Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer's disease
Zaplatic E, Bule M, Shah SZA, Uddin MS and Niaz K
Quercetin belongs to the flavonoids family, which is present in most of the plants including fruits, vegetables, green tea and even in red wine having antioxidant activities. It is available as a food supplement in the market and has physiological health effects. Quercetin has anti-inflammatory, anticancer and anti-prostate activities along with its beneficial effects on high cholesterol, kidney transplantation, asthma, diabetes, viral infections, pulmonary, schizophrenia and cardiovascular diseases. Quercetin possesses scavenging potential of hydroxyl radical (OH), hydrogen peroxide (HO), and superoxide anion (O). These reactive oxygen species (ROS) hampers lipid, protein, amino acids and deoxyribonucleic acid (DNA) processing leading to epigenetic alterations. Quercetin has the ability to combat these harmful effects. ROS plays a vital role in the progression of Alzheimer's disease (AD), and we propose that quercetin would be the best choice to overcome cellular and molecular signals in regulating normal physiological functions. However, data are not well documented regarding exact cellular mechanisms of quercetin. The neuroprotective effects of quercetin are mainly due to potential up- and/or down-regulation of cytokines via nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Paraoxonase-2, c-Jun N-terminal kinase (JNK), Protein kinase C, Mitogen-activated protein kinase (MAPK) signalling cascades, and PI3K/Akt pathways. Therefore, the aim of the present review was to elaborate on the cellular and molecular mechanisms of the quercetin involved in the protection against AD.
Hyperglycemia-induced oxidative brain injury: Therapeutic effects of Cola nitida infusion against redox imbalance, cerebellar neuronal insults, and upregulated Nrf2 expression in type 2 diabetic rats
Erukainure OL, Ijomone OM, Oyebode OA, Chukwuma CI, Aschner M and Islam MS
The therapeutic effect of the hot water infusion of Cola nitida against hyperglycemia-induced neurotoxicity, cerebellar neurodegeneration and elemental deregulations was investigated in fructose-streptozotocin induced rat model of type 2 diabetes (T2D). A diabetic group was administered drinking water, two other diabetic groups were treated with C. nitida at 150 and 300 mg/kg bodyweight respectively, while another group was administered metformin (200 mg/kg bodyweight). Two other groups consisting of normal rats, were administered drinking water and C. nitida (300 mg/kg bodyweight). After 6 weeks of treatment, their brains were collected. Treatment with C. nitida led to suppression of oxidative stress, significantly elevating reduced glutathione (GSH) levels, superoxide dismutase and catalase activities, concomitant with depletion of malondialdehyde (MDA) levels. Acetylcholinesterase and ATPase activities were significantly inhibited in C. nitida-treated diabetic rats. Histological and microscopic analysis also revealed a restorative effect of C. nitida on T2D-altered distribution of elements, neurons and axonal nodes. Treatment with C. nitida also led to significant inhibition of Nrf2 expression in the cerebellar cortex. These results suggest the therapeutic effects of C. nitida in maintenance of the neuronal integrity and antioxidant status of the brain in T2D. These neuroprotective activities can be attributed to the identified alkaloid, caffeine in the infusion.
Assessing the protective effect of rosiglitazone against electronic cigarette/tobacco smoke-induced blood-brain barrier impairment
Sivandzade F and Cucullo L
Smoking (TS) and recently e-cigarettes (EC) vaping, have been associated with vascular endothelial dysfunction primarily relevant to oxidative stress, exposure to nicotine, and smoking-induced inflammation. It is accepted that both EC and TS enhance glucose intolerance and the risk of developing type-2 diabetes mellitus which is also one of the causes of blood-brain barrier (BBB) damage and the higher risk of cerebrovascular diseases. Recent studies have shown how Metformin, the first common antidiabetic drug, can protect the BBB integrity through enhancement of nuclear factor erythroid 2-related factor (Nrf2) activity. Herein, we investigated the role of rosiglitazone (RSG; family of thiazolidinedione class used oral anti-diabetic drug) in TS/EC-induced BBB impairment.
An FTLD-associated SQSTM1 variant impacts Nrf2 and NF-κB signalling and is associated with reduced phosphorylation of p62
Foster A, Scott D, Layfield R and Rea SL
Elevated oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In response to oxidative stress, the Nrf2 transcription factor activates protective antioxidant genes. A critical regulator of Nrf2 is the inhibitory protein Keap1, which mediates Nrf2 degradation. In response to cellular stress an interaction between Keap1 and SQSTM1/p62 (p62), a signalling adaptor protein, allows for increased Nrf2 signalling as it escapes degradation. Mutations in SQSTM1 (encoding p62) are linked with ALS-FTLD. Previously, two ALS-FTLD-associated p62 mutant proteins within the Keap1 interacting region (KIR) of p62 were found to be associated with decreased Keap1-p62 binding and Nrf2 activation. Here we report that a non-KIR domain FTLD-associated variant of p62 (p.R110C), affecting a residue close to the N-terminal PB1 oligomerisation domain, also reduces Keap1-p62 binding in cellulo and thereby reduces Nrf2 activity in reporter assays. Further, we observed that expression of p.R110C increased NF-κB activation compared with wild type p62. Altered signalling appeared to be linked with reduced phosphorylation of p62 at Serine residues -349 and -403. Our results confirm that ALS-FTLD mutations affecting multiple domains of p62 result in a reduced stress response, suggesting that altered stress signalling may directly contribute to the pathology of some ALS-FTLD cases.
P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy
Ma F, Wu J, Jiang Z, Huang W, Jia Y, Sun W and Wu H
Diabetic nephropathy (DN) is the leading cause of end stage renal disease, posing a severe threat to public health. Previous studies reported the protective role of sirtuin 1 (SIRT1) in DN, encouraging the investigation of more potent and specific SIRT1 activators. SRT2104 is a novel, first-in-class, highly selective small-molecule activator of SIRT1, with its effect and mechanism unknown on DN. To this end, streptozotocin-induced C57BL/6 wild-type (WT) diabetic mice were treated with SRT2104, for 24 weeks. To determine whether SRT2104 acted through inhibition of P53 - a substrate of SIRT1, the P53 activator nutlin3a was administered to the WT diabetic mice in the presence of SRT2104. In order to test whether nuclear factor erythroid 2-related factor 2 (NRF2) - the master of cellular antioxidants - mediated SIRT1 and P53's actions, WT and Nrf2 gene knockout (KO) diabetic mice were treated with SRT2104 or the P53 inhibitor pifithrin-α (PFT-α). In the WT mice, SRT2104 enhanced renal SIRT1 expression and activity, deacetylated P53, and activated NRF2 antioxidant signaling, providing remarkable protection against the DM-induced renal oxidative stress, inflammation, fibrosis, glomerular remodeling and albuminuria. These effects were completely abolished in the presence of nutlin3a. Deletion of the Nrf2 gene completely abrogated the efficacies of SRT2104 and PFT-α in elevating antioxidants and ameliorating DN, despite their abilities to activate SIRT1 and inhibit P53 in the Nrf2 KO mice. The present study reports the beneficial effects of SRT2104 on DN, uncovering a SIRT1/P53/NRF2 pathway that modulates the pathogenesis of DN.
Current Status and Challenges of NRF2 as a Potential Therapeutic Target for Diabetic Cardiomyopathy
Ge ZD, Lian Q, Mao X and Xia Z
Diabetic cardiomyopathy is one of the main causes of heart failure and death in patients with diabetes mellitus. Reactive oxygen species produced excessively in diabetes mellitus cause necrosis, apoptosis, ferroptosis, inflammation, and fibrosis of the myocardium as well as impair the cardiac structure and function. It is increasingly clear that oxidative stress is a principal cause of diabetic cardiomyopathy. The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) activates the transcription of more than 200 genes in the human genome. Most of the proteins translated from these genes possess anti-oxidant, anti-inflammatory, anti-apoptotic, anti-ferroptotic, and anti-fibrotic actions. There is a growing body of evidence indicating that NRF2 and its target genes are crucial in preventing high glucose-induced oxidative damage in diabetic cardiomyopathy. Recently, many natural and synthetic activators of NRF2 are shown to possess promising therapeutic effects on diabetic cardiomyopathy in animal models of diabetic cardiomyopathy. Targeting NRF2 signaling by pharmacological entities is a potential approach to ameliorating diabetic cardiomyopathy. However, the persistent high expression of NRF2 in cancer tissues also protects the growth of cancer cells. This "dark side" of NRF2 increases the challenges of using NRF2 activators to treat diabetic cardiomyopathy. In addition, some NRF2 activators were found to have off-target effects. In this review, we summarize the current status and challenges of NRF2 as a potential therapeutic target for diabetic cardiomyopathy.
Naringenin, a dietary flavanone, enhances insulin-like growth factor 1 receptor-mediated antioxidant defense and attenuates methylglyoxal-induced neurite damage and apoptotic death
Tseng YT, Hsu HT, Lee TY, Chang WH and Lo YC
Recent studies revealed the neuroprotective effects of naringenin (NGEN), a common dietary bioflavonoid contained in citrus fruits. However, there are limited data on its protection against methylglyoxal (MG), the most potent precursor of advanced glycation end-products. The present study was to investigate the protection of NGEN on MG-induced neurotoxicity and the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling.
Attenuation of Myocardial ischemia reperfusion injury by Geniposide preconditioning in diabetic rats
Wang J, De-Qiong X, Hong DQ, Zhang QQ and Zhang J
Studies have shown that the NRF-2 /HO-1 pathway participates in myocardial ischemic reperfusion injury (MI/R) and that Geniposide (GEN) could protect the myocardial against MI/R. This study aims to examine the protective effects of GEN on MI/R in diabetic rats and further explore the possible mechanism of action. During MI/R in rats, NRF-2 /HO-1signals changed significantly including NRF-2 and HO-1up-regulation, resulting in heart dysfuction, histological damage and increasing oxidative stress and cell apoptosis. Treatment with GEN can significantly improve the general condition and heart function in diabetic rats with decreasing the expression of cTnI, CK-MB, blood glucose, MDA, ROS, cell apoptosis and pathological damage in MI/R. In addition, GEN precondition can also significantly increase the weight of rats and the activity of SOD, CAT and GPx with up-regulating the expression of NRF-2 and HO-1 in MI/R. This study implied that Geniposide has a protective effect on myocardial ischemia reperfusion injury in diabetic rats, and its mechanism is associated with activating NRF2/HO-1 signaling pathway to suppress oxidative stress.
Raffia palm (Raphia hookeri G. Mann & H. Wendl) wine modulates glucose homeostasis by enhancing insulin secretion and inhibiting redox imbalance in a rat model of diabetes induced by high fructose diet and streptozotocin
Erukainure OL, Oyebode OA, Ijomone OM, Chukwuma CI, Koorbanally NA and Islam MS
Raffia palm (Raphia hookeri) wine (RPW) is amongst the natural products from plants, utilized singly or in combination with other medicinal plants for the treatment of several ailments including Diabetes Mellitus (DM). However, there is a scientific dearth on its antidiabetic activity.
Association of SNP rs7181866 in the nuclear respiratory factor-2 beta subunit encoding GABPB1 gene with obesity and type-2 diabetes mellitus in South Indian population
Umapathy D, Balashanmugam P, Vanniya Subramanyam P, Rajan T, Natarajan P, Krishnamoorthy E, Viswanathan V and Kunka Mohanram R
GABPB1, known as nuclear respiratory factor 2 (Nrf2), activates mitochondrial genes that are responsible for oxidative phosphorylation. Earlier studies on GABPB1 reported that two single nucleotide polymorphisms (SNPs) such as rs7181866 and rs8031031, to be associated with increased endurance in athletes. In the present study, a cohort of 302 South Indians, including normoglycemic healthy controls, T2DM with and without obesity were genotyped for the two SNPs by PCR-RFLP method and correlated with serum adipokines. The 'G' allele of rs7181866 was found to be associated with obesity whereas rs8031031 didn't show any significant association with obese individuals. The increased levels of adipokines such as Leptin, IL-6 and TNF-α and decreased adiponectin were found among obese-T2DM, when compared to non-obese T2DM subjects. Further, Factor analysis on metabolic components revealed four factors which accounts for 71.5% for non-obese control and 88.3% for obese T2DM of variance. The bias-corrected and accelerated bootstrap analysis revealed GG genotype to have significant positive and negative correlation with both TNF-α and adiponectin. In conclusion, the G allele of (rs7181866 A/G) was found to be significantly associated with risk for obesity among T2DM subjects.
p62/SQSTM1 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein expression in oxidative muscle
Yamada M, Iwata M, Warabi E, Oishi H, Lira VA and Okutsu M
Increased muscle contractile activity, as observed with regular exercise, prevents oxidative stress-induced muscle wasting, at least partially, by improving the antioxidant defense system. Phosphorylated p62/sequestosome1 competitively binds to the Kelch-like ECH-associated protein 1, activating nuclear factor erythroid 2-related factor 2 (Nrf2), which stimulates transcription of antioxidant/electrophile responsive elements. However, it remains to be determined if this process is activated by regular exercise in skeletal muscle. Here, we demonstrate that muscle contractile activity increases antioxidants, Nrf2 translocation into nuclei, and Nrf2 DNA-binding activity in association with increased p62 phosphorylation (Ser351) in mouse oxidative skeletal muscle. Skeletal muscle-specific loss of Nrf2 [ i.e., Nrf2 muscle-specific knockout (mKO) mice] abolished the expression of the Nrf2 target antioxidant gene NAD(P)H-quinone oxidoreductase 1 (NQO1) in both glycolytic and oxidative muscles but reduced exercise-mediated increases of antioxidants ( i.e., copper/zinc superoxide dismutase (SOD) and extracellular SOD only in oxidative muscle. Interestingly, skeletal muscle-specific loss of p62 ( i.e., p62 mKO mice) also abolished the expression of NQO1 and reduced exercise-mediated increases of the same antioxidants in soleus muscle. Collectively, these findings indicate that p62 and Nrf2 cooperatively regulate the exercise-mediated increase of antioxidants in oxidative muscle.-Yamada, M., Iwata, M., Warabi, E., Oishi, H., Lira, V. A., Okutsu, M. p62/SQSTM1 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein expression in oxidative muscle.
Nrf2 exerts mixed inflammation and glucose metabolism regulatory effects on murine RAW264.7 macrophages
Ding L, Yuan X, Yan J, Huang Y, Xu M, Yang Z, Yang N, Wang M, Zhang C and Zhang L
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that mediates a broad range of cellular antioxidative, detoxification and anti-inflammatory effects. However, the precise mechanism by which Nrf2 regulates inflammation and metabolism in macrophages remains controversial and unclear. To further clarify the roles of Nrf2 in inflammation and glucose metabolism regulation, retrovirus-mediated knockdown of Nrf2 was performed in murine RAW264.7 macrophages, and the cells were stimulated with 100 ng/mL lipopolysaccharide for 24 h for M1 activation. qPCR and western blotting results indicated that Nrf2 knockdown significantly enhanced expression of the inflammatory genes Il1a and Il1b in unstimulated macrophages and increased expression of the inflammatory genes Il1a, Il1b, Il6, Il10, Ccl2, Ccl22, and CD38 but decreased that of Tnfa and Tgfb1 in M1 macrophages. Nrf2 knockdown also significantly elevated IL6 and IL10 secretion by M1 macrophages. Western blotting showed that Nrf2 knockdown reduced iNOS protein levels in resting macrophages and enhanced CD38 protein levels in both resting and M1 macrophages. The differential regulation of these macrophage inflammation and polarization markers by Nrf2 reveals multiple roles for Nrf2 in regulating inflammation in macrophages. Moreover, Nrf2 knockdown increased the Glu4 protein level and decreased AKT and GSK3β protein phosphorylation in M1 macrophages, suggesting multiple roles for Nrf2 in regulating glucose metabolism in macrophages. Overall, our results are the first to demonstrate mixed inflammation and glucose metabolism regulatory effects of Nrf2 in macrophages that may occur independent of its classic function in redox regulation. These findings support the potential of Nrf2 as a therapeutic target for the prevention and treatment of inflammation- and obesity-associated syndromes, including diabetes and atherosclerosis.
Reactive Oxygen Comes of Age: Mechanism-Based Therapy of Diabetic End-Organ Damage
Elbatreek MH, Pachado MP, Cuadrado A, Jandeleit-Dahm K and Schmidt HHHW
Reactive oxygen species (ROS) have been mainly viewed as unwanted by-products of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources. Disease can occur when ROS accumulate in nonphysiological concentrations, locations, or forms. By focusing on disease-relevant sources and targets of ROS, and leaving ROS physiology intact, precise therapeutic interventions are now possible and are entering clinical trials. Their outcomes are likely to profoundly change our concepts of ROS in DM and in medicine in general.
Pueraria montana var. lobata root extract inhibits photoaging on skin through Nrf2 pathway
Heo HS, Han GE, Won J, Cho Y, Woo H and Lee JH
Pueraria montana var. lobata is a bioactive substance, in possession of a variety of beneficial health effects, which has long been extensively used as a traditional medication for the treatment of fever, acute dysentery, diabetes, and cardiovascular diseases in North-East Asian countries. The purpose of this study was to evaluate the cytoprotective activity of Pueraria montana var. lobata ethanol extract (PLE) for ultraviolet B (UVB) induced oxidative stress in human dermal fibroblasts (HDF). It was hypothesized that PLE treatment (25-100 μg/mL) would reduce intracellular reactive oxygen species (ROS) levels as well as increase collagen production in UVB-irradiated HDF. The results confirmed this theory, with collagen production increasing in the PLE treatment group in a dose-dependent manner. In addition, regulators of cellular ROS accumulation, including HO-1 and NOQ-1, were activated by Nrf2, which was mediated by PLE. Hence, intracellular levels of ROS were also reduced in the PLE treatment group in a dose-dependent manner. In conclusion, PLE increases collagen production and maintains hyaluronic acid (HA) levels in human dermal fibroblasts exposed to UVB-irradiation, thereby inhibiting photoaging.
Amelioration of diabetic nephropathy using pomegranate peel extract-stabilized gold nanoparticles: assessment of NF-κB and Nrf2 signaling system
Manna K, Mishra S, Saha M, Mahapatra S, Saha C, Yenge G, Gaikwad N, Pal R, Oulkar D, Banerjee K and Das Saha K
Diabetic nephropathy (DN), an end-stage renal disorder, has posed a menace to humankind globally, because of its complex nature and poorly understandable intricate mechanism. In recent times, functional foods as potential health benefits have been gaining attention of consumers and researchers alike. Rich in antioxidants, the peel and seed of pomegranate have previously demonstrated protection against oxidative-stress-related diseases, including cardiovascular disorders, diabetes, and cancer.