Activation of Nrf2 by Natural Bioactive Compounds: A Promising Approach for Stroke?

Stroke represents one of the main causes of disability and death worldwide. The pathological subtypes of stroke are ischemic stroke, the most frequent, and hemorrhagic stroke. Nrf2 is a transcription factor that regulates redox homeostasis. In stress conditions, Nrf2 translocates inside the nucleus and induces the transcription of enzymes involved in counteracting oxidative stress, endobiotic and xenobiotic metabolism, regulators of inflammation, and others. Different natural compounds, including food and plant-derived components, were shown to be able to activate Nrf2, mediating an antioxidant response. Some of these compounds were tested in stroke experimental models showing several beneficial actions. In this review, we focused on the studies that evidenced the positive effects of natural bioactive compounds in stroke experimental models through the activation of Nrf2 pathway. Interestingly, different natural compounds can activate Nrf2 through multiple pathways, inducing a strong antioxidant response associated with the beneficial effects against stroke. According to several studies, the combination of different bioactive compounds can lead to a better neuroprotection. In conclusion, natural bioactive compounds may represent new therapeutic strategies against stroke.

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Anti-atherosclerotic effects of fruit bioactive compounds: A review of current scientific evidence

Canadian Journal of Plant Science ◽

10.4141/cjps2011-090 ◽

2012 ◽

Vol 92 (3) ◽

pp. 407-419 ◽

Cited By ~ 36

Author(s):

Surangi H. Thilakarathna ◽

H. P. Vasantha Rupasinghe

Keyword(s):

Bioactive Compounds ◽

Antioxidant Activities ◽

Scientific Evidence ◽

Experimental Models ◽

Lipid Lowering ◽

Experimental Conditions ◽

Beneficial Effects ◽

Positive Effects

Thilakarathna, S. H. and Rupasinghe, H. P. V. 2012. Anti-atherosclerotic effects of fruit bioactive compounds: A review of current scientific evidence. Can. J. Plant Sci. 92: 407–419. Atherosclerosis is a condition which leads to a cascade of processes involved in thickening of arterial walls as a result of fatty deposition, which can increase the risk of cardiovascular diseases. Among numerous remedies, the consumption of fruits is believed to have beneficial effects on atherosclerosis development. Various bioactive compounds are present in fruits and they have been found to be responsible for exerting these beneficial effects. Fruit flavonoids and certain terpenoids are among the most efficacious fruit bioactive compounds that have shown positive effects on different in vitro as well as in vivo research models of atherosclerosis. The mechanisms of actions of these compounds vary from exerting antioxidant activities to anti-atherogenic and lipid lowering activities, based on different experimental models. This review article briefly explains how some of the fruit bioactive compounds have affected atherosclerosis under experimental conditions.

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A Clinical Perspective of Low Carbohydrate Ketogenic Diets: A Narrative Review

Frontiers in Nutrition ◽

10.3389/fnut.2021.642628 ◽

2021 ◽

Vol 8 ◽

Author(s):

Samir Giuseppe Sukkar ◽

Maurizio Muscaritoli

Keyword(s):

Case Reports ◽

Scientific Evidence ◽

Experimental Models ◽

Narrative Review ◽

Caloric Content ◽

Beneficial Effects ◽

Cellular Processes ◽

Positive Effects ◽

Ketogenic Diets ◽

Morbid Conditions

Low carbohydrates diets (LCDs), which provide 20–120 g of carbohydrates per day, have long been used as therapeutic options in the treatment of severe obesity, type 2 diabetes mellitus and other morbid conditions, with good results in terms of weight loss and control of the main metabolic parameters, at least in the short and medium term. According to the caloric content and the macronutrient composition, we can classify LCDs in hypocaloric, normoproteic diets [such as the Very Low-Calorie Ketogenic Diet (VLCKD) or the protein-sparing modified fasting (PSMF)], hypocaloric, hyperproteic and hyperlipidic diets (e.g., Atkins, Paleo diets…) and normocaloric, normo-/hyperproteic diets (eucaloric KD), the latter mainly used in patients with brain tumors (gliomas) and refractory epilepsy. In addition to LCD diets, another interesting dietary approach which gained attention in the last few decades is fasting and its beneficial effects in terms of modulation of metabolic pathways, cellular processes and hormonal secretions. Due to the impossibility of using fasting regimens for long periods of time, several alternative strategies have been proposed that can mimic the effects, including calorie restriction, intermittent or alternating fasting, and the so-called fasting mimicking diets (FMDs). Recent preclinical studies have shown positive effects of FMDs in various experimental models of tumors, diabetes, Alzheimer Disease, and other morbid conditions, but to date, the scientific evidence in humans is limited to some opens studies and case reports. The purpose of our narrative review is to offer an overview of the characteristics of the main dietary regimens applied in the treatment of different clinical conditions as well as of the scientific evidence that justifies their use, focusing on low and zero-carb diets and on the different types of fasting.

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Potential Implications of Quercetin and its Derivatives in Cardioprotection

International Journal of Molecular Sciences ◽

10.3390/ijms21051585 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1585 ◽

Cited By ~ 6

Author(s):

Kristina Ferenczyova ◽

Barbora Kalocayova ◽

Monika Bartekova

Keyword(s):

Therapeutic Potential ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Cardiac Injury ◽

Experimental Models ◽

Cardiac Effects ◽

Beneficial Effects ◽

Positive Effects ◽

Number Of Patients ◽

Wide Range

Quercetin (QCT) is a natural polyphenolic compound enriched in human food, mainly in vegetables, fruits and berries. QCT and its main derivatives, such as rhamnetin, rutin, hyperoside, etc., have been documented to possess many beneficial effects in the human body including their positive effects in the cardiovascular system. However, clinical implications of QCT and its derivatives are still rare. In the current paper we provide a complex picture of the most recent knowledge on the effects of QCT and its derivatives in different types of cardiac injury, mainly in ischemia-reperfusion (I/R) injury of the heart, but also in other pathologies such as anthracycline-induced cardiotoxicity or oxidative stress-induced cardiac injury, documented in in vitro and ex vivo, as well as in in vivo experimental models of cardiac injury. Moreover, we focus on cardiac effects of QCT in presence of metabolic comorbidities in addition to cardiovascular disease (CVD). Finally, we provide a short summary of clinical studies focused on cardiac effects of QCT. In general, it seems that QCT and its metabolites exert strong cardioprotective effects in a wide range of experimental models of cardiac injury, likely via their antioxidant, anti-inflammatory and molecular pathways-modulating properties; however, ageing and presence of lifestyle-related comorbidities may confound their beneficial effects in heart disease. On the other hand, due to very limited number of clinical trials focused on cardiac effects of QCT and its derivatives, clinical data are inconclusive. Thus, additional well-designed human studies including a high enough number of patients testing different concentrations of QCT are needed to reveal real therapeutic potential of QCT in CVD. Finally, several negative or controversial effects of QCT in the heart have been reported, and this should be also taken into consideration in QCT-based approaches aimed to treat CVD in humans.

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Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

Frontiers in Physiology ◽

10.3389/fphys.2021.727806 ◽

2021 ◽

Vol 12 ◽

Author(s):

Camille Audousset ◽

Toby McGovern ◽

James G. Martin

Keyword(s):

Oxidative Stress ◽

Pulmonary Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Protective Role ◽

Experimental Models ◽

Chronic Obstructive ◽

Related Factor ◽

Obstructive Pulmonary Disease

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor involved in redox homeostasis and in the response induced by oxidative injury. Nrf2 is present in an inactive state in the cytoplasm of cells. Its activation by internal or external stimuli, such as infections or pollution, leads to the transcription of more than 500 elements through its binding to the antioxidant response element. The lungs are particularly susceptible to factors that generate oxidative stress such as infections, allergens and hyperoxia. Nrf2 has a crucial protective role against these ROS. Oxidative stress and subsequent activation of Nrf2 have been demonstrated in many human respiratory diseases affecting the airways, including asthma and chronic obstructive pulmonary disease (COPD), or the pulmonary parenchyma such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Several compounds, both naturally occurring and synthetic, have been identified as Nrf2 inducers and enhance the activation of Nrf2 and expression of Nrf2-dependent genes. These inducers have proven particularly effective at reducing the severity of the oxidative stress-driven lung injury in various animal models. In humans, these compounds offer promise as potential therapeutic strategies for the management of respiratory pathologies associated with oxidative stress but there is thus far little evidence of efficacy through human trials. The purpose of this review is to summarize the involvement of Nrf2 and its inducers in ARDS, COPD, asthma and lung fibrosis in both human and in experimental models.

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Nitrosative Redox Homeostasis and Antioxidant Response Defense in Disused Vastus lateralis Muscle in Long-Term Bedrest (Toulouse Cocktail Study)

Antioxidants ◽

10.3390/antiox10030378 ◽

2021 ◽

Vol 10 (3) ◽

pp. 378

Author(s):

Dieter Blottner ◽

Daniele Capitanio ◽

Gabor Trautmann ◽

Sandra Furlan ◽

Guido Gambara ◽

...

Keyword(s):

Defense Response ◽

Antioxidant Defense ◽

Vastus Lateralis ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Vastus Lateralis Muscle ◽

Related Factor ◽

Label Free ◽

Positive Effects ◽

Intervention Protocol

Increased oxidative stress by reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a major determinant of disuse-induced muscle atrophy. Muscle biopsies (thigh vastus lateralis, VL) obtained from healthy male subjects enrolled in the Toulouse Cocktail bedrest (BR) study were used to assess efficacy of an antioxidant cocktail (polyphenols, omega-3, vitamin E, and selenium) to counteract the increased redox homeostasis and enhance the antioxidant defense response by using label-free LC–MS/MS and NITRO-DIGE (nitrosated proteins), qPCR, and laser confocal microscopy. Label-free LC–MS/MS indicated that treatment prevented the redox homeostasis dysregulation and promoted structural remodeling (TPM3, MYH7, MYBPC, MYH1, MYL1, HRC, and LUM), increment of RyR1, myogenesis (CSRP3), and skeletal muscle development (MUSTN1, LMNA, AHNAK). These changes were absent in the Placebo group. Glycolysis, tricarboxylic acid cycle (TCA), oxidative phosphorylation, fatty acid beta-oxidation, and mitochondrial transmembrane transport were normalized in treated subjects. Proteins involved in protein folding were also normalized, whereas protein entailed in ion homeostasis decreased. NITRO-DIGE analysis showed significant protein nitrosylation changes for CAT, CA3, SDHA, and VDAC2 in Treatment vs. Placebo. Similarly, the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response element (Nrf-2 ARE) signaling pathway showed an enhanced response in the Treatment group. Increased nitrosative redox homeostasis and decreased antioxidant defense response were found in post-BR control (Placebo, n = 10) vs. the antioxidant cocktail treated group (Treatment, n = 10). Taken together, increased nitrosative redox homeostasis and muscle deterioration during BR-driven physical inactivity were prevented, whereas decreased antioxidant nitrosative stress defense response was attenuated by Treatment suggesting positive effects of the nutritional intervention protocol in bedrest.

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Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

Cancers ◽

10.3390/cancers10120481 ◽

2018 ◽

Vol 10 (12) ◽

pp. 481 ◽

Cited By ~ 40

Author(s):

Azhwar Raghunath ◽

Kiruthika Sundarraj ◽

Frank Arfuso ◽

Gautam Sethi ◽

Ekambaram Perumal

Keyword(s):

Hepatocellular Carcinoma ◽

Transcription Factor ◽

Cancer Progression ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Related Factor ◽

Liver Malignancy ◽

Beneficial Effects ◽

Nrf2 Activation ◽

Key Factor

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor.

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Targeting Melanoma-Initiating Cells by Caffeine: In Silico and In Vitro Approaches

Molecules ◽

10.3390/molecules26123619 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3619

Author(s):

Claudio Tabolacci ◽

Martina Cordella ◽

Stefania Rossi ◽

Marialaura Bonaccio ◽

Adriana Eramo ◽

...

Keyword(s):

Bioactive Compounds ◽

In Silico ◽

Molecular Mechanisms ◽

In Silico Analysis ◽

Experimental Models ◽

Conditioned Media ◽

Antiproliferative Effects ◽

Beneficial Effects ◽

Large Heterogeneity

The beneficial effects of coffee on human diseases are well documented, but the molecular mechanisms of its bioactive compounds on cancer are not completely elucidated. This is likely due to the large heterogeneity of coffee preparations and different coffee-based beverages, but also to the choice of experimental models where proliferation, differentiation and immune responses are differently affected. The aim of the present study was to investigate the effects of one of the most interesting bioactive compounds in coffee, i.e., caffeine, using a cellular model of melanoma at a defined differentiation level. A preliminary in silico analysis carried out on public gene-expression databases identified genes potentially involved in caffeine’s effects and suggested some specific molecular targets, including tyrosinase. Proliferation was investigated in vitro on human melanoma initiating cells (MICs) and cytokine expression was measured in conditioned media. Tyrosinase was revealed as a key player in caffeine’s mechanisms of action, suggesting a crucial role in immunomodulation through the reduction in IL-1β, IP-10, MIP-1α, MIP-1β and RANTES secretion onto MICs conditioned media. The potent antiproliferative effects of caffeine on MICs are likely to occur by promoting melanin production and reducing inflammatory signals’ secretion. These data suggest tyrosinase as a key player mediating the effects of caffeine on melanoma.

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ACE2 as therapeutic agent

Clinical Science ◽

10.1042/cs20200570 ◽

2020 ◽

Vol 134 (19) ◽

pp. 2581-2595

Author(s):

Qiuhong Li ◽

Maria B. Grant ◽

Elaine M. Richards ◽

Mohan K. Raizada

Keyword(s):

Therapeutic Agent ◽

Renin Angiotensin System ◽

Peptide Hormone ◽

Experimental Models ◽

Electrolyte Balance ◽

Ang Ii ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Overwhelming Evidence ◽

Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

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Targeting PPARalpha in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666170505094549 ◽

2018 ◽

Vol 15 (4) ◽

pp. 345-354 ◽

Cited By ~ 13

Author(s):

Barbara D'Orio ◽

Anna Fracassi ◽

Maria Paola Cerù ◽

Sandra Moreno

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Peroxisome Proliferator ◽

Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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Effects of Evocative Audio-Visual Installations on the Restorativeness in Urban Parks

Sustainability ◽

10.3390/su13158328 ◽

2021 ◽

Vol 13 (15) ◽

pp. 8328

Author(s):

Massimiliano Masullo ◽

Luigi Maffei ◽

Aniello Pascale ◽

Vincenzo Paolo Senese ◽

Simona De Stefano ◽

...

Keyword(s):

Social Inclusion ◽

Road Traffic ◽

Traffic Noise ◽

Human Perception ◽

Urban Parks ◽

Well Being ◽

Road Traffic Noise ◽

Beneficial Effects ◽

Positive Effects ◽

Experimental Laboratory

Road traffic noise is responsible for several negative health effects for citizens in modern cities. Inside urban parks, which citizens use for social inclusion and cohesion, psychological and physical restoration, and physical activities, road traffic noise may significantly reduce the potential of these places to induce or enhance well-being. Although access restriction schemes and screens could be effective solutions to limit noise inside urban park areas, preserving their potential regenerative role may engender mobility, social, aesthetic, and architectural issues. Due to the positive effects that natural elements and water sounds can have on human perception, and based on the previous findings of the beneficial effects of audio-visual installations, this paper investigates the possibility of using audio-visual installations that simply evoke some natural features to improve the restoration of individuals inside urban parks. The study has been carried out using immersive virtual environments in two different experimental laboratory sessions in Hong Kong (China) and Aversa (Italy). The results showed that the positive effects provided by evocative installations were similar to those provided by traditional installations. Furthermore, the effects on the restoration increased as the installations became larger and included enveloping shapes. Furthermore, we found that the amount of evocative water installations’ material was responsible for changes in restoration. In contrast, the Chinese groups were less influenced by these installations.

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