetables and Medicinal Plants, Department of Vegetable Crops and Medicinal Plants, University of Life Sciences in Lublin, 15 Akademicka Street, 20-950 Lublin, Poland;
| | - May N. Bin-Jumah
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11474, Saudi Arabia;
| | - Hesham R. El-Seedi
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China;
- Pharmacognosy Group, Department of Pharmaceutical Biosciences, Uppsala University, SE-751 23 Uppsala, Sweden
- Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom 32512, Egypt
| | - Mohamed M. Abdel-Daim
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
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Rambaran TF. Nanopolyphenols: a review of their encapsulation and anti-diabetic effects. SN APPLIED SCIENCES 2020. [DOI: 10.1007/s42452-020-3110-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
AbstractPolyphenols are believed to possess numerous health benefits and can be grouped as phenolic acids, flavonoids or non-flavonoids. Research involving the synthesis of nanopolyphenols has attracted interest in the areas of functional food, nutraceutical and pharmaceutical development. This is in an effort to overcome current challenges which limit the application of polyphenols such as their rapid elimination, low water-solubility, instability at low pH, and their particle size. In the synthesis of nanopolyphenols, the type of nanocarrier used, the nanoencapsulation technique employed and the type of polymers that constitute the drug delivery system are crucial. For this review, all mentioned factors which can influence the therapeutic efficacy of nanopolyphenols were assessed. Their efficacy as anti-diabetic agents was also evaluated in 33 publications. Among these were phenolic acid (1), flavonoids (13), non-flavonoids (17) and polyphenol-rich extracts (2). The most researched polyphenols were quercetin and curcumin. Nanoparticles were the main nanocarrier and the size of the nanopolyphenols ranged from 15 to 333 nm with encapsulation efficiency and drug loading capacities of 56–97.7% and 4.2–53.2%, respectively. The quantity of nanomaterial administered orally ranged from 1 to 300 mg/kg/day with study durations of 1–70 days. Most studies compared the effect of the nanopolyphenol to its free-form and, in all but three cases, significantly greater effects of the former were reported. Assessment of the polyphenol to understand its properties and the subsequent synthesis of its nanoencapsulated form using suitable nanocarriers, polymers and encapsulation techniques can result in effective therapeutic agents for the treatment of diabetes.
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Wang X, Zimmermann HR, Ma T. Therapeutic Potential of AMP-Activated Protein Kinase in Alzheimer's Disease. J Alzheimers Dis 2020; 68:33-38. [PMID: 30776001 DOI: 10.3233/jad-181043] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Currently there is no cure or effective disease-modifying therapy for Alzheimer's disease (AD), the most common form of dementia that is becoming a global threat to public health. It is important to develop novel therapeutic strategies targeting AD pathophysiology particularly synaptic failure and cognitive impairments. Recent studies revealed several molecular signaling pathways potentially linked to brain pathology and synaptic failure in AD, including AMP-activated protein kinase (AMPK), a master kinase that plays a central role in the maintenance of cellular energy homeostasis. Particularly, hyperactive AMPK via phosphorylation has been linked to AD-associated synaptic plasticity impairments, indicating suppression of AMPK activity might be beneficial for cognitive deficiency in AD. In this review, we will discuss how targeting dysregulation of AMPK signaling could be a feasible therapeutic approach for AD.
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Affiliation(s)
- Xin Wang
- Department of Internal Medicine, Gerontology & Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Helena R Zimmermann
- Department of Internal Medicine, Gerontology & Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Tao Ma
- Department of Internal Medicine, Gerontology & Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC, USA
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AMPK-SIRT1-PGC1α Signal Pathway Influences the Cognitive Function of Aged Rats in Sevoflurane-Induced Anesthesia. J Mol Neurosci 2020; 70:2058-2067. [PMID: 32514740 DOI: 10.1007/s12031-020-01612-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/22/2020] [Indexed: 12/22/2022]
Abstract
To understand the effect of AMP-activated protein kinase (AMPK)-SIRT1 (silent information regulator 1)-PPARγ coactivator-1α (PGC1α) signaling pathway on the cognitive function of sevoflurane-anesthetized aged rats. Aged rats were divided into Normal group, Sevo group (Sevoflurane anesthesia), Sevo + AICAR (the AMPK activator) group, Sevo + EX527 group (the AMPK inhibitor), and Sevo + AICAR + EX527 group. The cognitive function of rats was determined by the Morris water maze. Hippocampal neuronal apoptosis was evaluated by TUNEL and Fluoro-Jade C (FJC) staining, and the expression of cleaved caspase-3 was detected by immunohistochemistry. ROS, SOD, and MDA levels and the fluorescence intensity of GFAP in the hippocampus were assayed. The mitochondrial membrane potential (MMP), mitochondrial mass, ATP level, and the expression of AMPK-SIRT1-PGC1α were determined by the corresponding methods. Rats in the Sevo group manifested significant extension in the escape latency, with fewer platform crossings; and meanwhile, the apoptotic rate, the number of FJC-positive cells, and the fluorescence intensity of GFAP of neurons were elevated, with up-regulation of cleaved caspase-3. Moreover, the level of MDA and ROS was increased evidently, with significant down-regulation of SOD activity, ATP, mitochondrial mass and MMP levels, and AMPK, SIRT1 and PGC-1α protein expressions. However, sevoflurane-induced changes above were improved after the administration of AICAR, and EX527 could reverse AICAR-induced improvements in Sevo-anesthetized aged rats. Activating AMPK-SIRT1-PGC1α pathway can improve the cognitive function and mitigate the neuronal injury in Sevo-anesthetized aged rats by antagonizing the oxidative stress and maintaining the mitochondrial function.
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Neuroprotective Effects of Emodin against Ischemia/Reperfusion Injury through Activating ERK-1/2 Signaling Pathway. Int J Mol Sci 2020; 21:ijms21082899. [PMID: 32326191 PMCID: PMC7215870 DOI: 10.3390/ijms21082899] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/11/2020] [Accepted: 04/16/2020] [Indexed: 01/28/2023] Open
Abstract
Background: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. Methods: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. Results: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. Conclusion: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.
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Abdelkader NF, Eitah HE, Maklad YA, Gamaleldin AA, Badawi MA, Kenawy SA. New combination therapy of gliclazide and quercetin for protection against STZ-induced diabetic rats. Life Sci 2020; 247:117458. [PMID: 32092333 DOI: 10.1016/j.lfs.2020.117458] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/13/2020] [Accepted: 02/19/2020] [Indexed: 12/11/2022]
Abstract
AIMS The use of natural agents with anti-diabetic effect in combination therapy adds further positive clinical implications in the management of diabetes mellitus. Interestingly, quercetin is one of the most potent naturally occurring antioxidant which possesses various pharmacological actions including anti-diabetic effect. Thus, this research was conducted to assess the efficiency of a new combination from gliclazide and quercetin on glycemic control as well as pancreatic islets and beta cells in STZ-experimental model of diabetes. MAIN METHODS Diabetes has been induced by a single intraperitoneal injection of streptozotocin (STZ; 45 mg/kg) in adult male Wistar rats. For 3 consecutive weeks, diabetic rats were given orally either gliclazide (10 mg/kg), quercetin (50 mg/kg), or their combination. At the end of the experiment, histological, immunohistochemical and morphometrical examination of pancreatic tissues was performed. Furthermore, the changes in glucose metabolism, lipid profile, oxidative and inflammatory status were evaluated. KEY FINDINGS Treatment with gliclazide alone decreased serum glucose, total cholesterol, triglycerides, malondialdehyde, tumor necrosis factor-alpha and nuclear factor kappa-Beta while increased serum C-peptide, superoxide dismutase, reduced glutathione and adiponectin levels. Combined administration of quercetin with gliclazide markedly augmented serum superoxide dismutase and reduced glutathione more than gliclazide alone and normalized all the above-mentioned parameters. Besides, this combination therapy restored immunostaining intensity, number of pancreatic islets and beta cells along with its area and perimeter. SIGNIFICANCE Based on the aforementioned results, this combination could be considered a promising one in diabetes mellitus management.
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Affiliation(s)
- Noha F Abdelkader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Hebatollah E Eitah
- Department of Medicinal and Pharmaceutical Chemistry, Pharmacology Group, National Research Centre, Cairo, Egypt
| | - Yousreya A Maklad
- Department of Medicinal and Pharmaceutical Chemistry, Pharmacology Group, National Research Centre, Cairo, Egypt
| | | | - Manal A Badawi
- Department of Pathology, National Research Centre, Cairo, Egypt
| | - Sanaa A Kenawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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The Bewildering Effect of AMPK Activators in Alzheimer's Disease: Review of the Current Evidence. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9895121. [PMID: 32149150 PMCID: PMC7049408 DOI: 10.1155/2020/9895121] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 01/14/2020] [Accepted: 01/29/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease is a multifactorial neurodegenerative disease characterized by progressive cognitive dysfunction. It is the most common form of dementia. The pathologic hallmarks of the disease include extracellular amyloid plaque, intracellular neurofibrillary tangles, and oxidative stress, to mention some of them. Despite remarkable progress in the understanding of the pathogenesis of the disease, drugs for cure or disease-modifying therapy remain somewhere in the distance. From recent time, the signaling molecule AMPK is gaining enormous attention in the AD drug research. AMPK is a master regulator of cellular energy metabolism, and recent pieces of evidence show that perturbation of its function is highly ascribed in the pathology of AD. Several drugs are known to activate AMPK, but their effect in AD remains to be controversial. In this review, the current shreds of evidence on the effect of AMPK activators in Aβ accumulation, tau aggregation, and oxidative stress are addressed. Positive and negative effects are reported with regard to Aβ and tauopathy but only positive in oxidative stress. We also tried to dissect the molecular interplays where the bewildering effects arise from.
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Effects of Huang-Lian-Jie-Du Decoction on Oxidative Stress and AMPK-SIRT1 Pathway in Alzheimer's Disease Rat. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:6212907. [PMID: 31976005 PMCID: PMC6959142 DOI: 10.1155/2020/6212907] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/08/2019] [Accepted: 10/15/2019] [Indexed: 12/13/2022]
Abstract
Huang-Lian-Jie-Du Decoction (HLJDD), traditional Chinese medicine (TCM), is proven to have ameliorative effects on learning and memory deficits of Alzheimer's disease (AD). The current study aims to reveal the underlying mechanism of HLJDD in the treatment of AD by simultaneous determination on the regulation of HLJDD on oxidative stress, neurotransmitters, and AMPK-SIRT1 pathway in AD. AD model rat was successfully established by injection of D-galactose and Aβ25-35-ibotenic acid. Morris Water Maze (MWM) test was used to evaluate the success of AD modelling. On this basis, an advanced technique with UPLC-QqQ MS/MS was built up and applied to determine the levels of 8 neurotransmitters in rat plasma. Significant alternation in methionine, glutamine, and tryptophan was observed in AD rats' plasma after the administration of HLJDD, relative to the model group. Meanwhile, HLJDD could upregulate the levels of SOD, GSH-Px, AMPK, and SIRT1 and downregulate the content of MDA in the peripheral system of the AD rats. The underlying therapeutic mechanism of HLJDD for the treatment of AD was associated with alleviating oxidation stress, inflammation, neurotransmitters, and energy metabolism. These data provide solid foundation for the potential use of HLJDD to treat AD.
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Quercetin Regulates the Integrated Stress Response to Improve Memory. Int J Mol Sci 2019; 20:ijms20112761. [PMID: 31195662 PMCID: PMC6600673 DOI: 10.3390/ijms20112761] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 06/02/2019] [Accepted: 06/03/2019] [Indexed: 12/11/2022] Open
Abstract
The initiation of protein synthesis is suppressed under several stress conditions, inducing phosphorylation of the α-subunit of the eukaryotic initiation factor 2 (eIF2α), thereby inactivating the GTP-GDP recycling protein eIF2B. By contrast, the mammalian activating transcription factor 4 (ATF4, also known as cAMP response element binding protein 2 (CREB2)) is still translated under stress conditions. Four protein kinases (general control nonderepressible-2 (GCN2) kinase, double-stranded RNA-activated protein kinase (PKR), PKR-endoplasmic reticulum (ER)-related kinase (PERK), and heme-regulated inhibitor kinase (HRI)) phosphorylate eIF2α in the presence of stressors such as amino acid starvation, viral infection, ER stress, and heme deficiency. This signaling reaction is known as the integrated stress response (ISR). Here, we review ISR signaling in the brain in a mouse model of Alzheimer’s disease (AD). We propose that targeting ISR signaling with quercetin has therapeutic potential, because it suppresses amyloid-β (Aβ) production in vitro and prevents cognitive impairments in a mouse model of AD.
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Wu X, Cai H, Pan L, Cui G, Qin F, Li Y, Cai Z. Small Molecule Natural Products and Alzheimer's Disease. Curr Top Med Chem 2019; 19:187-204. [PMID: 30714527 DOI: 10.2174/1568026619666190201153257] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/16/2018] [Accepted: 11/16/2018] [Indexed: 02/05/2023]
Abstract
Alzheimer's disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. Several hypotheses have been proposed for the pathogenesis based on the pathological changes in the brain of AD patients during the last few decades. Unfortunately, there is no effective agents/therapies to prevent or control AD at present. Currently, only a few drugs, which function as acetylcholinesterase (AChE) inhibitors or N-methyl-Daspartate (NMDA) receptor antagonists, are available to alleviate symptoms. Since many small molecule natural products have shown their functions as agonists or antagonists of receptors, as well as inhibitors of enzymes and proteins in the brain during the development of central nervous system (CNS) drugs, it is likely that natural products will play an important role in anti-AD drug development. We review recent papers on using small molecule natural products as drug candidates for the treatment of AD. These natural products possess antioxidant, anti-inflammatory, anticholinesterase, anti-amyloidogenic and neuroprotective activities. Moreover, bioactive natural products intended to be used for preventing AD, reducing the symptoms of AD and the new targets for treatment of AD are summarized.
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Affiliation(s)
- Xiaoai Wu
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Huawei Cai
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lili Pan
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Gang Cui
- Drug Clinical Trial Research Center, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Feng Qin
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - YunChun Li
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhengxin Cai
- PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut 06520, United States
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Jamsheer K M, Jindal S, Laxmi A. Evolution of TOR-SnRK dynamics in green plants and its integration with phytohormone signaling networks. JOURNAL OF EXPERIMENTAL BOTANY 2019; 70:2239-2259. [PMID: 30870564 DOI: 10.1093/jxb/erz107] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/26/2019] [Indexed: 05/07/2023]
Abstract
The target of rapamycin (TOR)-sucrose non-fermenting 1 (SNF1)-related protein kinase 1 (SnRK1) signaling is an ancient regulatory mechanism that originated in eukaryotes to regulate nutrient-dependent growth. Although the TOR-SnRK1 signaling cascade shows highly conserved functions among eukaryotes, studies in the past two decades have identified many important plant-specific innovations in this pathway. Plants also possess SnRK2 and SnRK3 kinases, which originated from the ancient SnRK1-related kinases and have specialized roles in controlling growth, stress responses and nutrient homeostasis in plants. Recently, an integrative picture has started to emerge in which different SnRKs and TOR kinase are highly interconnected to control nutrient and stress responses of plants. Further, these kinases are intimately involved with phytohormone signaling networks that originated at different stages of plant evolution. In this review, we highlight the evolution and divergence of TOR-SnRK signaling components in plants and their communication with each other as well as phytohormone signaling to fine-tune growth and stress responses in plants.
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Affiliation(s)
- Muhammed Jamsheer K
- Amity Food & Agriculture Foundation, Amity University Uttar Pradesh, Noida, India
| | - Sunita Jindal
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
| | - Ashverya Laxmi
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
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