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Neurological disorders are the foremost occurring diseases across the globe resulting in progressive dysfunction, loss of neuronal structure ultimately cell death. Therefore, attention has been drawn toward the natural resources for the search of neuroprotective agents. Plant-based food bioactives have emerged as potential neuroprotective agents for the treatment of neurodegenerative disorders. This comprehensive review primarily focuses on various plant food bioactive, mechanisms, therapeutic targets, in vitro and in vivo studies in the treatment of neurological disorders to explore whether they are boon or bane for neurological disorders. In addition, the clinical perspective of plant food bioactives in neurological disorders are also highlighted. Scientific evidences point toward the enormous therapeutic efficacy of plant food bioactives in the prevention or treatment of neurological disorders. Nevertheless, identification of food bioactive components accountable for the neuroprotective effects, mechanism, clinical trials, and consolidation of information flow are warranted. Plant food bioactives primarily act by mediating through various pathways including oxidative stress, neuroinflammation, apoptosis, excitotoxicity, specific proteins, mitochondrial dysfunction, and reversing neurodegeneration and can be used for the prevention and therapy of neurodegenerative disorders. In conclusion, the plant based food bioactives are boon for neurological disorders.

Neurodegenerative disorders, particularly in the elderly population, represent one of the most pressing social and health-care problems in the world. Besides the well-established role of both oxidative stress and inflammation, alterations of the immune response have been found to be closely linked to the development of neurodegenerative diseases. Interestingly, various scientific evidence reported that an altered gut microbiota composition may contribute to the development of neuroinflammatory disorders. This leads to the proposal of the concept of the gut-brain-immune axis. In this scenario, polyphenols play a pivotal role due to their ability to exert neuroprotective, immunomodulatory and microbiota-remodeling activities. In the present review, we summarized the available literature to provide a scientific evidence regarding this neuroprotective and immunomodulatory effects and the interaction with gut microbiota of polyphenols and, the main signaling pathways involved that can explain their potential therapeutic application in neurodegenerative diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Flavonoids are major dietary constituents of plant-based food found ubiquitously in plant kingdom where they are usually present in substantial amounts. Rutin is a flavonol-type polyphenol which consists of the flavonol quercetin and the disaccharide rutinose. Rutin has been reported to exert diverse biological effects such as antitumor and antimicrobial mainly associated to its antioxidant and anti-inflammatory activities. Mental, neurological, and behavioural disorders are an important and growing cause of morbidity. Most of these disorders combine a high prevalence, early onset, progressive clinical course, and impairment of critical brain functions making them a major contributor to the global disease burden. In the present work, the biological in vitro and in vivo effects and the potential therapeutic applications of rutin in neurodegenerative processes are reviewed, as well as their bioavailability and pharmacokinetics, which are essential for a better understanding of its biological effectiveness. Moreover, the present review also provides an overview of the molecular mechanisms through which rutin is proposed to exert its neuroprotective effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurodegenerative disorders (NDDs) such as Alzheimer's and Parkinson's diseases are the most common age-related pathologies that affect millions of people all over the world. To date, effective therapy for NDDs is not available and current approaches to disease management include neuroprotection strategy with a hope of maintaining and enhancing the function of survising neurons. Of course, such an approach by its own will not offer a cure but is likely to delay the disease progression by ameliorating the increase of neurotoxic agents such reactive oxygen species (ROS) as well as the associated inflammatory cascades. In this regard, natural products including flavonods that offer neuroprotection through multiple mechanisms have gained a lot of interest in recent years. In this communication, evidences from the various experimental models and clinical trials on the therapeutic potential of one promising flavonod, apigenin, is presented. Its chemistry, mechanism of action and potential benefits in the various examples of NDDs are discussed in the light of drug discovery aspects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The incidence of neurological disorders is growing in developed countries together with increased lifespan. Nowadays, there are still no effective treatments for neurodegenerative pathologies, which make necessary to search for new therapeutic agents. Natural products, most of them used in traditional medicine, are considered promising alternatives for the treatment of neurodegenerative diseases. Honokiol is a natural bioactive phenylpropanoid compound, belonging to the class of neolignan, found in notable amounts in the bark of Magnolia tree, and has been reported to exert diverse pharmacological properties including neuroprotective activities. Honokiol can permeate the blood brain barrier and the blood-cerebrospinal fluid to increase its bioavailability in neurological tissues. Diverse studies have provided evidence on the neuroprotective effect of honokiol in the central nervous system, due to its potent antioxidant activity, and amelioration of the excitotoxicity mainly related to the blockade of glutamate receptors and reduction in neuroinflammation. In addition, recent studies suggest that honokiol can attenuate neurotoxicity exerted by abnormally aggregated Aβ in Alzheimer's disease. The present work summarizes what is currently known concerning the neuroprotective effects of honokiol and its potential molecular mechanisms of action, which make it considered as a promising agent in the treatment and management of neurodegenerative diseases. © 2017 BioFactors, 43(6):760-769, 2017., (© 2017 International Union of Biochemistry and Molecular Biology.)

Neurodegenerative diseases, namely Alzheimer's disease and Parkinson's disease represent a deleterious impact worldwide. Despite extensive preclinical and clinical research in neurodegenerative disorders, therapeutic strategies aimed at the prevention and chronic treatment of neurodegenerative conditions have not been successfully translated to the clinic. Therefore, the identification of novel pharmacological intervention derived from natural products is warranted. Nobiletin and tangeretin are important citrus flavonoids derived from the peel and other parts of Citrus L. genus, and have been shown to exhibit neuroprotective effects in several in vitro and in vivo studies. Apart from there antioxidant and anti-inflammatory effects, nobiletin and tangeretin have been shown to attenuate cholinergic deficits, reduce the abnormal accumulation of neurotoxic amyloid-beta peptides, reverse N-methyl- D-aspartate (NMDA) receptor hypofunction, ameliorate ischemic injury, inhibit hyperphosphorylation of tau protein, enhance neprilysin levels, modulate several signaling cascades, and protect against 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Taken together, these naturally occurring phytochemicals may represent beneficial drug candidates for the treatment and prevention of Alzheimer's and Parkinson's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: The plant milk thistle and silymarin has been traditionally used as a natural remedy for the treatment of various ailments including neurological disorders such as Alzheimer's and Parkinson's disease and cerebral ischemia for over 2000 years., Objective: In this article we review the neuroprotective effects of silymarin against various neurological dysfunctions., Results: The neuroprotective effects conferred by silymarin include modulation of various antioxidant mechanisms, and several kinases involved in cell signaling pathways, inhibition of the inflammatory response generated during neurodegeneration, neurotropic effects, regulation of neurotransmitters and inhibition of apoptosis. The ease of availability, comparative low cost and safety profile provide additional advantages for the use of this compound as a potent drug with immense clinical benefit. However, there is a growing need for improvements in the bioavailability of silymarin and related products, and more consistent and reliable human trials are required to accurately validate the neuroprotective efficacy of this natural compound., Conclusion: The promising outcomes of the studies mentioned in this review provide renewed insight into the clinical relevance of silymarin in a variety of neurodegenerative disorders where neuroinflammation and oxidative stress are pathologically relevant to disease progression., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: At present, much attention has been focused on the beneficial effects of natural products on the human health due to their high efficacy and low adverse effects. Among them, polyphenolic compounds are known as one of the most important and common classes of natural products, which possess multiple range of health-promotion effects including anti-inflammatory and antioxidant activities. A plethora of scientific evidence has shown that polyphenolic compounds possess beneficial effects on the central nervous system., Methods: Data were collected from Web of Science (ISI Web of Knowledge), Medline, Pubmed, Scopus, Embase, and BIOSIS Previews (from 1950 to 2015), through searching of these keywords: "chlorogenic acid and mental diseases" and "chlorogenic acid and neuroprotection"., Results: Chlorogenic acid is known as one of the most common polyphenolic compounds, and is found in different types of fruits and vegetables, spices, wine, olive oil, as well as coffee. The potential neuroprotective effects of chlorogenic acid have been highlighted in several in vitro and in vivo studies. This review critically analyses the available scientific evidence regarding the neuroprotective effects of chlorogenic acid, and its neuropharmacological mechanisms of action. In addition, we also discuss its biosynthesis, sources, bioavailability and metabolism, to provide a broad perspective of the therapeutic implications of this compound in brain health and disease., Conclusion: The present review showed that chlorogenic acid possesses neuroprotective effects under the both in vitro and in vivo models., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Ginsenosides represent the major bioactive components of ginseng. These triterpenoid saponins have been shown to exert numerous beneficial effects on the human body. Recent evidences suggest that ginsenosides may be useful for the management and treatment of several diseases of the central nervous system (CNS). In particular, numerous in vitro and in vivo models have shown that ginsenosides can modulate numerous pharmacological effects on the brain, including attenuation of excitotoxicity, oxidative stress and neuroinflammation, maintenance of neurotransmitter balance, anti-apoptotic effects, and mitochondrial stabilization effects. Regulations of these pathophysiological mechanisms have been shown to improve cognitive function and protect the brain against several neurodegenerative diseases. This review will critically address the pharmacological effects and mechanisms of action of ginsenosides in the CNS, and particularly those associated with therapeutic efficacies in Parkinson's disease, Alzheimer's disease, Huntington's disease, and traumatic brain injury, and ischemia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Multiple lines of evidence suggest that disease-related neurodegeneration seems to be a multifactorial process that involves different cytotoxic pathways converging in cell death. Neuropathological evidence indicates that neuroinflammation, excitotoxicity, redox-active metals, increased reactive oxygen and nitrogen species, abnormalities in the activity of the ubiquitin-proteasome system, impairments in endogenous antioxidant defense mechanisms, mitochondrial dysfunction, as well as a reduction in the expression of trophic factors in neuronal tissues might play a role in the pathobiology of disease. In addition, increased expression of proapoptotic proteins, which leads to neuronal cell death, plays an important role in the onset and progression of neurodegeneration. With respect to the inefficacy of single-target drugs for the treatment of numerous neurodegenerative disorders, much attention has been paid to natural products with pluripharmacological properties as well as negligible adverse effects. Ellagic acid is known as an important natural phenolic antioxidant, that is widely found in different fruits and vegetables. Recent studies have shown that ellagic acid may invoke a spectrum of cell signaling pathways to attenuate or slow down the development of neurodegenerative disorders. Ellagic acid possesses potent neuroprotective effects through its free radical scavenging properties, iron chelation, activation of different cell signaling pathways, and mitigation of mitochondrial dysfunction. The aim of this review is to critically summarize and analyze the available literature regarding the neuroprotective effects of ellagic acid with emphasis on its molecular mechanisms of action. In addition, we also discuss the biosynthesis, sources, bioavailability, and metabolism, of ellagic acid to provide as accurately as possible the much needed information for assessment of the overall protective effects of this compound in the central nervous system.

Neurodegenerative diseases are the leading cause of disability in the elderly. Growing evidence suggests that oxidative stress, which is associated with aging, is the basis of most neurodegenerative disorders; and polyphenols, acting as antioxidant agents, reduce the risk of neurodegenerative diseases. Quercetin is a flavonoid occurring in many plant foods commonly consumed as part of a regular diet. It shows a number of biological properties connected to its antioxidant activity. This review assesses the molecular structure of quercetin, its food sources and bioavailability. Moreover, the main results obtained from in vitro studies, observing the mechanisms of action through which quercetin exerts its antioxidant activity, are reported. However, most of these effects have only been observed in vitro and clinical studies are lacking.

According to the epidemiological reports published by the World Health Organization, the proportion of elderly people (over 60 years) will increase from 11% to 22% by 2050 worldwide. This increase will be associated with a growing rate of morbidity and mortality of age-related diseases. Mental and neurodegenerative diseases are important health problems in elderly people. Therefore, recent research has been focused on finding effective neuroprotective agents with low adverse effects. Over the last two decades, much attention has been drawn to plant-derived bioactive compounds as novel therapeutic agents for treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Among them, flavonoid chemical class is known as one of the most bioactive and non-toxic phytochemicals, which are widely found in different herbal medicines and edible plants. Fisetin is one of the most common and bioactive flavonoids which possesses potential neuroprotective effects. Fisetin also enhances learning and memory, decreases neuronal cell death, and suppresses oxidative stress. The present paper aims to critically evaluate the available literature regarding the beneficial effects of fisetin on neurodegenerative diseases, especially AD and PD. In addition, we provide information regarding the chemistry, sources, bioavailability and clinical impacts of fisetin to provide a broad spectrum for the use of this compound as a new approach to the treatment of AD and PD.

The World Health Organization estimated that the proportion of older people (over 60 years) will increase from 11% to 22% during next 40 years throughout the world. With respect to this, the morbidity and mortality rates of age-related diseases will increase. Mental diseases are the most common and important health problems among elderly people. Therefore, much attention has been paid to the discovery of neuroprotective drugs with high efficacy and negligible adverse effects. A growing body of scientific evidence has shown that phytochemicals possess neuroprotective effects and also mitigate neurodegeneration under both in vivo and in vitro conditions. Polyphenolic compounds, especially flavonoids, are known as most common chemical class of phytochemicals which possess a multiple range of health promoting effects. Chrysin, belonging to the flavone class, is one of the most important bioactive constituents of different fruits, vegetables and even mushrooms. Chrysin possesses potent neuroprotective effects and suppress neuroinflammation. In addition, chrysin improves cognitive decline and possesses a potent anti-amyloidogenic and neurotrophic effects. Furthermore, beneficial effects of chrysin on both depression and epilepsy have been reported. The present paper aimed to critically review the available literature data regarding the neuroprotective effects of chrysin as well as its chemistry, sources and bioavailability., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

According to the World Health Organization, two billion people will be aged 60 years or older by 2050. Aging is a major risk factor for a number of neurodegenerative disorders. These age-related disorders currently represent one of the most important and challenging health problems worldwide. Therefore, much attention has been directed towards the design and development of neuroprotective agents derived from natural sources. These phytochemicals have demonstrated high efficacy and low adverse effects in multiple in vitro and in vivo studies. Among these phytochemicals, dietary flavonoids are an important and common chemical class of bioactive products, found in several fruits and vegetables. Luteolin is an important flavone, which is found in several plant products, including broccoli, pepper, thyme, and celery. Numerous studies have shown that luteolin possesses beneficial neuroprotective effects both in vitro and in vivo. Despite this, an overview of the neuroprotective effects of luteolin has not yet been accomplished. Therefore, the aim of this paper is to provide a review of the available literature regarding the neuroprotective effects of luteolin and its molecular mechanisms of action. Herein, we also review the available literature regarding the chemistry of luteolin, its herbal sources, and bioavailability as a pharmacological agent for the treatment and management of age-related neurodegenerative disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Extensive evidences has shown the promising effects of Ginkgo biloba consumption on several diseases such as Alzheimer's and Parkinson's diseases, and ischemic stroke, etc. Several studies also have reported its beneficial role on motor activity and cognitive functions. This species contain a unique class of diterpenes, namely Ginkgolide B, which possess several pharmacological activities such as protective effect against cardiovascular disease; the most important causes of death worldwide. The promising effects of Ginkgolide B on stroke, both ischemic and hemorrhagic, are suggested by an overwhelming body of scientific evidences. Many studies have shown that the increase of sirt1 expression, the suppression of nuclear factor kappa-B (NF-kB, the inhibition of the PI3K/Akt pathway and toll-like receptor 4 (TLR4/NF-kB, the up-regulation of heme oxygenase 1, erythropoietin secretion and anti-apoptotic protein expression, the inhibition of pro-apoptotic proteins expression, and the improvement of endothelial NO synthesis are the main molecular mechanisms involved in the protective effect of Ginkgolide B on ischemic stroke. In this review, all the available data on the chemistry, mechanisms of neuroprotection and clinical impacts of Ginkgolide B are critically discussed.

Rosemary (Rosmarinus officinalis L.) is one of the most common household herbs, used as spices in a variety of foods, and employed in traditional medicine for its healing properties. Rosemary is a rich source of active antioxidant constituents such as phenolic diterpenes, flavonoids and phenolic acids. Caffeic acid and rosmarinic acid are the most important bioactive constituents. Rosmarinic acid is the ester of caffeic acid and 3,4-dihydroxyphenyllactic acid and is widely identified in different plant species. Chemical structure of rosmarinic acid contains two phenolic rings: one of them is derived from phenylalanine via caffeic acid and the other from tyrosine via dihydroxyphenyl-lactic acid. Its large-scale production is obtained from plant cell cultures of Coleus blumei Benth. It is easily absorbed through gastrointestinal tract as well as the skin. Rosmarinic acid is one of the most important and well known natural antioxidant compounds, which possesses neuroprotective effects in different models of neuroinflammation, neurodegeneration, as well as chemicalinduced neurotoxicity and oxidative stress. Therefore, in present review, we aim to discuss about chemistry, sources, biotechnological production and neuroprotective actions of rosmarinic acid with emphasis on its possible molecular mechanisms of neuroprotection.

Dementia is a strongly age-related syndrome due to cognitive decline that can be considered a typical example of the combination of physiological and pathological aging-associated changes occurring in old people; it ranges from intact cognition to mild cognitive impairment, which is an intermediate stage of cognitive deterioration, and dementia. The spread of this syndrome has induced to study and try to reduce dementia modifiable risk factors. They include insulin resistance and hyperinsulinaemia, high blood pressure, obesity, smoking, depression, cognitive inactivity or low educational attainment as well as physical inactivity and incorrect diet, which can be considered one of the most important factors. One emerging strategy to decrease the prevalence of mild cognitive impairment and dementia may be the use of nutritional interventions. In the last decade, prospective data have suggested that high fruit and vegetable intakes are related to improved cognitive functions and reduced risks of developing a neurodegenerative process. The protective effects against neurodegeneration could be in part due to the intake of flavonoids that have been associated with several health benefits such as antioxidant and anti-inflammatory activities, increased neuronal signaling, and improved metabolic functions. The present article is aimed at reviewing scientific studies that show the protective effects of flavonoid intake against mild cognitive impairment and dementia.

Stroke is an important cerebrovascular disease which causes chronic disability and death in patients. Despite of its high morbidity and mortality, there are limited available effective neuroprotective agents for stroke. In recent years, the research aimed at finding novel neuroprotective agents from natural origins has been intensified. Camellia sinensis L. (tea) is the second most consumed beverage worldwide, after water. It is classified into green and white, oolong, black and red, and Pu-erh tea based on the manufacturing process. Catechins are the main phytochemical constituents of Camellia sinensis which are known for their high antioxidant capacity. On other hand, it is well known that oxidative stress plays an important role in the initiation and progression of different cardiovascular diseases such as stroke. Therefore, the present article is aimed to review scientific studies that show the protective effects of tea consumption against ischemic stroke.

Gallic acid (3,4,5-trihydroxybenzoic acid) is a phenolic acid widely distributed in many different families of higher plants, both in free state, and as a part of more complex molecules, such as ester derivatives or polymers. In nature, gallic acid and its derivatives are present in nearly every part of the plant, such as bark, wood, leaf, fruit, root and seed. They are present in different concentrations in common foodstuffs such as blueberry, blackberry, strawberry, plums, grapes, mango, cashew nut, hazelnut, walnut, tea, wine and so on. After consumption, about 70% of gallic acid is adsorbed and then excreted in the urine as 4-O-methylgallic acid. Differently, the ester derivatives of gallic acid, such as catechin gallate ester or gallotannins, are hydrolyzed to gallic acid before being metabolized to methylated derivatives. Gallic acid is a well known antioxidant compounds which has neuroprotective actions in different models of neurodegeneration, neurotoxicity and oxidative stress. In this review, we discuss about the neuroprotective actions of gallic acid and derivatives and their potential mechanisms of action.

Methyl-3-O-methyl gallate (M3OMG) is a rare natural product that showed promising in vitro antioxidant activities. In this study, the protective role of synthetic M3OMG against sodium fluoride (NaF)-induced oxidative stress in rat brain was evaluated. Animals were treated with either M3OMG (10 and 20 mg/kg i.p.), vitamin C (10 mg/kg i.p.) as the standard antioxidant or the vehicle (5 % dimethyl sulfoxide; 1 ml/kg) for 1 week. Oxidative stress was induced in the brain by adding 600 ppm NaF in the drinking water for 7 days. At the end of the treatment period, the levels of thiobarbituric acid reactive substances (TBARS), reduced glutathione and the activities of antioxidant enzymes (superoxide dismutase and catalase) were evaluated in brain homogenates. M3OMG treatment mitigated the NaF-induced oxidative stress through normalization of the level of TBARS, reduced levels of glutathione and by the restoration of the diminished antioxidant enzyme activities. In conclusion, M3OMG could have a potential for treating neurotoxicity induced by fluoride or related environmental pollutants.

Context: Quercetin is a well known aglycone flavonoid that is widely found in different food sources., Objective: In this study, the in vivo neuroprotective potential of quercetin against sodium fluoride-induced oxidative stress was evaluated., Materials and Methods: Wistar rats were divided into five treatment groups and then subjected to daily intraperitoneally treatment with quercetin (at 10 and 20 mg/kg body weight), vitamin C (at 10 mg/kg), or vehicle. After a 1 week treatment period, all groups except saline treated (normal group), were intoxicated with sodium fluoride (NaF) for 1 week. Rat brains were then removed and homogenized for measurement of antioxidant markers including superoxide dismutase (SOD), reduced glutathione, catalase, and lipid peroxidation final products., Results: The thiobarbituric acid reactive substances (TBARS) levels in the heart homogenate of sodium fluoride treated rats (42.04 ± 2.14 nmol MDA eq/g tissue) increased compared to the normal rats (35.99 ± 1.08 nmol MDA eq/g tissue). Animals which were pretreated with quercetin at 20 mg/kg for 1 week prior to sodium fluoride intoxication showed significant reduction in the TBARS level (36.13 ± 1.12 nmol MDA eq/g tissue). Also, pretreatment with quercetin (20 mg/kg) restored the SOD and catalase activities and modified the level of reduced glutathione compared with the control group (p > 0.05)., Discussion and Conclusion: The present study revealed a potent neuroprotective potential of quercetin against NaF-induced toxicity.

Gallic acid is known as a potent antioxidant active compound of the edible and medicinal plant Peltiphyllum peltatum. The main objective of this study was to evaluate the neuroprotective effects of gallic acid against sodium fluoride induced oxidative stress in rat brain. Gallic acid (10 and 20 mg/kg) and vitamin C (10 mg/kg) were intraperitoneally administrated for 1 week prior to sodium fluoride intoxication. After the treatment period, brain tissues were collected and homogenized, and antioxidant parameters were measured in the homogenates. The level of thiobarbituric acid reactive substances in sodium fluoride intoxicated rats (42.04 ± 2.14 nmol MDA eq/g tissue, p < 0.01 vs. normal) increased compared to the normal rats (35.99 ± 1.08 nmol MDA eq/g tissue). Pretreatment with gallic acid at 20 mg/kg was exhibited significant reduction in the thiobarbituric acid reactive substances level (37.06 ± 1.4 nmol MDA eq/g tissue, p > 0.05 vs. normal). This increasing in thiobarbituric acid reactive substances level was accompanied with a decrease in the level of reduced glutathione (6.74 ± 0.28 μg/mg of protein, p < 0.001 vs. normal), superoxide dismutase (53.24 ± 1.62 U/mg of protein, p < 0.001 vs. normal) and catalase (70.73 ± 2.94 μmol/min/mg of protein p < 0.001 vs. normal) activities in sodium fluoride intoxicated rat. Gallic acid at 20 mg/kg was significantly modified the level of reduced glutathione (11.02 ± 0.53 μg/mg of protein, p < 0.05 vs normal) and catalase activity (89.22 ± 3.67 μmol/min/mg of protein, p > 0.05 vs. normal) in rat brain. However, gallic acid at 20 mg/kg was significantly more effective in retrieving superoxide dismutase (124.78 ± 5.7 U/mg of protein) activity than vitamin C (115.5 ± 4.97 U/mg of protein).