Re: 프리 라디칼, 산화 스트레스 --＞ 항산화제 탐구 2023년

[문형철]

Oxidative stress, free radicals and antioxidants: potential crosstalk in the pathophysiology of human diseases

• science and Biotechnology, Banasthali University Vanasthali, Rajasthan, India
• 2Department of Toxicology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
• 3Al-Farabi Kazakh National University, Faculty of Chemistry and Chemical Technology, Almaty, Kazakhstan
• 4Department of Food Science, Faculty of Food` Science and Technology, Universiti Putra Malaysia, Selangor, Malaysia
• 5Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
• 6Department of Biochemistry, Faculty of Science, University of Maiduguri, Maiduguri, Nigeria
• 7Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania
• 8Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador

Introduction: Free radicals are reactive oxygen species that constantly circulate through the body and occur as a side effect of many reactions that take place in the human body. Under normal conditions, they are removed from the body by antioxidant processes. If these natural mechanisms are disrupted, radicals accumulate in excess and contribute to the development of many diseases.

Methodology: Relevant recent information on oxidative stress, free radicals, reactive oxidative species, and natural and synthetic antioxidants was collected by researching electronic databases such as PubMed / Medline, Web of Science, and Science Direct.

Results: According to the analysed studies, this comprehensive review provided a recent update on oxidative stress, free radicals and antioxidants and their impact on the pathophysiology of human diseases.

Discussion: To counteract the condition of oxidative stress, synthetic antioxidants must be provided from external sources to supplement the antioxidant defense mechanism internally. Because of their therapeutic potential and natural origin, medicinal plants have been reported as the main source of natural antioxidants phytocompounds. Some non-enzymatic phytocompounds such as flavonoids, polyphenols, and glutathione, along with some vitamins have been reported to possess strong antioxidant activities in vivo and in vitro studies. Thus, the present review describes, in brief, the overview of oxidative stress-directed cellular damage and the unction of dietary antioxidants in the management of different diseases. The therapeutic limitations in correlating the antioxidant activity of foods to human health were also discussed.

소개:

프리 라디칼은

체내를 끊임없이 순환하며 인체에서 일어나는

많은 반응의 부작용으로 발생하는

활성 산소 종입니다.

정상적인 상태에서는

항산화 과정을 통해 체내에서 제거됩니다.

이러한 자연적인 메커니즘이 중단되면

라디칼이 과도하게 축적되어

많은 질병의 발병에 기여합니다.

방법론: 산화 스트레스, 자유 라디칼, 반응성 산화 종, 천연 및 합성 항산화제에 대한 관련 최신 정보는 PubMed/Medline, Web of Science, Science Direct와 같은 전자 데이터베이스를 조사하여 수집했습니다.

결과: 분석된 연구에 따르면 산화 스트레스, 활성산소 및 항산화제에 대한 최근 업데이트와 인간 질병의 병태생리에 미치는 영향에 대한 종합적인 검토를 제공했습니다.

토론:

산화 스트레스 상태에 대응하기 위해서는

외부에서 합성 항산화제를 공급하여

내부의 항산화 방어 메커니즘을 보완해야 합니다.

치료 잠재력과 천연 유래로 인해 약용 식물은

천연 항산화제 파이토화합물의 주요 공급원으로 보고되었습니다.

플라보노이드,

폴리페놀,

글루타치온과 같은 일부 비효소성 파이토 화합물과

일부 비타민은 생체 내 및 시험관 내 연구에서

강력한 항산화 활성을 가진 것으로 보고되었습니다.

따라서

본 리뷰에서는

산화 스트레스로 인한 세포 손상에 대한 개요와

다양한 질병 관리에서 식이 항산화제의 역할에 대해 간략하게 설명합니다.

식품의 항산화 활성과

인체 건강과의 상관관계에 대한

치료적 한계에 대해서도 논의했습니다.

1 Introduction

Human beings have always involved themselves in various activities to ensure their wellbeing and survival. In doing so, the human body has directed the release of different free radicals or reactive substances which are either inhaled or consumed (Engwa, 2018). The reactive nitrogen and oxygen species (RNS/ROS) play a twofold role as both toxic and beneficial compounds to the organism’s system. At lower concentrations, they have beneficial effects and indulged in different physiological processes such as redox regulation, mitogenic responses, cellular signaling pathways, and an immune function while at a higher level, these reactive species generate nitrosative and oxidative stress (Phaniendra et al., 2015). To reduce or prevent free radical-directed oxidative damage, the human body has developed an antioxidant defence mechanism that involves free radical scavenging, metal chelating, and enzymatic activities to neutralize the reactive species just after they have formed. In addition, the consumption of dietary antioxidants can maintain an adequate level of antioxidants in the organism’s body (Lobo et al., 2010). The level of reactive species in the cellular system may be reduced by antioxidants either by restricting the expression‎ or activities of free radical-producing enzymes such as xanthine oxidase (XO) and NAD(P)H oxidase, or by enhancing the expression‎ and activities of antioxidant enzymes such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) (Aziz et al., 2019).

The growing interest in antioxidants among the public, health professionals, and food scientists is due to their protective function in food items against oxidative deterioration and the organism body against oxidative stress-directed abnormal processes. These potent natural antioxidants are in huge demand for pharmaceuticals/nutraceuticals and as food preservatives. Effective search for new sources of naturally occurring antioxidants and formulation of new antioxidant compounds need reliable methods for eval‎uation of the antioxidant activity. Many biological models, food models, and chemical assays have been developed that can measure the reducing power, radical scavenging activity and other related attributes along with overall oxidation inhibition in the more complex biological system and food items. These processes vary in terms of ease of operation, result expression‎, oxidation initiator, substrate type, and antioxidant mechanism. Selection of a specific or combination of the method is required for the proper assessment of antioxidant potential as a health-enhancing agent or as a food preservative (Shahidi and Zhong, 2015; Chaudhary and Janmeda, 2022a). Thus, the current review updates the current information about free radicals, their origin, types, and antioxidants with their mode of action against reactive species. This paper is found to be very helpful for scientists and researchers who are working on the investigation of the molecular and chemical mechanism of antioxidants. It also benefits the physician who is interested in antioxidant therapy for the cure of diseases.

1 소개

인간은 항상 자신의 건강과 생존을 위해 다양한 활동을 해왔습니다.

이 과정에서 인체는

흡입하거나 섭취하는 다양한 활성산소 또는

반응성 물질의 방출을 유도해 왔습니다(Engwa, 2018).

반응성 질소 및 산소 종(RNS/ROS)은

유기체 시스템에 독성이 있는 동시에

유익한 화합물로서 두 가지 역할을 합니다.

낮은 농도에서는

산화 환원 조절,

유사 분열 반응,

세포 신호 전달 경로 및 면역 기능과 같은

다양한 생리적 과정에 유익한 영향을 미치는 반면,

높은 수준에서는 이러한 반응성 종은

질산화 및 산화 스트레스를 생성합니다(Phaniendra et al., 2015).

활성산소에 의한 산화적 손상을 줄이거나 예방하기 위해 인체는

활성산소 제거,

금속 킬레이트화,

반응성 종을 형성한 직후 중화시키는 효소 활동을 포함하는

항산화 방어 메커니즘을 개발해 왔습니다.

또한

식이 항산화제를 섭취하면

유기체의 체내에서 적절한 수준의 항산화제를 유지할 수 있습니다 (Lobo et al., 2010).

세포 시스템의 반응성 종의 수준은

산화 방지제에 의해

크 산틴 산화 효소 (XO) 및 NAD (P) H 산화 효소와 같은

자유 라디칼 생성 효소의 발현 또는 활동을 제한하거나

글루타티온 퍼 옥시다아제 (GPx), 카탈라제 (CAT) 및 슈퍼 옥사이드 디스 뮤 타제 (SOD)와 같은

항산화 효소의 발현 및 활동을 강화함으로써 감소 될 수있다 (Aziz 외, 2019).

일반인, 건강 전문가, 식품 과학자들 사이에서 항산화제에 대한 관심이 높아지는 이유는

산화적 열화에 대한 식품의 보호 기능과

산화 스트레스로 인한 비정상적인 과정에 대한 유기체의 보호 기능 때문입니다.

이러한 강력한 천연 항산화제는

의약품/건강기능식품 및 식품 보존제로서 수요가 매우 높습니다.

자연적으로 발생하는 항산화제의 새로운 공급원을 효과적으로 탐색하고

새로운 항산화 화합물을 제조하려면

항산화 활성을 평가할 수 있는 신뢰할 수 있는 방법이 필요합니다.

보다 복잡한 생물학적 시스템과 식품에서 전반적인 산화 억제와 함께 환원력, 라디칼 소거 활성 및 기타 관련 특성을 측정할 수 있는 많은 생물학적 모델, 식품 모델 및 화학적 분석법이 개발되었습니다. 이러한 프로세스는 작동의 용이성, 결과 표현, 산화 개시제, 기질 유형 및 항산화 메커니즘 측면에서 다양합니다. 건강 증진제 또는 식품 보존제로서 항산화 잠재력을 적절히 평가하려면 특정 방법 또는 방법 조합을 선택해야 합니다(Shahidi and Zhong, 2015; Chaudhary and Janmeda, 2022a).

따라서

이번 리뷰에서는

활성산소, 그 기원, 유형, 항산화제에 대한 최신 정보와

반응성 종에 대한 항산화제의 작용 방식을 업데이트합니다.

이 논문은

항산화제의 분자 및 화학적 메커니즘을 연구하는 과학자 및 연구자에게

매우 유용한 것으로 밝혀졌습니다.

또한

질병 치료를 위한 항산화 요법에 관심이 있는 의사에게도

도움이 될 것입니다.

2 Methodology

Relevant recent information on oxidative stress, free radicals, reactive oxidative species, and natural and synthetic antioxidants was collected by researching electronic databases such as PubMed/Medline, Web of Science, and Science Direct using the following MeSH terms: “Antioxidants/analysis”, “Antioxidants/metabolism”, “Antioxidants/therapeutic use”, “Diet”, “Food Analysis, Forecasting, Free Radicals/adverse effects”, “Free Radicals/antagonists and inhibitors”, “Free Radicals/metabolism”, “Humans”, “Lipid Peroxidation/physiology”, “Reactive Oxygen Species/adverse effects”, “Reactive Oxygen Species/metabolism”, “Reactive Oxygen Species/therapeutic use”, “Antioxidants/metabolism Free Radicals/adverse effects”, “free Radicals/metabolism”, “Humans Oxidative Stress Oxygen/metabolism”. The taxonomy of the plants mentioned in this review was verified using “The PlantList”.

3 Reactive oxygen species (ROS): From physiology to pathology

Free radicals are molecular species that exist independently and contain an unpaired form of an electron in their atomic orbital. These radicals are highly unstable and reactive. They either donate or accept an electron, therefore acting as oxidants and reductants (Lobo et al., 2010). The generation of highly reactive ROS is an important feature of the normal cellular system such as fertilization, ovulation, arachidonic acid metabolism, phagocytosis, and mitochondrial respiratory chain. Their generation gets multiplies many folds during pathological complications. During the recovery phases, the release of oxygen-free radicals has been observed from many pathological stimuli and reached cerebral tissue (Snezhkina et al., 2020). Reactive species include nitric oxide (•NO), alkoxy (-OR), peroxyl (ROO·), hydroxyl (·OH), hydrogen peroxide (H2O2), and superoxide (O2.-), respectively. Majorly the superoxide radicals are generated from microsomal and mitochondrial electron transport chains. Except for cytochrome oxidase which retains the reduced form of oxygen intermediates to their active site, all the other elements of the mitochondrial respiratory chain transfer the electrons directly to oxygen and do not retain any reduced intermediate of oxygen at their active site to protect the cell against oxidative damages. On the internal membrane of mitochondria, the superoxide anions may be produced by the auto-oxidation of semiquinones. A major part of mitochondrial-generated superoxide anions is dismutation to H2O2. The alkoxyl and hydroxyl free radicals are reactive and rapidly target the major macromolecules in cells (Strzelak et al., 2018).

Free radicals produced by ROS direct undesirable changes and result from lipid peroxidation, DNA fragmentation, cell death, DNA damage, protein modification, and membrane damage. This oxidative stress is not only involved in the toxicity of xenobiotics but also in the pathophysiology of various ailments like ischaemia reperfusion injury, vascular endothelium, deep injuries, organ dysfunction, shock, inflammation, sepsis, diabetic retinopathy, cancer, cognitive dysfunction, cataract, and heart disease. Alterations in the concentration of iron have been observed in amyotrophic lateral sclerosis, spastic paraplegia, and multiple sclerosis which strengthens the knowledge that the accumulation of iron is a secondary factor that is related to neurodegenerative diseases. It can also be associated with gliosis in the affected area or alter the integrity of the blood-brain barrier resulting in inflammatory events and altered tissue vascularization (Stephenson et al., 2014).

3 활성 산소 종(ROS): 생리학에서 병리학까지

자유 라디칼은

독립적으로 존재하며

원자 궤도에 짝을 이루지 않은 형태의 전자를 포함하는 분자 종입니다.

이러한 라디칼은

매우 불안정하고 반응성이 높습니다.

이들은

전자를 기증하거나 수용하여

산화제 및 환원제로 작용합니다(Lobo et al., 2010).

반응성이 높은 ROS의 생성은

수정, 배란, 아라키돈산 대사,

식세포 작용 및 미토콘드리아 호흡 사슬과 같은

정상적인 세포 시스템의 중요한 특징입니다.

병적 합병증이 발생하면

그 수가 몇 배로 증가합니다.

회복 단계에서 많은 병리학 적 자극에서

무산소 라디칼의 방출이 관찰되어 대뇌 조직에 도달했습니다 (Snezhkina et al., 2020).

반응성 종에는 각각

산화 질소 (-NO), 알콕시 (-OR), 퍼 옥실 (ROO-), 하이드 록실 (-OH), 과산화수소 (H2O2) 및 슈퍼 옥사이드 (O2.-)가 포함됩니다.

nitric oxide (•NO), alkoxy (-OR), peroxyl (ROO·), hydroxyl (·OH), hydrogen peroxide (H2O2), and superoxide (O2.-), respectively

주로

슈퍼옥사이드 라디칼은

마이크로솜과 미토콘드리아 전자 수송 사슬에서 생성됩니다.

환원된 형태의 산소 중간체를 활성 부위에 유지하는 시토크롬 산화 효소를 제외한

미토콘드리아 호흡 사슬의 다른 모든 요소는

전자를 산소로 직접 전달하고

산화 손상으로부터 세포를 보호하기 위해 활성 부위에 환원된 산소 중간체를 보유하지 않습니다.

미토콘드리아의 내부 막에서는

세미퀴논의 자가 산화에 의해

과산화물 음이온이 생성될 수 있습니다.

미토콘드리아에서 생성되는 슈퍼옥사이드 음이온의 주요 부분은

H2O2로 변이됩니다.

알콕실 및 하이드 록실 자유 라디칼은

반응성이 있으며 세포의 주요 거대 분자를 빠르게 표적으로 삼습니다 (Strzelak et al., 2018).

ROS에 의해 생성된 활성산소는

지질 과산화, DNA 단편화, 세포 사멸, DNA 손상, 단백질 변형, 막 손상 등

바람직하지 않은 변화를 유도합니다.

이러한

산화 스트레스는

이종 생물의 독성뿐만 아니라 허혈 재관류 손상, 혈관 내피, 심부 손상, 장기 기능 장애, 쇼크,

염증, 패혈증, 당뇨병성 망막증, 암, 인지 기능 장애, 백내장, 심장병 등

다양한 질환의 병리 생리에도 관여합니다.

근위축성 측삭 경화증, 경련성 마비, 다발성 경화증에서

철분 농도의 변화가 관찰되어

철분 축적이 신경 퇴행성 질환과 관련된 이차적 요인이라는 사실을 뒷받침하고 있습니다.

또한

영향을 받은 부위의 신경교증과 연관되거나

혈액-뇌 장벽의 완전성을 변화시켜

염증 반응과 조직 혈관 형성을 변화시킬 수 있습니다(Stephenson et al., 2014).

3.1 Roles of ROS and NO in the pathophysiology of human diseases

3.1.1 Oxidative stress, ROS, inflammatory markers and different types of cancer: Connecting the dots

3.1.1.1 Role in carcinogenesis

The mechanism of carcinogenesis is divided into different stages: progression, promotion, and initiation. In the initiation stage, an endogenous or exogenous carcinogen induces certain changes in the DNA of a cell. This causes an abnormal change that can be inheritable and confers that the cell has the capacity for neoplastic growth (Klaunig and Kamendulis, 2004). This is reported after the metabolic activation of a procarcinogen, which includes oxidative metabolism directed by phase I enzyme to produce reactive oxygen species and electrophiles. The potency of carcinogens is determined by the ability to induce heritable alterations in the specific gene or by the stability of adducts formed with DNA (Klaunig and Kamendulis, 2004). DNA damage is the main cause of several diseases like cancer. The main focus has been given to the consequences and extent of Dfocusations in response to oxygen radicals and other associated reactive species. ROS damaged the cellular DNA which is determined to be a main carcinogenic factor This mis-repaired DNA can result in mutations. These mutations carried out the conversion of a proto-oncogene into a carcinogenic oncogene, which is responsible for different types of cancer (Marnett, 2000). The main damage is the generation of hydroxylated bases of DNA, which is regarded as a crucial event in the process of chemical carcinogenesis (Marnett, 2000). RNS/ROS can cause damage to nucleic acid. The mitochondrial DNA is more prone to get attached by ROS as compared to the nuclear DNA because it is present close to the site of ROS generation. Hydroxyl radicals directly target the different components of DNA such as deoxyribose sugar backbone, pyrimidine and purine bases, and result from single and double-stranded breaks in the DNA (Nita and Grzybowski, 2016). The purine targeted by hydroxyl radical generates various purine adducts like 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 8-hydroxy deoxy adenosine, and 8-hydroxydeoxy guanosine. The pyrimidine adducts formed by the attack of hydroxy radical include hydantoin, 5-hydroxy deoxycytidine, 5-hydroxydeoxy uridine, uracil glycol, and thymine glycol, respectively. On another side, the RNS, mainly the peroxynitrite (ONOO−) interact with guanine to generate oxidative and nitrative DNA damage such as 8-oxodeoxyguanosine and 8-nitroguanine, respectively (Phaniendra et al., 2015).

3.1 인간 질병의 병태생리에서 ROS와 NO의 역할

3.1.1 산화 스트레스, ROS, 염증 마커 및 다양한 유형의 암: 점 연결하기

3.1.1.1 발암에서의 역할

발암의 메커니즘은

진행, 촉진, 개시 등 여러 단계로 나뉩니다.

개시 단계에서는

내인성 또는 외인성 발암 물질이

세포의 DNA에 특정 변화를 유도합니다.

이는 유전될 수 있는 비정상적인 변화를 일으키고

세포에 종양 성장 능력을 부여합니다(Klaunig and Kamendulis, 2004). 이는 발암 물질의 대사 활성화 후에 보고되며, 여기에는 활성 산소 종과 친전기를 생성하기 위해 1단계 효소에 의해 지시되는 산화 대사가 포함됩니다.

발암 물질의 효능은

특정 유전자의 유전적 변이를 유도하는 능력 또는

DNA로 형성된 부가물의 안정성에 의해 결정됩니다(Klaunig and Kamendulis, 2004).

DNA 손상은

암과 같은 여러 질병의 주요 원인입니다.

주요 초점은

산소 라디칼 및 기타 관련 반응성 종에 대한

반응의 결과와 정도에 주어졌습니다.

ROS는

주요 발암 인자로 확인된 세포 DNA를 손상시킵니다.

이렇게 잘못 복구된 DNA는

돌연변이를 일으킬 수 있습니다.

이러한 돌연변이는

원발암 유전자를 발암성 발암 유전자로 전환시켜

다양한 유형의 암을 유발합니다(Marnett, 2000).

주요 손상은

화학적 발암 과정에서 중요한 사건으로 간주되는

DNA의 수산화 염기 생성입니다(Marnett, 2000).

RNS/ROS는

핵산 손상을 일으킬 수 있습니다.

미토콘드리아 DNA는

ROS 생성 부위에 가깝게 존재하기 때문에

핵 DNA에 비해 ROS에 더 쉽게 부착되기 쉽습니다.

하이드록실 라디칼은

데옥시리보스 당 백본, 피리미딘 및 퓨린 염기와 같은

DNA의 다양한 구성 요소를 직접 표적으로 삼으며,

DNA의 단일 및 이중 가닥 단절로 인해 발생합니다(Nita and Grzybowski, 2016).

Hydroxyl radicals directly target the different components of DNA such as

deoxyribose sugar backbone,

pyrimidine and purine bases, and result from

single and double-stranded breaks in the DNA 

하이드록실 라디칼의 표적이 되는 퓨린은

2,6-디아미노-4-하이드록시-5-포름아미도피리미딘,

8-하이드록시데옥시 아데노신,

8-하이드록시데옥시 구아노신과 같은

다양한 퓨린 부가물을 생성합니다.

하이드 록시 라디칼의 공격에 의해 형성된 피리 미딘 부가체에는

각각 히단 토인, 5- 하이드 록시 데 옥시 티딘, 5- 하이드 록시 데 옥시 우리 딘, 우라 실 글리콜 및 티민 글리콜이 포함됩니다.

'''''''''''''''''3

다른 측면에서,

주로 퍼옥시니트라이트(ONOO-)를 중심으로 한

RNS는 구아닌과 상호 작용하여

각각 8-옥소데옥시구아노신과 8-니트로구아닌과 같은

산화적 및 질소적 DNA 손상을 생성합니다(Phaniendra et al., 2015).

3.1.1.2 Chronic inflammation, cancer and ROS

The main component in the relationship between chronic inflammation and cancer is ROS as shown in Figure 1. It can target the level, presence, and type of modulating factors related to inflammation such as growth factors, chemokines, inflammatory cytokines, p53, peroxisome proliferated-activated receptor gamma (PPAR-γ), NF-kB, hypoxia-inducible factor (HIF-1α), ß-catenin/Wnt (wingless related integration site), and activator protein 1 (AP-1) (Reuter et al., 2010; Kashyap et al., 2019). There is typical crosstalk between cancer progression, ROS accumulation, and chronic inflammation Under tumor microenvironment, inflammatory cells direct a massive generation of ROS by the activation of oxidant-generating enzymes such as upregulation of lipoxygenase (LOX), myeloperoxidase (MPO), cyclooxygenase 2 (COX2), xanthine oxidase (XO), NADPH oxidase, and inducible nitric oxide synthase (iNOS) to disrupt the physical, chemical, and biological factors. Excessive ROS accumulation causes oxidative damage to mitochondria, lipids, proteins, RNA, and DNA (Reuter et al., 2010; Kashyap et al., 2019).

3.1.1.2 만성 염증, 암 및 ROS

만성 염증과 암 사이의 관계에서

주요 구성 요소는 그림 1 과 같이

ROS입니다.

이는

성장 인자,

케모카인,

염증성 사이토카인,

p53,

퍼옥시좀 증식 활성화 수용체 감마(PPAR-γ),

NF-kB,

저산소 유도 인자(HIF-1α),

ß-catenin/Wnt(날개 없는 관련 통합 부위),

활성화 단백질 1(AP-1) 등 염증과 관련된

조절 인자의 수준, 존재 및 유형을 표적으로 삼을 수 있습니다(Reuter 외, 2010; Kashyap 외, 2019).

암 진행,

ROS 축적,

만성 염증 사이에는 전형적인 상호 작용이 있습니다.

종양 미세 환경에서 염증 세포는

리폭시게나제(LOX),

미엘로페록시다제(MPO),

시클로옥시게나제 2(COX2),

크산틴 산화효소(XO),

NADPH 산화효소,

유도성 산화질소 합성효소(iNOS) 등의 산화제 생성 효소의 상향 조절로

ROS를 대량 생성하여

물리, 화학 및 생물학적 요인에 장애를 일으킵니다.

과도한 ROS 축적은

미토콘드리아,

지질,

단백질,

RNA 및 DNA에 산화적 손상을 일으킵니다(Reuter et al., 2010; Kashyap et al., 2019).

FIGURE 1

FIGURE 1. Illustrative scheme regarding the correlation between chronic inflammation and cancer mechanisms. Abbreviations and symbols: ↑increase, ↓decrease, ROS (reactive oxidative species), NO (nitric oxide), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells).

3.1.1.3 Cancer metastasis and ROS

Excessive level of ROS leads to metastasis via the stimulation of mitogen-activated protein kinase (MAPK), and phosphoinositide-3-kinase regulatory subunit/AKT serine/threonine kinases/mechanistic target of rapamycin kinase (PI2K/Akt/mTOR) signaling pathways that directs the activation of downstream metalloproteinase 9 (MMP9), metalloproteinase 2 (MMP2), SNAIL enzymes which initiate epithelial-mesenchymal transition (EMT) to metastasis (Deepika et al., 2013). The ROS results in genetic instability due to mutation load and DNA damage. Exposure to ROS can also bring modulation the expression‎ of different transcription factors such as nuclear factor kappa B (NF-kB), and activator protein 1 (AP-1), involved in cancer stem cell maintenance, metastasis, and proliferation. It is determined that ROS are implicated in different cancer-associated processes such as angiogenesis, inflammation, metastasis, and apoptosis (Kashyap et al., 2019).

3.1.1.3 암 전이와 ROS

과도한 수준의 ROS는

미토겐 활성화 단백질 키나아제(MAPK),

포스포이노시타이드-3-키나아제 조절 서브유닛/AKT 세린/트레오닌 키나아제/라파마이신 키나아제의 기계적 타겟(PI2K/Akt/mTOR) 신호 경로를 자극하여

다운스트림 메탈로프로테이나제 9(MMP9)의 활성화를 지시함으로써

전이를 유도합니다,

메탈로프로테아제 2(MMP2),

상피-중간엽 전이(EMT)에서 전이를 개시하는 SNAIL 효소(Deepika et al. , 2013).

ROS는 돌연변이 부하와 DNA 손상으로 인해 유전적 불안정성을 초래합니다.

또한

ROS에 노출되면

암 줄기세포의 유지,

전이 및 증식에 관여하는 핵 인자 카파 B(NF-kB) 및 활성화 단백질 1(AP-1)과 같은

다양한 전사인자의 발현이 조절될 수 있습니다.

ROS는

혈관 신생, 염증, 전이 및 세포 사멸과 같은

다양한 암 관련 과정에 관여하는 것으로 확인되었습니다(Kashyap et al., 2019).

3.1.1.4 Pro-angiogenic role of ROS

Activation of angiogenesis through ROS via vascular endothelial growth factor (VEGF) independent and VEGF dependent pathways are shown in Figure 2. The VEGF-dependent pathway raises the expression‎ of vascular endothelial growth factor (VEGF) via MAPK (Mitogen-activated protein kinases), and the phosphoinositide-3-kinase regulatory subunit/AKT serine/threonine kinases/mechanistic target of rapamycin kinase (PI3K/Akt/mTOR), PTEN (phosphatase and tensin homolog) signaling pathway via p70S6K1 (ribosomal protein S6 kinase B1) and HIF-1α (Hypoxia-inducible factor1-alpha), that releases different growth factors, cytokines, and undergo the upregulation of MMPs which leads to angiogenesis. Whereas the VEGF-independent pathway results in angiogenesis via oxidative ligands of lipids which activate NF-kB via Toll-like receptor (TLR) (Deepika et al., 2013).

3.1.1.4 ROS의 혈관 신생 촉진 역할

혈관내피세포성장인자(VEGF) 독립 경로와

VEGF 의존 경로를 통한 ROS를 통한

혈관신생 활성화는 그림 2 에 나와 있습니다.

vascular endothelial growth factor

VEGF 의존 경로는

MAPK(미토겐 활성화 단백질 키나제)와

포스포이노시타이드-3-키나제 조절 서브유닛/AKT 세린/트레오닌 키나제/라파마이신 키나제의

기계적 표적(PI3K/Akt/mTOR)을 통해

혈관 내피세포 성장 인자(VEGF)의 발현을 높입니다,

p70S6K1(리보솜 단백질 S6 키나제 B1) 및

HIF-1α(저산소 유도 인자1-알파)를 통한

PTEN(포스파타제 및 텐신 동족체) 신호 경로는

다양한 성장 인자, 사이토카인을 방출하고

혈관 신생을 유도하는 MMP의 상향 조절을 거치게 됩니다.

반면

VEGF 독립 경로는

톨유사수용체(TLR)를 통해 NF-kB를 활성화하는

지질의 산화적 리간드를 통해 혈관 신생을 유도합니다(Deepika et al., 2013).

FIGURE 2

FIGURE 2. Angiogenesis through the activation of reactive oxygen species.

Abbreviations and symbols: ↑ increased, ↓ decreased, ROS reactive oxygen species, TLR Toll-like receptors, VEGFR Vascular endothelial growth factors, NF-kβ nuclear factor kappa B, MAPK mitogen-activated protein kinase, HIF-1α (Hypoxia-inducible factor 1-alpha).

3.1.1.5 Lung cancer

The lung is the only organ that is under more exposure to ambient air than the skin. It is therefore easily affected by oxidants, pathogens, pollutants, gases, and inhaled toxins. In addition, endogenous oxidants produced by different pathophysiological processes in the lung and anywhere in the body also increased the oxidative burden. To control these effects, the epithelium of the lung is protected by a lining of fluid containing an armamentarium of antioxidants. When the equilibrium between the antioxidants and oxidants is compromised then it leads to oxidative stress. In response to this stress, an inflammatory response is directed which results in the release of different cytokines and pro-inflammatory chemokines. This leads to the invasion of leukocytes and monocytes into the inflammatory environment. Continuous inhalation of injurious agents directs the initiation of prolonged oxidative stress in the lungs, which results in chronic inflammation characterized by a pronounced release of reactive nitrogen and oxygen species. This condition is related to significant DNA damage and genomic instability, leading to neoplastic progression and initiation (Valavanidis et al., 2013).

3.1.1.5 폐암

폐는

피부보다 주변 공기에 더 많이 노출되는 유일한 기관입니다.

따라서

산화제, 병원균, 오염 물질, 가스 및 흡입 독소에

쉽게 영향을 받습니다.

또한

폐와 신체 어느 곳에서나

다양한 병리 생리학적 과정에 의해 생성되는 내인성 산화 물질도

산화 부담을 증가시킵니다.

이러한 영향을 제어하기 위해

폐 상피는 항산화 물질이 함유된

체액 내막으로 보호됩니다.

항산화 물질과 산화 물질 사이의 균형이 깨지면

산화 스트레스가 발생합니다.

이 스트레스에 대한 반응으로 염증 반응이 일어나

다양한 사이토카인과 염증 유발 케모카인이 방출됩니다.

이로 인해 백혈구와 단핵구가 염증 환경으로 침입하게 됩니다.

유해 물질을 지속적으로 흡입하면

폐에서 장기간의 산화 스트레스가 시작되어

반응성 질소 및 산소 종의 뚜렷한 방출을 특징으로하는

만성 염증이 발생합니다.

이 상태는

심각한 DNA 손상 및 게놈 불안정성과 관련이 있어

종양 진행 및 발병으로 이어집니다(Valavanidis 외., 2013).

3.1.1.6 Liver cancer

Different evidence has shown that oxidative stress plays a potent role in the development of hepatic carcinogenesis by disrupting genetic material, the normal functioning of the cell, and by interfering with various pathways of cell signaling (Jain et al., 2020). The application of antioxidant agents can limit oxidative stress-directed damages in vitro. But no drug is found to be effective under in vivo conditions with a smaller number of side effects. To find a more effective method for the cure and treatment of HCC, research for a better understanding of the mechanism involved in the development of cancer, OS-induced damage, and the effects of antioxidants is urgently required (Wang et al., 2016).

The liver is the main organ that is targeted by reactive species. Primary cells, i.e., parenchymal cells subjected to oxidative stress-directed damage in the liver (Jain et al., 2020). The peroxisomes, microsomes, and mitochondria in parenchymal cells lead the production of ROS by regulating the PPARα, which is involved in the expression‎ of genes related to fatty acid oxidation. Moreover, endothelial cells, hepatic stellate cells, and kupffer cells are more sensitive towards oxidative stress-associated molecules. Different types of cytokines such as TNF-α can be released in Kupffer cells in response to oxidative stress, which might trigger the process of apoptosis and inflammation (Li S et al., 2015).

3.1.1.6 간암

여러 증거에 따르면 산화 스트레스는 유전 물질, 세포의 정상적인 기능을 방해하고 다양한 세포 신호 전달 경로를 방해함으로써 간 발암의 발생에 강력한 역할을 하는 것으로 나타났습니다(Jain et al., 2020). 항산화제를 적용하면 시험관 내에서 산화 스트레스로 인한 손상을 제한할 수 있습니다. 그러나 생체 내 조건에서 부작용이 적으면서 효과적인 것으로 밝혀진 약물은 아직 없습니다. 간세포암의 치료 및 치료를 위한 보다 효과적인 방법을 찾기 위해서는 암의 발생, OS에 의한 손상 및 항산화제의 효과와 관련된 메커니즘에 대한 더 나은 이해를 위한 연구가 시급히 필요합니다(Wang et al., 2016).

간은

반응성 종의 표적이 되는 주요 기관입니다.

간에서 산화 스트레스에 의한 손상을 받는 일차 세포, 즉 실질 세포 (Jain et al., 2020). 실질 세포의 퍼옥시좀, 마이크로솜, 미토콘드리아는 지방산 산화와 관련된 유전자의 발현에 관여하는 PPARα를 조절하여 ROS 생성을 주도합니다.

또한

내피 세포,

간 성상 세포 및 쿠퍼 세포는

산화 스트레스 관련 분자에 더 민감합니다.

산화 스트레스에 반응하여

쿠퍼 세포에서 TNF-α와 같은 다양한 유형의 사이토카인이 방출되어

세포 사멸 및 염증 과정을 유발할 수 있습니다(Li S 외., 2015).

3.1.1.7 Colorectal cancer

Colorectal cancer is the most common cancer globally, with the greatest incidence in Western nations. This cancer arises from the epithelial cells that line the bowel. The epithelial cells reported to have a great metabolic rate and divide rapidly which has been considered to be a potent factor responsible for the oxidation of DNA. Studies on rat colonocytes reported that the lower crypt cells are very much more sensitive towards hydrogen peroxide-induced damage than the differentiated cells located at the crypt surface (Perše, 2013). Since proliferating cells in the colon are present in the lower part of the crypt, this may determine that these cells are supposed to be the main targeted cells in case of colon carcinogenesis Progenitors or stem cells are very sensitive towards the redox environment. The differentiation and self-renewal of these cells are based majorly on the redox environment of the gut mucosa. Proliferating cells are also found to be sensitive to DNA damage as DNA is available in the form of a sgle strands in the S-phase of the cell cycle and further serves as a template in daughter cells. The damage of DNA in a single strand can lead to multiple mutations in the DNA of daughter cells, which could not get repaired (Oberreuther-Moschner et al., 2005). DNA damage causes genomic instability, replication error, induction of signal transduction pathways, induction of transcription and cell cycle arrest, all of which are related to colon carcinoma. However, the latest investigation has reported that the production of ROS may play a vital role in all the phases of carcinogenesis, i.e., progression, promotion, and initiation (Valko et al., 2007).

3.1.1.7 대장암

대장암은 전 세계적으로 가장 흔한 암으로 서구 국가에서 가장 많이 발생합니다. 이 암은 장을 감싸고 있는 상피 세포에서 발생합니다.

상피 세포는

신진대사율이 높고 빠르게 분열하는 것으로 보고되어

DNA의 산화를 일으키는 강력한 요인으로 여겨져 왔습니다.

쥐의 대장 세포를 대상으로 한 연구에 따르면 하부 토굴 세포가 토굴 표면에 위치한 분화 세포보다 과산화수소에 의한 손상에 훨씬 더 민감하다고 보고되었습니다(Perše, 2013). 대장 내 증식 세포가 토굴의 하부에 존재하기 때문에 대장 발암의 경우 이 세포가 주요 표적 세포가 될 것으로 판단할 수 있습니다. 전구 세포 또는 줄기 세포는 산화 환원 환경에 매우 민감합니다. 이러한 세포의 분화와 자기 재생은 주로 장 점막의 산화 환원 환경에 기반합니다.

증식하는 세포는 또한 세포 주기의 S 단계에서

DNA가 가닥 형태로 존재하고

딸세포에서 주형 역할을 하기 때문에

DNA 손상에 민감한 것으로 밝혀졌습니다.

단일 가닥의 DNA 손상은 딸세포의 DNA에 여러 돌연변이를 일으킬 수 있으며, 이는 복구되지 않습니다(Oberreuther-Moschner 외., 2005). DNA 손상은 게놈 불안정성, 복제 오류, 신호 전달 경로의 유도, 전사 및 세포주기 정지를 유발하며, 이는 모두 대장암과 관련이 있습니다. 그러나 최근 조사에 따르면 ROS의 생성은 발암의 모든 단계, 즉 진행, 촉진 및 개시 단계에서 중요한 역할을 할 수 있다고 보고되었습니다(Valko et al., 2007).

3.1.1.8 Breast cancer

Breast tumor with increased proliferative capacity produces a great level of ROS during the chronic cycles of angiogenesis, reperfusion, and ischemia. Tumor cells can direct oxidative damage in surrounding healthy tissues. Enhanced levels of circulating malondialdehyde has been observed in the advanced stages of breast cancer as compared to early stages, which shows differences in the stage of oxidative stress. Patients with breast cancer have been reported to have a greater level of malondialdehyde, a marker of oxidative stress and peroxidation product, than the control patients (Coughlin, 2018). A breast tumor is a highly complex structure composed of old stromal and neoplastic cells. Carcinoma-associated fibroblasts (CAFs) has been usually reported in the cancer stroma, where they enhance vascularity and tumor growth. Under the influence of oxidative stress, fibroblast gets activated to become myofibroblast. These cells are greatly contractile and mobile and more often express mesenchymal markers. The activation of CAF is irreversible, which makes it difficult to be removed by nemesis. In cases of breast tumor, around 80% of stromal fibroblast needs an activated phenotype that manifests by the release of an enhanced level of metalloproteinase, cytokines, and growth factors. They also generate hydrogen peroxide, which directs the production of different sets of tumorigenic alterations and activated fibroblasts in the case of epithelial cells. Under oxidative stress, the tumor stroma produces a wide range of nutrients that support cancer cell survival and growth (Jezierska-Drutel et al., 2013).

3.1.1.8 유방암

증식 능력이 증가한 유방 종양은 혈관 신생, 재관류 및 허혈의 만성 주기 동안 많은 양의 ROS를 생성합니다. 종양 세포는 주변의 건강한 조직에 산화적 손상을 일으킬 수 있습니다.

유방암의 초기 단계에 비해 진행 단계에서

순환하는 말론다이알데히드 수치가 증가하여

산화 스트레스 단계에 차이를 보이는 것으로 관찰되었습니다.

유방암 환자는 대조군 환자보다 산화 스트레스 및 과산화 산물의 지표인 말론다이알데히드 수치가 더 높은 것으로 보고되었습니다(Coughlin, 2018). 유방 종양은 오래된 기질 세포와 종양 세포로 구성된 매우 복잡한 구조입니다. 암종 관련 섬유아세포(CAF)는 일반적으로 암 기질에서 혈관 및 종양 성장을 촉진하는 것으로 보고되었습니다. 산화 스트레스의 영향을 받으면 섬유아세포가 활성화되어 근섬유아세포가 됩니다. 이 세포는 수축성과 이동성이 뛰어나며 중간엽 마커를 더 자주 발현합니다. CAF의 활성화는 되돌릴 수 없기 때문에 천적에 의해 제거되기 어렵습니다. 유방 종양의 경우 기질 섬유아세포의 약 80%가 활성화된 표현형을 필요로 하며, 이는 향상된 수준의 메탈로프로테아제, 사이토카인 및 성장 인자의 방출로 나타납니다. 또한 과산화수소를 생성하여 상피 세포의 경우 다양한 종양 유발 변화와 활성화된 섬유아세포의 생성을 유도합니다. 산화 스트레스를 받으면 종양 간질은 암세포의 생존과 성장을 지원하는 다양한 영양소를 생성합니다(Jezierska-Drutel 외., 2013).

3.1.1.9 Prostate cancer

Prostate cancer is very common among males in Western nations. This chronic disease is very difficult to diagnose and has very limited treatment options. In vivo and in vitro studies determine oxidative stress as the main factor responsible for the occurrence of chronic prostatitis, prostatic cancer, and benign prostatic hyperplasia. Thus, the cascade of oxidative stress is the potential target for the cure of prostate-related disorders (Roumeguére et al., 2017).

3.1.2 Roles of ROS in the pathophysiology of other diseases

3.1.2.1 Liver diseases

The liver is the second largest organ in the organism’s body. It includes a broad range of vital functions such as storage of material absorbed from the digestive tract, hormone catabolism, synthesis of different compounds like clotting factors, globulin, and albumin and detoxification reactions. In alcoholic individuals, the main organ responsible for the removal of excessive alcohol is the liver and hence alcoholics are more prone to liver damage. Alcohol gets metabolized in the liver and during its metabolism, it generates free radicals. Metabolism of ethanol results in oxidative stress in hepatocytes through the generation of ROS. During metabolism, the molecules of alcohol break down into smaller molecules, which after further reactions leads to the production of ROS in the liver organ (Ceni et al., 2014), Figure 3. Alcohol promotes the production of ROS in various ways: 1) stimulating cytochrome P450s activity, 2) altering certain metal concentrations, 3) decreasing the antioxidants level, 4) directing the conversion of xanthine dehydrogenase (XDO) into xanthine oxidase (XO). These radicals raise peroxidation of lipids which leads to liver disorders such us: 1) Ischemic reperfusion injury (IRI): ROS generated by activated liver cells act as a vital mediator in liver ischemic-reperfusion injury (Zhang W et al., 2007) 2) Alcohol-induced oxidative stress: In ethanol-associated liver disorders, ROS plays an important role (Tan et al., 2020).

FIGURE 3

FIGURE 3. Highlights the impact of ROS in chronic diseases: liver, renal and kidney. Abbreviations and symbols: ↑ (increased), ↓ (decreased), ROS (reactive oxidative species), XDO (xanthine dehydrogenase), XO (xanthine oxidase), DNA (Deoxyribonucleic Acid).

3.1.2.2 Renal diseases

The kidney is greatly vulnerable to alterations induced by ROS because of polyunsaturated fatty acids in the lipids of the kidney (Ander et al., 2003). The renal sources of ROS are leucocytes, fibroblasts, glomerular cells, interstitial cells, vascular cells, and activated macrophages. Oxidative stress played a potent role in various renal diseases such as tubule-interstitial fibrosis, ischemia-reperfusion injury, progressive and acute renal failure, and glomerulosclerosis (Ratliff et al., 2016; Duni et al., 2019), (Figure 3). Oxygen radical results in the following changes: 1) These free radicals result in hypertrophy of tubular cells, 2) Oxygen radical reacts with nitric oxide which is an endothelial vasodilator and inhibits its function. The products generated in this reaction are peroxynitrite (ONOO−) which results from the formation of hydroxyl radical (·OH), which is greatly reactive and results in the alteration of cellular functioning and cause dysfunction of endothelial cells, and 3) Massive generation of O2− may result in proliferation and apoptotic death of epithelial cells (Pacher et al., 2007; Ratliff et al., 2016). Generally, renal patients required regular dialysis and this process undergoes the removal of small antioxidant molecules from the blood. This decreases the protection against reactive species and causes peroxidation of several biomolecules such as lipids. This raised the level of oxidative stress that can further lead to renal complications (Liakopoulos et al., 2017).

3.1.2.2 신장 질환

신장은

신장 지질의 고도 불포화 지방산으로 인해

ROS에 의해 유발되는 변화에 매우 취약합니다(Ander et al., 2003).

신장의 ROS 공급원은

백혈구, 섬유아세포, 사구체 세포, 간질 세포,

혈관 세포 및 활성화된 대식세포입니다.

산화 스트레스는

세뇨관 간질 섬유증, 허혈-재관류 손상, 진행성 및 급성 신부전, 사구체 경화증과 같은

다양한 신장 질환에서 강력한 역할을 합니다(Ratliff 등, 2016; Duni 등, 2019), (그림 3).

활성산소는 다음과 같은 변화를 초래합니다:

1) 이러한 자유 라디칼은 관상 세포의 비대를 초래하고,

2) 산소 라디칼은 내피 혈관 확장제인 산화질소와 반응하여 그 기능을 억제합니다.

이 반응에서 생성되는 생성물은 퍼옥시니트라이트(ONOO-)인데,

이는 반응성이 큰 수산화라디칼(-OH)을 형성하여 세포 기능을 변화시키고 내피세포의 기능 장애를 유발하며,

3) 대량으로 생성되면 상피세포의 증식 및 세포사멸을 초래할 수 있다(Pacher 등, 2007; Ratliff 등, 2016).

일반적으로 신장 환자는 정기적인 투석이 필요하며 이 과정에서 혈액에서 작은 항산화 분자가 제거됩니다. 이는 반응성 종에 대한 보호 기능을 감소시키고 지질과 같은 여러 생체 분자의 과산화를 유발합니다. 이로 인해 신장 합병증을 유발할 수 있는 산화 스트레스 수준이 높아집니다(Liakopoulos et al., 2017).

3.1.2.3 Lung diseases

The lung organ exists in an oxygen-rich environment. Their large blood supply and greater surface area make this organ more susceptible to damage caused by oxidative stress. Exposure to exogenous ROS such as cigarette smoke, airborne particulate matter, and carbonyls/aldehydes, can result in oxidative stress and triggers the inflammation response in the lungs. On another side, an insufficient antioxidant defence mechanism in inflammatory cells, macrophages and lung epithelial cells can also result in high-level production of endogenous ROS in the lung tissues (Park et al., 2009; Pereira and Martel, 2014; Maynard, 2015; Bhatia, 2017). Mitochondria are majorly included in ROS-dependent pathways. Mitochondrial dysfunction also plays an important role in non-energetics pathogenesis and bioenergetics metabolism in different cases of lung disease. The genome of mitochondria acts as a guard to govern the cytotoxic response of pulmonary cells to oxidant stress (Schumacker et al., 2014; Kim et al., 2015). Mitochondria are included in ROS-initiated lung diseases such as lung cancer, chronic airway disease, asbestos, and lung fibrosis. The mitochondrial genome is more sensitive than the nuclear genome. Damage to mitochondrial DNA results in loss of mitochondrial membrane potential, impairment in the electron transport chain, and drives the immune and inflammatory responses (Liu and Chen, 2017), (Figure 3).

3.1.2.4 Neurological disease

Neurodegenerative diseases are a heterogenous group of disorders that are characterized by the extensive loss of neurons. In the case of cerebral ischemia (CI), oxidative stress takes part in neuroinflammatory reactions. In postischemia brains, oxidative stress directs the activation of astrocytes and microglia which brings striking elevation in the inflammatory mediators such as matrix metalloproteases, chemokines, and cytokines and results in the loss of endothelial cell integrity in the brain by upregulating the neutrophil infiltration and cell adhesion molecules. M any studies reported that both nondopaminergic and dopaminergic cells undergo degeneration in the case of Parkinson’s disease. (Kim et al., 2015).

The innate mechanism of PD involves inflammatory responses and a spectrum of oxidative stress that results in neurodegeneration. Loss of dopaminergic neurons involves neuroinflammatory mechanism and oxidative stress through the elevated level of inducible nitric oxide synthase (iNOS) followed by activated astrogliosis, T-cell infiltration, and microglia that leads to the accumulation of NO and O2− free radicals. Overexpression‎ of cyclooxygenase-2 (COX2) is also responsible for dopaminergic neuronal loss via oxidative stress-mediated inflammation. In addition, the increasing level of myeloperoxidase by reactive astrocytes could also raise the level of reactive NO2− and ∙OH radicals that could result in neuronal loss in Parkinson’s disease. Enhanced OS may direct mitochondrial dysfunction, impairment in the DNA repair system, and cellular damage, all of these processes have been regarded as the key factor responsible in the acceleration of the aging process and the initiation of other neurological diseases (Kim et al., 2015).

3.1.2.4 신경계 질환

신경 퇴행성 질환은

뉴런의 광범위한 손실을 특징으로 하는 이질적인 질환 그룹입니다.

뇌허혈(CI)의 경우

산화 스트레스가 신경염증 반응에 관여합니다.

허혈 후 뇌에서 산화 스트레스는

성상세포와 미세아교세포의 활성화를 유도하여

매트릭스 메탈로프로테아제, 케모카인, 사이토카인과 같은

염증 매개체의 현저한 상승을 가져오고

호중구 침윤 및 세포 부착 분자를 상향 조절하여

뇌의 내피 세포 완전성을 잃게 만듭니다.

파킨슨병의 경우

비도파민성 세포와 도파민성 세포 모두 퇴화를 겪는다는 연구 결과도 있습니다. (Kim et al., 2015).

파킨슨병의 선천적 메커니즘은

염증 반응과 신경 퇴행을 초래하는 다양한 산화 스트레스와 관련이 있습니다.

도파민성 뉴런의 손실은

유도성 산화질소 합성효소(iNOS) 수준의 상승을 통한

신경 염증 메커니즘과 산화 스트레스를 수반하고

성상교세포증, T세포 침윤, 미세아교세포가 활성화되어

NO와 활성산소가 축적되는 과정을 거쳐 신경 퇴행을 초래합니다.

사이클로옥시게나제-2(COX2)의 과발현은

산화 스트레스 매개 염증을 통한

도파민성 신경세포 손실의 원인이기도 합니다.

또한,

반응성 성상교세포에 의한 미엘로퍼옥시다아제 수치의 증가는

파킨슨병에서 신경세포 손실을 초래할 수 있는

반응성 NO2 및 ∙OH 라디칼의 수치를 높일 수도 있습니다.

활성산소는

미토콘드리아 기능 장애, DNA 복구 시스템의 손상, 세포 손상을 유발할 수 있으며,

이러한 모든 과정은 노화 과정을 가속화하고

다른 신경 질환을 유발하는 핵심 요인으로 간주되어 왔습니다(Kim et al., 2015).

3.1.2.5 Cardiovascular disease

ROS work as a secondary messenger within the heart as they are indulged in various physiological processes including contraction-excitation, proliferation, and differentiation. However, when the generation of ROS exceeds the level of antioxidant molecules in the heart, oxidative stress arises, which results from heart failure, cell death, hypertrophy, ischemia-reperfusion injury, and cardiac dysfunction. Endogenous ROSs in the heart are produced by uncoupled nitric oxide synthase, monoamine oxidases, cytochrome P450, NADPH oxidase, and xanthine oxidoreductase. ROS are also responsible for the initiation of some problems associated with specific clinical settings, comprising POAF, and chemotherapy-directed cardiotoxicity, as well as in the condition of diabetic cardiomyopathy, which determines a type of heart disorder in diabetic patients in the absence of other complications related to diabetes (D’Oria et al., 2020).

3.1.2.6 Rheumatoid arthritis

Rheumatoid arthritis (RA) is a condition which gives rise to oxidative stress. A 5-fold increase in the concentration of mitochondrial ROS in monocyte and whole blood of RA patients is reported as compared with a healthy individual which suggests that OS has a pathogenic effect in RA. (Ponist et al., 2019; Yadav et al., 2023). Free radicals or reactive species are indirectly associated with joint damage, as they play the role of secondary messenger in the immune and inflammatory response in RA. The exposure of T-cells to raised OS become refractory to different stimuli including those for death and growth and may preserve the abnormal immune response. On the other hand, free radicals directly degrade the joint cartilage by targeting its proteoglycan and restricting its synthesis. Oxidative products of lipid peroxidation, oxidative damage of hyaluronic acid, and oxidation of low-density carbonyl and lipoproteins increment have been observed in RA patients. Raised levels of synovial fluid and 4-HNE have also been determined in the serum of RA patients (Ponist et al., 2019; Yadav et al., 2023).

3.1.2.7 Cataract

A cataract is a partial or complete opacification on or in the human lens or in the capsule, which degrades vision. It is the main cause of reversible blindness in the globe today. It is determined that oxidation is an initial stage in the sequence of steps that lead to cataracts. Researchers have proposed a variety of factors which are related to the onset of cataractogenesis: enhanced permeability of the lens membrane, a decreased function of chaperone related to alpha crystalline, augmented non-enzymatic glycosylation, enhanced lipid peroxidation, and low capacity of antioxidant defence mechanism. These results have shown that the OS plays a major role in the pathogenesis of cataracts, which can be ameliorated and prevented by antioxidant molecules (Kaur et al., 2012).

4 Antioxidants: A brief synopsis

Mizanur Rahaman et al. (2023) Antioxidants work by preventing or delaying the oxidation of chemicals. The initial study on the antioxidant is majorly focused on their application in preventing unsaturated fats from getting rancid. However, the identification of vitamin E, C, and A in the living organism has led to an understandiof ng the function of antioxidants. They are usually divided into non-enzymatic and enzymatic. Among them, there are different types of compounds with different places amodesode of action and varied final effects (Flieger et al., 2021). They act as metal-chelatisynergists synergist, enzyme inhibitor, singscavengersn scavengedecomposerse decomposerdonorsctron donors, hydrogen donor, and radical scavenger (Sharifi-Rad et al., 2022). Both non-enzymatic and enzymatic antioxidants exist in extracellular and intracellular environment to detoxify the ROS. Two main principal mechanisms of action of that described for antioxidants are: The first mechanism is chain breaking in which primary antioxidants donated an electron to the free radicals whereas the second mechanism directs the removal of reactive species initiators (secondary antioxidants) by quenching the catalyst that initiate the chain of reaction. So, antioxidants extra t efonct in biological ssystemswith the help of various mechanisms such as gene expression‎ regulation, co-antioxidants, metal ion chelation, and electron donation (Lobo et al., 2010). Antioxidants are the agent that when available in low concentration in comparison to the oxidizable substrate remarkably reduces or delays the oxidation of the substrate. The organism’s body has developed a different endogenous system to counteract the generation of reactive oxygen intermediates. The endogenous system is further categorized into non-enzymatic and enzymatic groups. The main function of antioxidants is to detoxify the reactive species in the body (Kurutas, 2016). Figure 4 shows the sites of action that are targeted by different antioxidants.

4 항산화제: 간단한 시놉시스

미자누르 라하만 외(2023)

항산화제는

화학물질의 산화를 방지하거나 지연시키는 작용을 합니다.

항산화제에 대한 초기 연구는

주로 불포화 지방이 산패되는 것을 방지하는 데

항산화제를 적용하는 데 초점을 맞추고 있습니다.

그러나

살아있는 유기체에서

비타민 E, C, A가 확인되면서

항산화제의 기능에 대한 이해가 높아졌습니다.

일반적으로 비효소계와 효소계로 나뉩니다.

그중에는

작용 부위와 다양한 최종 효과를 가진

다양한 유형의 화합물이 있습니다 (Flieger et al., 2021).

이들은

금속 킬레이트 시너지제,

효소 억제제,

가수 분해제,

가수 분해제,

수소 기증자,

라디칼 제거제 역할을 합니다(Sharifi-Rad et al., 2022).

they act as metal-chelatisynergists synergist, enzyme inhibitor, singscavengersn scavengedecomposerse decomposerdonorsctron donors, hydrogen donor, and radical scavenger

비효소적 항산화제와 효소적 항산화제는 모두

세포 외 및 세포 내 환경에 존재하여

ROS를 해독합니다.

효소적 항산화제 - SOD, Catalase, GPx(glutathione peroxidase)

항산화제에 대해 설명한 두 가지 주요 작용 메커니즘은 다음과 같습니다:

첫 번째 메커니즘은

1차 항산화제가 자유 라디칼에 전자를 기증하는 연쇄 파괴이고,

두 번째 메커니즘은

반응 연쇄를 시작하는 촉매를 소멸시켜

반응성 종 개시제(2차 항산화제)의 제거를 유도하는 것입니다.

따라서

항산화제는

유전자 발현 조절, 보조 항산화제, 금속 이온 킬레이트화 및 전자 기증과 같은

다양한 메커니즘을 통해 생물학적 시스템에 추가적인 효과를 발휘합니다(Lobo et al., 2010).

항산화제는

산화 가능한 기질에 비해 낮은 농도로 존재할 때

기질의 산화를 현저하게 줄이거나 지연시키는 물질입니다.

유기체의 신체는

활성산소 중간체의 생성에 대응하기 위해 다양한 내인성 시스템을 개발했습니다.

내인성 시스템은

비효소 그룹과 효소 그룹으로 더 분류됩니다.

항산화제의 주요 기능은 신체의 반응성 종을 해독하는 것입니다(Kurutas, 2016).

그림 4는 다양한 항산화제가 표적으로 삼는 작용 부위를 보여줍니다.

FIGURE 4

FIGURE 4. Summarized scheme regarding ROS generation at the mitochondrial level.

4.1 Role of endogenous/enzymatic antioxidants

Fortunately, the organism’s body contains a free radical defense mechanism. Every cell releases an antioxidant enzyme which protects the cells during the metabolism of oxygen, and further breaks down the harmful free radicals into balanced molecules like water (Lobo et al., 2010), (Table 2).

4.1 내인성/효소성 항산화제의 역할

다행히도 유기체의 몸에는

자유 라디칼 방어 메커니즘이 있습니다.

모든 세포는

산소 대사 과정에서 세포를 보호하는 항산화 효소를 방출하고

유해한 활성 산소를 물과 같은 균형 잡힌 분자로 분해합니다(Lobo et al., 2010), (표 2).

4.1.1 Superoxide dismutase (SOD)

Living organisms have evolved a system for the scavenging of free radicals and reactive species. Superoxide dismutase carried out the removal of O2•-.

2O∙–2+2H+−−→SODH2O2+O22O2•–+2H+→SOD H2O2+O2

In another step, the hydrogen peroxide generated is eliminated by GPx and catalase system. Various isoenzymes of SOD are indulged in the scavenging activity of free radicals. The first isoenzyme is present in the mitochondria and is Mn2+ dependent whereas another isoenzyme is available in the cytoplasm and is dependent on Cu. Another extracellular Cu-Zn-dependent isoenzyme is also reported. Two different mechanisms have been reported for the SOD action that restricts the transformation 1) It majorly acts at the cell membrane level and eliminate or prevent the generation of radical that can result from the peroxidation of lipid and leads to the chain of extra-nuclear and nuclear events, ultimately cause transformation. This concept explains the model of a membrane that mediates chromosomal aberration, 2) It has been reported that oxygen radicals could be generated in a growth medium and act as a promoter of transformation that will be removed by SOD (Kowald et al., 2006).

4.1.1 슈퍼옥사이드 디스뮤타제(SOD)

생명체는 자유 라디칼과 반응성 종을 제거하는 시스템을 진화시켜 왔습니다.

슈퍼옥사이드 디스뮤타제는

O2--의 제거를 수행합니다.

또 다른 단계에서 생성된 과산화수소는

GPx와 카탈라아제 시스템에 의해 제거됩니다.

SOD의 다양한 동종 효소가

활성산소 제거 활동에 관여합니다.

첫 번째 동종 효소는

미토콘드리아에 존재하며

Mn2+에 의존하는 반면,

다른 동종 효소는 세포질에 존재하며

Cu에 의존합니다.

또 다른 세포 외 Cu-Zn 의존성 이소효소도 보고되었습니다.

변형을 제한하는 SOD 작용에 대해 두 가지 다른 메커니즘이 보고되었습니다.

1) 주로 세포막 수준에서 작용하여 지질의 과산화로 인해 발생할 수 있는 라디칼 생성을 제거하거나 방지하고 핵 외 및 핵 사건의 연쇄를 유도하여 궁극적으로 변형을 유발합니다. 이 개념은 염색체 이상을 매개하는 막의 모델을 설명하며,

2) 성장 배지에서 산소 라디칼이 생성되어 SOD에 의해 제거되는 형질 전환 촉진제로 작용할 수 있다고 보고되었습니다 (Kowald et al., 2006).

4.1.2 Catalase (CAT)

Catalase is present exclusively in peroxisomes. The purified form of catalase contains four subunits of protein, each of which has a heme (Fe III-protoporphyrin) group attached to its active site. Catalase is reported to play a dual role (Nandi et al., 2019).

4.1.2 카탈라아제(CAT)

카탈라아제는

퍼옥시좀에만 존재합니다.

정제된 형태의 카탈라아제는

4개의 단백질 서브유닛으로 구성되어 있으며,

각 서브유닛에는 활성 부위에 헴(Fe III-프로토포르피린) 그룹이 부착되어 있습니다.

카탈라아제는

이중 역할을 하는 것으로 보고되고 있습니다(Nandi et al., 2019).

DNA cleavage by X-ray and mitomycin C induced malignant transformation which was found to be suppressed by the catalase enzyme. According to some studies, factors such as brain-derived neurotrophic factor (BNDF) and stress are responsible for the antioxidant activity of several endogenous antioxidants (Lobo et al., 2010). The mice with BNDF deficiency under the stress circumstances showed increased activity of catalase enzyme in comparison to the stressed wild type. This indicates that the capacity to scavenge free radicals was reduced and this determines that the normal wild type has better tolerance capability than the BNDF heterogeneous mice (Hacioglu et al., 2016).

엑스레이와 미토마이신 C에 의한 DNA 절단은 카탈라아제 효소에 의해 억제되는 것으로 밝혀진 악성 형질 전환을 유도했습니다. 일부 연구에 따르면 뇌유래신경영양인자(BNDF) 및 스트레스와 같은 요인이 여러 내인성 항산화 물질의 항산화 작용을 담당합니다(Lobo et al., 2010). 스트레스 상황에서 BNDF가 결핍된 생쥐는 스트레스를 받은 야생형에 비해 카탈라아제 효소의 활성이 증가한 것으로 나타났습니다. 이는 자유 라디칼을 제거하는 능력이 감소했음을 나타내며, 이는 정상 야생형이 BNDF 이질성 마우스보다 내성 능력이 더 우수하다는 것을 결정합니다 (Hacioglu et al., 2016).

4.1.3 Glutathione systems

The system of glutathione includes glutathione-S-transferase, glutathione peroxidase, glutathione reductase, and glutathione. This system is reported in microorganisms, plants and animals. Glutathione peroxidase is an enzyme that contains 4 units of selenium as cofactors which catalyzes the breakdown of organic hydroperoxides and hydrogen peroxides. About four different isoenzymes of glutathione peroxidase are reported in animals. Glutathione peroxidase 1 is the efficient scavenger of hydrogen peroxide while glutathione peroxidase 4 is found to be more effective with lipid hydroperoxides. The glutathione S-transferase shows greater activity with lipid peroxides. These enzymes are present at high concentrations in the liver and also help in the metabolism of detoxification (Lobo et al., 2010).

Glutathione is a non-protein thiol that coordinates the processes of antioxidant defense in the body. Alterations in the status of glutathione have been reported to cause several complications. Administration of thiol compounds such as methionine, cysteine, and glutathione are known to protect against oxidative stress in animals and humans. The reduced form of thiols has been utilized for the recycling of other antioxidants such as vitamin C and vitamin E (Noctor et al., 2011).

4.1.3 글루타치온 시스템

글루타치온 시스템에는

글루타치온-S 전이 효소,

글루타치온 퍼옥시다제,

글루타치온 환원 효소 및

글루타치온이 포함됩니다.

glutathione-S-transferase,

glutathione peroxidase,

glutathione reductase, and

glutathione

이 시스템은 미생물, 식물 및 동물에서 보고되고 있습니다.

글루타티온 퍼옥시다아제는

4단위 셀레늄을 보조 인자로 포함하는 효소로

유기 과산화수소와 과산화수소의 분해를 촉매하는 효소입니다.

organic hydroperoxides and

hydrogen peroxides

동물에서 보고된 글루타치온 퍼옥시다아제의 동종 효소는 약 4가지입니

글루타티온 퍼옥시다제 1은

과산화수소를 효율적으로 제거하는 반면,

글루타티온 퍼옥시다제 4는

지질 과산화수소에 더 효과적인 것으로 밝혀졌습니다.

글루타치온 S-전달효소는

지질 과산화물에서 더 큰 활성을 보입니다.

이 효소는 간에서 고농도로 존재하며 해독 대사를 돕습니다 (Lobo et al., 2010).

글루타티온은

신체의 항산화 방어 과정을 협응력있게 조정하는

비 단백질 티올입니다.

글루타치온 상태의 변화는

여러 가지 합병증을 유발하는 것으로 보고되었습니다.

메티오닌, 시스테인, 글루타치온과 같은 티올 화합물의 투여는

동물과 사람의 산화 스트레스로부터 보호하는 것으로 알려져 있습니다.

환원된 형태의 티올은

비타민 C 및 비타민 E와 같은 다른 항산화 물질의 재활용에 활용되었습니다(Noctor et al., 2011).

4.1.4 Glucose-6-phosphate dehydrogenase

Protection against OS is largely depending upon the reductive power of NADPH, whose level is eval‎uated with the help of glucose-6-phosphate dehydrogenase (G6PD). Animal cells contain few enzymes that can generate NADPH, and among them, G6PD is the most important one (Peters and Van Noorden, 2009). G6PD catalysis is the rate-limiting step of the pentose phosphate pathway (PPP), which provide nucleotide precursors for DNA replication, as well as reductive power to NADPH for the detoxification of ROS and de novo synthesis of lipid (Stanton, 2012). The relation of PPP and G6PD in the detoxification of ROS is determined by the fact that mice deficient in G6PD have higher levels of oxidative damage in the brain. Animal cells also respond against oxidative stress by enhancing their PPP-directed NADPH production. The overexpression‎ of G6PD in Drosophila melanogaster protects against oxidative stress and can also expand their lifespan (Nóbrega-Pereira et al., 2016).

4.1.4 글루코스-6-포스페이트 탈수소효소

OS에 대한 보호는

글루코스-6-포스페이트 탈수소효소(G6PD)의 도움으로 수준을 평가하는

NADPH의 환원력에 크게 의존합니다.

동물 세포에는 NADPH를 생성할 수 있는 효소가 거의 없으며, 그중에서도 G6PD가 가장 중요한 효소입니다(Peters and Van Noorden, 2009). G6PD 촉매는 펜토오스 인산염 경로(PPP)의 속도 제한 단계로, DNA 복제를 위한 뉴클레오티드 전구체를 제공할 뿐만 아니라 ROS의 해독과 지질의 신규 합성을 위한 NADPH로의 환원력을 제공합니다(Stanton, 2012). ROS 해독에서 PPP와 G6PD의 관계는 G6PD가 결핍된 마우스가 뇌에서 더 높은 수준의 산화적 손상을 보인다는 사실에 의해 결정됩니다. 동물 세포는 또한 PPP에 의해 유도된 NADPH 생성을 강화하여 산화 스트레스에 대응합니다. 초파리에서 G6PD의 과발현은 산화 스트레스로부터 보호하고 수명을 연장할 수 있습니다(Nóbrega-Pereira et al., 2016).

4.2 Role of exogenous antioxidants

4.2.1 Vitamins and selenium

Exogenous antioxidants like vitamins E, C, and A played a supporting role. They scavenge the free radicals and reactive species by donating an electron and maintaining a chemical balance. These dietary agents get saturated easily, only once as they donate the electron (Table 1).

4.2 외인성 항산화제의 역할

4.2.1 비타민과 셀레늄

비타민 E, C, A와 같은 외인성 항산화제는

보조적인 역할을 합니다.

이들은 전자를 기증하고

화학적 균형을 유지함으로써

자유 라디칼과 반응성 종을 제거합니다.

이러한 식이 보조제는 전자를 한 번만 기증하면 쉽게 포화 상태가 됩니다(표 1).

TABLE 1

TABLE 1. Classification of major antioxidants and their roles.—this Table must totally re-written/updated according to the reviewer 3 comments.

4.2.1.1 Vitamin E

Vitamin E (alpha-tocopherol) is considered to be an important antioxidant that involves in the chain-breaking process in the case of humans. Vitamin E is present within the cell membrane to interrupt the peroxidation of lipid and also play a major role in the modulation of cell signaling pathways that are dependent on reactive oxygen intermediates (ROI). They also can directly scavenge the reactive species, including •OH, O2•-, and 1O2 (Traber and Atkinson, 2007). Vitamin E also plays a potent role in decreasing the cases of cancer. It functions by donating the hydrogen atom to fatty peroxyl radicals and disrupting the lipid peroxidation process. It also has the potential to make a reaction with two peroxyl radicals as shown below:

4.2.1.1 비타민 E

비타민 E(알파-토코페롤)는

인간의 경우 연쇄 파괴 과정에 관여하는 중요한 항산화 물질로 간주됩니다.

비타민 E는

세포막 내에 존재하여 지질의 과산화를 방해하고

활성 산소 중간체(ROI)에 의존하는 세포 신호 경로를 조절하는 데 중요한 역할을 합니다.

또한 -OH, O2-- 및 1O2를 포함한

반응성 산소종을 직접 제거할 수 있습니다(Traber and Atkinson, 2007).

비타민 E는

암 발생을 줄이는 데도 강력한 역할을 합니다.

비타민 E는

수소 원자를 지방 과산화 라디칼에 기증하고

지질 과산화 과정을 방해하는 기능을 합니다.

또한 아래 그림과 같이 두 개의 퍼옥실 라디칼과 반응할 수 있는 잠재력을 가지고 있습니다:

The vitamin E synthesized in Equation assumes to have a resonance-stabilized conformation which allows this vitamin to react with other peroxyl radicals to form a stable adduct, LOO-α-tocopherol. Alpha-tocopherol restricts the generation of new free radical whereas gamma-tocopherol neutralizes or trap the existing reactive species. OS has been associated with various possible diseases but rather vitamin E helps to delay or prevent the chronic ailments associated with free reactive molecules (Traber and Stevens, 2011).

식에서 합성된 비타민 E는 다른 과산화 라디칼과 반응하여 안정적인 부가물인 LOO-α-토코페롤을 형성할 수 있도록 공명 안정화된 형태를 갖는다고 가정합니다. 알파-토코페롤은 새로운 활성산소의 생성을 제한하는 반면 감마-토코페롤은 기존의 활성산소를 중화하거나 가두어 둡니다. 활성산소는 다양한 질병과 연관되어 있지만 오히려 비타민 E는 활성산소와 관련된 만성 질환을 지연시키거나 예방하는 데 도움이 됩니다(Traber and Stevens, 2011).

4.2.1.2 Vitamin C

Uric acid, cysteine, glutathione, and vitamin C (ascorbic acid) work as a hydrophilic scavenger of oxygen radicals (Lobo et al., 2010). Natural ascorbate restricts the carcinogenic process of various nitroso compounds, fed to animals by converting them to an inactive form. This vitamin C can be utilized to detoxify the different organic compounds in vivo by a simple reduction process (Combet et al., 2007). Ascorbic acid is a potent scavenger and reducing agent of reactive species in the biological system. It is included in the first line of ddefenceof antioxidants, protecting the proteins and lipid membrane from damage (Pehlivan, 2017). Due to its water-soluble nature, vitamin C can work both outside and inside the cells and can neutralize the free reactive species to avoid any damage. This vitamin works as an excellent source of electrons for the reactive species that are finding out an electron to acquire their stability. They can donate electrons to those free radicals and scavenge their reactivity (Padayatty and Levine, 2016). Cysteine is the physiological precursor of glutathione (GSH) and has been known widely for its protective function against mutagenesis and radiation. Vitamin C or ascorbic acid reacts with singlet oxygen (1O2), peroxyl radical (ROO•), hydrogen peroxide (H2O2), and hydroxyl radical (OH), to form the dehydroascorbate A) and semidehydroascorbate radical (A‾) as shown in equation below (Phaniendra et al., 2015).

4.2.1.2 비타민 C

요산,

시스테인,

글루타치온,

비타민 C(아스코르브산)는

산소 라디칼의 친수성 제거제로 작용합니다(Lobo et al., 2010).

Uric acid,

cysteine,

glutathione, and

vitamin C (ascorbic acid) work as a

hydrophilic scavenger of oxygen radicals

천연 아스코르브산염은

동물에게 먹이는 다양한 니트로소 화합물의 발암 과정을 비활성 형태로 전환하여

발암을 제한합니다. 이 비타민 C는 간단한 환원 과정을 통해 생체 내 다양한 유기 화합물을 해독하는 데 활용될 수 있습니다(Combet et al., 2007).

아스코르브산은

생물학적 시스템에서 반응성 종의 강력한 청소 및 환원제입니다.

그것은

단백질과 지질막을 손상으로부터 보호하는

항산화제의 첫 번째 라인에 포함되어 있습니다 (Pehlivan, 2017).

수용성 특성으로 인해 비타민 C는

세포 외부와 내부에서 모두 작용할 수 있으며

자유 반응성 종을 중화하여 손상을 방지 할 수 있습니다.

이 비타민은 안정성을 얻기 위해 전자를 찾는 반응성 종에게 훌륭한 전자 공급원으로 작용합니다. 시스테인은 활성산소에 전자를 기증하여 활성산소의 반응성을 제거할 수 있습니다(Padayatty and Levine, 2016). 시스테인은 글루타치온(GSH)의 생리적 전구체이며 돌연변이 유발 및 방사선에 대한 보호 기능으로 널리 알려져 있습니다. 비타민 C 또는 아스코르브산은 아래 식과 같이 단일 산소(1O2), 퍼옥실 라디칼(ROO-), 과산화수소(H2O2), 수산화 라디칼(OH)과 반응하여 탈하이드로아스 코르 베이트 A) 및 반하이드로아스 코르 베이트 라디칼(A‾)을 형성합니다(Phaniendra et al., 2015).

AH−+∙OH−−→VitCH2O+A∙ˉAH−+•OH →Vit C H2O+A•‾

AHˉ+1O2+H+−−→VitCH2O2+A∙−AH‾+1O2+H+ →Vit C H2O2+A•−

AHˉ+ROO∙−−→VitCRH+A∙ˉAH‾+ROO• →Vit C RH+A•‾

AHˉ+H2O2+H+−−→VitC2H2O+AAH‾+H2O2+H+→Vit C 2H2O+A

4.2.1.3 Vitamin A

Vitamin A and ß-carotene are important antioxidants as they interfere with the process of peroxidation. ß-Carotene is also found to be useful in decreasing the incidence of cancer. Two major functions of ß-carotene are the ability to neutralize and trap certain organic free radicals and to deactivate the oxygen radicals present in exciting form, produced as a byproduct of metabolic reactions (Fiedor and Burda, 2014). The consistent and strongest conformation regarding the protective effect of large consumption of carotene-rich food comes from studies of the esophagus and lung cancer (Patel et al., 2018). ß-Carotene act as an antioxidant under low oxygen tension and can also act as a prooxidant under more oxidizing and high concentration level in the case of smokers (Tapiero et al., 2004).

The reaction of ß-carotene (CAR) with lipid peroxyl radicals (LOO•) to form various carbon-centred radicals such as (LOO)2-CAR-(OOL)2) (LOO)2-CAR-OOL•, LOO-CAR-OOL, and LOO-CAR• is represented in equation.

4.2.1.3 비타민 A

비타민 A와 ß-카로틴은

과산화 과정을 방해하는 중요한 항산화제입니다.

ß-카로틴은 암 발생률을 낮추는 데도 유용한 것으로 밝혀졌습니다. ß-카로틴의 두 가지 주요 기능은 특정 유기 자유 라디칼을 중화 및 포획하는 능력과 대사 반응의 부산물로 생성되는 흥분된 형태로 존재하는 산소 라디칼을 비활성화하는 능력입니다(Fiedor and Burda, 2014). 카로틴이 풍부한 식품의 다량 섭취에 따른 보호 효과에 관한 일관되고 가장 강력한 정합성은 식도암과 폐암에 대한 연구에서 비롯됩니다(Patel et al., 2018). ß-카로틴은 낮은 산소 장력 하에서 항산화제로 작용하며 흡연자의 경우 더 산화되고 고농도 수준에서 항산화제로 작용할 수도 있습니다 (Tapiero et al., 2004).

ß-카로틴(CAR)이 지질 과산화 라디칼(LOO-)과 반응하여 (LOO)2-CAR-(OOL)2) (LOO)2-CAR-OOL-, LOO-CAR-OOL 및 LOO-CAR-와 같은 다양한 탄소 중심 라디칼을 형성하는 것을 식으로 나타낼 수 있습니다.

CAR+LOO∙−−−→β−caroLOO−CAR∙CAR+LOO• →β−caro LOO−CAR•

LOO−CAR∙+LOO−−−→β−caroLOO−CAR−OOLLOO−CAR•+LOO →β−caro LOO−CAR−OOL

LOO−CAR−OOL+LOO∙2−−−→β−caro(LOO)2−CAR−OOL∙LOO−CAR−OOL+LOO2•→β−caro LOO2−CAR−OOL•

(LOO)2−CAR−OOL∙+LOO∙−−−→β−caro(LOO)2−CAR−(OOL)2LOO2−CAR−OOL•+LOO•→β−caro LOO2−CAR−OOL2

A sole molecule of ß-carotene is determined to eliminate around 1,000 of singlet oxygen with the help of a physical mechanism which involves the transfer of energy before it gets oxidized and loses its antioxidant activity (Tan et al., 2018). The rate of ß-carotene oxidation is dependent upon the partial pressure of oxygen. The carbon-centred radicals get resonance stabilized when the oxygen pressure is lowered. The balanced reaction rapidly shifts to the left side to lower the concentration of peroxyl radicals (LOO•), and the autooxidation rate of ß-carotene get reduced (Iannone et al., 1998). The ß-carotene activity towards peroxyl radicals and the stability of other carbon-centred radicals are the two main features that provide the carotene molecule with its antioxidant properties (Fiedor and Burda, 2014).

ß-카로틴의 단일 분자는 산화되어 항산화 활성을 잃기 전에 에너지 전달을 포함하는 물리적 메커니즘을 통해 약 1,000개의 단일 산소를 제거하는 것으로 결정됩니다(Tan et al., 2018). ß-카로틴 산화 속도는 산소의 분압에 따라 달라집니다. 탄소 중심의 라디칼은 산소 분압이 낮아지면 공명 안정화됩니다. 균형 잡힌 반응은 빠르게 왼쪽으로 이동하여 과산화 라디칼(LOO-)의 농도를 낮추고 ß-카로틴의 자가 산화 속도를 감소시킵니다(Iannone et al., 1998). 퍼옥실 라디칼에 대한 ß-카로틴의 활성과 다른 탄소 중심 라디칼의 안정성은 카로틴 분자에 항산화 특성을 제공하는 두 가지 주요 특징입니다(Fiedor and Burda, 2014).

4.2.1.4 Selenium

Selenium is a natural element which has gained focus due to its potential to decrease the process of carcinogenesis. The antioxidant activity of selenium concerning vitamin C was studied broadly (Tan et al., 2018). Deficiency of selenium results in the consequent cellular and tissue damage raised peroxidation of lipids and leads to the formation of free radicals. Damage caused to unsaturated fatty acids in the subcellular membrane by peroxidation reaction can be reduced by Se and vitamin E (Mourente et al., 2007). The metabolisms of Se and vitamin E are interrelated and Se plays a major role in vitamin E storage.

4.2.1.4 셀레늄

셀레늄은 발암 과정을 감소시킬 수 있는 잠재력으로 인해 주목을 받고 있는 천연 원소입니다. 비타민 C와 관련된 셀레늄의 항산화 활성은 광범위하게 연구되었습니다(Tan et al., 2018). 셀레늄 결핍은 결과적으로 세포 및 조직 손상을 초래하여 지질의 과산화를 증가시키고 자유 라디칼을 형성합니다. 과산화 반응에 의한 세포하막의 불포화 지방산 손상은 Se와 비타민 E에 의해 감소될 수 있습니다(Mourente et al., 2007). Se와 비타민 E의 대사는 서로 연관되어 있으며 Se는 비타민 E 저장에 중요한 역할을 합니다.

4.2.2 Natural antioxidants

4.2.2.1 Phenolic compounds

Phenolic compounds are a heterogenous group of phytocompounds that are broadly spread in the plant kingdom (Chaudhary et al., 2023). Flavonoid belongs to a class of naturally occurring polyphenolic compounds and they provide different colors to leaves, fruit, and flower (Chaudhary et al., 2023). Flavonoids are further divided into the following classes: anthocyanidins, flavones, flavonols, flavanones, and flavonols. Among the classes, variations are based on the arrangement and number of hydroxyl groups, and glycosylation or alkylation of these groups. The broad varieties of flavonoids and the greatest difference in their content make it difficult to determine the daily intake estimate of flavonoids (Panche et al., 2016). Phenolics and flavonoids act as an antioxidant through several pathways The most potent one is likely to be by scavenging the free radicals in which polyphenols carried out the breakdown of several free radical chain reactions (Kaurinovic and Vastag, 2019). For a molecule to act as an antioxidant, it must fulfil the two criteria.

(i) at low concentrations, it can prevent the oxidation of the substrate

(ii) the radical generated on the polyphenols must be stable enough so that it can prevent itself from acting as a chain-propagating radical (Dangles, 2012).

This stabilization is usually through intramolecular hydrogen bonding and delocalization or by reaction with other lipid radicals and further oxidation. A large number of investigations have been done on the structure-antioxidant activity relationship of flavonoids (Table 2). Some of the common ones are flavanol, flavonoid, and quercetin which are abundant in onion, broccoli, and apple; catechin, another flavanol present in different tea and fruits; naringenin, the major flavanone in grapefruit; glycitein, genistein, and daidzein are the major isoflavanones in soybean; and cyanogen glycosides are abundant in blackberry, raspberry, and black currant.

TABLE 2

TABLE 2. The role of natural antioxidants in the chemoprevention of cancer.

4.2.2.2 Curcumin

Curcumins target free radicals through various mechanisms. It can restrict the activation of ROS-producing enzymes such as xanthine oxidase/hydrogenase, and cyclooxygenase/lipoxygenase, it can modulate the activity of SOD, catalase, and GSH enzymes for the neutralization reaction, and it can also have the ability to scavenge the reactive nitrogen and oxygen species. Additionally, curcumin is a lipophilic molecule, which makes it useful in the scavenging of peroxyl radicals. Therefore, like vitamin E, curcumin is also utilized as a chain-breaking natural agent.

4.2.2.3 Tannins

Tannin is the common name for phenolic molecules that are used for tanning leather and the precipitation of gelatin from solution. They are further categorized into the condensed form of proanthocyanidins, in which the main structural unit is the phenolic flavan-3-ol nucleus and hexahydroxydiphenoyl and galloyl ester and their derivatives, ellagitannins and gallotannins (Clifford and Scalbert, 2000). The two main groups of phenolic acids are hydroxycinnamic acid and hydroxybenzoic acid, both of which are obtained from cinnamic acid and benzoid molecule, respectively (Kumar and Goel, 2019). These phenolic acids contain benzoic acid derivatives such as cinnamic acid derivatives (ferulic, caffeic and coumaric acid) and gallic acid. Caffeic acid is majorly found in vegetables and fruits, most commonly esterified with quinic acid as in chlorogenic acid, the main phenolic in coffee. Another common phenolic acid is ferulic acid which is esterified with hemicellulose and present in cereals (Dai and Mumper, 2010).

4.2.2.4 Phenolic acids

4.2.2.4.1 Caffeic acid

Caffeic acid is produced by different plant species and is found to be available in various food products such as tea, wine, and coffee and other medicines such as propolis. Phenolic acid and its derivatives have anticarcinogenic, anti-inflammatory, and antioxidant activities. In vivo and in vitro investigations have determined the anticarcinogenic property of this agent in the case of hepatocarcinoma, which is considered to be a highly aggressive form of cancer, responsible for the large rate of mortality across the globe. The anticancer activity of this compound is related to its pro-oxidant and antioxidant capacity due to its complex structure including double bond in the carbonic chain, the position and number of OH group and free phenolic hydroxyl in the catechol group, respectively (Kiokias et al., 2020). The pharmacokinetic investigation determined that this compound is being hydrolyzed by the microbial colonies and metabolized in the mucosa of the intestine through phase II enzymes, submitted to methylation and conjugation process, forming methylated, glucuronic, and sulphated conjugates by the action of o-methyltransferase, UDP-glucosyltransferases, and sulfotransferases, respectively (Monteiro Espindola et al., 2019). The transmembrane flux of this compound in intestinal cells occurs via the active transport carried out by the carriers of monocarboxylic acid. It can act by suppressing the expression‎ of MMP-9 and MMP-2, blocking STATs, reducing the angiogenesis of tumor cells, inducing the oxidation of DNA of tumor cells, and preventing the generation of ROS (Monteiro Espindola et al., 2019).

4.2.2.4.2 Gallic acid

Gallic acid exerts its antioxidant effects by modulating the pro-oxidant/anti-oxidant balance. It can induce apoptosis, autophagy, and cell cycle arrest via activating the ROS generation and caspase pathway. Additionally, they can restrict metastasis and invasion by reducing the activity and expression‎ of matrix metalloproteinase (Kahkeshani et al., 2019).

4.2.2.4.3 Ferulic acid

The antioxidant activity of ferulic acid is very complex. It is majorly based on the restriction of RNS and ROS formation and neutralization of free radicals. This compound also acts as a hydrogen donor; donating atoms directly to free radicals. This acid is found to be important for the protection of lipidic acids in the cell membrane from the unwanted autoxidation process. As a secondary compound, ferulic acid and its derivatives can bind with copper and iron and avoid the generation of toxic hydroxyl radicals, which direct cellular damage (Zduńska et al., 2018).

4.2.2.4.4 Carnosic acid

This acid is extracted from Rosmarinus and Salvia species and reported with various antioxidant and functional properties. It is most commonly used in the pharmaceuticals and cosmetic sector. In vitro experimental investigation, it has been observed that the administration of 20 μg/mL of Car A resulted in the cure of breast cancer via the activation of apoptotic and antioxidant genes (Einbond et al., 2012).

4.2.2.4.5 p-Coumaric acid

This acid is most commonly found in cereals, vegetables and fruits. It acts as a potent antioxidant and scavenges free radicals and reactive species. p-coumaric acid is a phenolic acid and is a hydroxyl derivative of cinnamic acid. It reduces the prefigure oxidation of low-density lipoprotein and decreases the risk of stomach cancer (Kiliç and Yeşiloğlu, 2013).

4.2.2.5 Stilbenes

Stilbenes comprise two phenyl moieties which are connected by the methylene bridge of two carbon atoms. The availability of stilbenes in an organism’s diet is very low. Majorly these compounds act as an antifungal phytoalexin, the compound which is synthesized in response to injury. One of the widely known stilbenes is resveratrol, found majorly in grapes. Products of red wine and grapes contain a significant amount of resveratrol, respectively (Rocha-González et al., 2008).

4.2.2.6 Lignans

Lignans are the phenolic compounds and have 2,3-dibenzylbutane structures that is resulted from the dimerization of two cinnamic acid residues; lignans such as secoisolariciresinol are considered phytoestrogen. The increasing interest in the beneficial effect of phenolic compounds has resulted in the development of such diets that are rich in vegetables and fruits and provide protection against cancer and cardiovascular diseases. The linseed act as a source which provides secoisolariciresinol (up to 3.7 g/kg dry weight) and a low amount of mataresinol, respectively (Milder et al., 2005).

4.2.2.7 Alkaloids

Erythroxylum cuneatum, a tropical flowering plant of the Erythroxylaceae family utilized in Thailand and Malaysia as traditional medicine. The alkaloid extract of E. cuneatum leaf possesses both anti-inflammatory and antioxidative activity suggesting its role in the development of anti-inflammatory and antioxidant drugs (Li S et al., 2015). Two isoquinoline alkaloids kareemine 2) and iraqiine 1), along with N-methylouregidione 7), atherospermidine 6), O-methylmoschatoline 5), kinabaline 4), and muniranine 3) were isolated from the dichloromethane extract of Alphonsea cylindrica bark. Compounds 4, 3, and 1 possess higher DPPH scavenging activity (Obaid Aldulaimi et al., 2019). The antioxidant activity of alkaloid boldine and Peumus boldus extract was reported against Fe(II)-citrate-induced damage in rat liver mitochondria in vitro (Klimaczewski et al., 2014). Stephania rotunda Lour., a Cambodian wild plant utilized in traditional medicine and food for the treatment of fever. The antioxidant activity of fangchinoline and cepharanthine was reported from Stephania rotunda by in vitro assays (Gülçin et al., 2010). The results determined an effective radical scavenging and antioxidant activity of fangchinoline and cepharanthine. Five new alkaloids (1–5) along with two new phenanthrene and three aporphine alkaloids, in total 10 (6–15) compounds were isolated from the roots of Stephania tetandra. Based on electronic circular dichroism, single crystal X-ray, and spectroscopic analysis, compound 13, and 7–10 exhibited great antioxidant activities (Wang R et al., 2020).

4.2.2.8 Terpenoids

Terpenes play an important role in the metabolic processes of a broad range of microorganisms, plants, and animals in which they are formed Naturally, terpenoids can be utilized for different purposes including as key agents in metabolic processes, signaling, and defense (Baccouri and Rajhi, 2021). These terpenes have had applications in medicine, cosmetics, and perfumery for thousands of years and are still procured from different plants for the above-mentioned uses. The antioxidant activities of terpenes may explain their capacity to adjust the neural signal transmission, immunological effects, and inflammation. They protect against oxidative stress situations including ageing, diabetes, neurodegenerative, cardiovascular disease, cancer, liver, and renal mechanisms (Baccouri and Rajhi, 2021). Bourgou et al. (2012) reported the antioxidant activity of isolated terpenoids from Tunisian Nigella sativa L. essential oils and also their ability in restricting the production of nitric oxides. The chemical characterization and antioxidant activity of essential oils isolated from Euphorbia heterophylla L. (Elshamy et al., 2019) and their allelopathic potential were reported against Cenchrus echinatus L. Sesquiterpenes-rich essential oil isolated from the above parts of Pulicaria somalensis showed great antioxidant activity and allelopathic effect against weeds (Assaeed et al., 2020). In a study to determine the antitumor effects of terpenoids, it was found that paclitaxel, geraniol, and perillyl alcohol are the terpenoids with better anticancer activities (Yang et al., 2020). The anti-inflammatory activity of paeoniflorin and its derivatives, 4-O-methylbenzoyl paeoniflorin, 4-O-methyl paeoniflorin, and other monoterpenes was reported (Bi et al., 2017). The results reported that most of these monoterpenes can inhibit the production of tumor necrosis factor-alpha (TNF-α), interleukins-6 (IL-6), and inflammatory factor nitric oxide (NO) induced by lipopolysaccharides (LPs).

5 Antioxidants: Mode of action and molecular mechanisms

The mode of action of antioxidants can be explained by the following routes.

5.1 Preventive antioxidants

ROS such as OH, O2•, and H2O2 are generated irreversibly during the process of metabolism. Other free radicals such as ROOH, and organic hydroperoxide are generated by the reaction of radicals with the cellular components such as nucleobases and lipids. The RO, ROO. peroxyl, and alkoxy radicals are oxygen centered organic types of radicals. Lipids form take part in the peroxidation reaction of lipids. They are generated in the presence of oxygen by abstraction of hydrogen and addition of radicals to double bonds. Hypochlorous acid or HOCl are generated from hydrogen peroxide in the presence of myeloperoxidase. They are highly reactive and readily oxidized protein constituents such as methionine, amino groups, and thiol groups. Peroxynitrite radical is generated in a reaction of superoxide with nitric oxide. The protonation reaction results in the formation of peroxynitrous acid which undergo hemolytic cleavage to form nitrogen dioxide and hydroxyl radicals (Lobo et al., 2010). Therefore, various methods have been applied to decrease the damage caused by oxidative stress. Endogenous antioxidant enzymes which are generated inside the cells work as a protective mechanism against reactive free species. Heme oxygenase, reductase, thioredoxin, GST, GR, GPx, CAT and SOD are the most vital antioxidant enzymes. The SOD carried out the conversion of O2•– into H2O2, which is further converted into H2O with the help of the Fenton reaction, GPx, and CAT. Thus, there is a conversion of toxic species to the harmless product. Peroxides generated during the process of metabolism, get eliminated by GPx and GST. GRd is found to be useful to maintain the equivalent of oxidized glutathione (GSSG) and GSH, as the ratio of GSSG/GSH is an indicator of oxidative stress. So, GRd functions by raising the concentration of GSH, which is required for the maintenance of oxide-redox conditions in a living organism. The GPx is available throughout the cells whereas CAT is restricted to the peroxisome. The brain is very sensitive towards the damage caused by free radicals so; it contains 7 times more concentration of GPx than the CAT. The greatest level of CAT is found in erythrocytes, kidneys, and the liver, where it decomposes most of the hydrogen peroxide (Aziz et al., 2019).

5.2 Free radical scavengers

The utilization and consumption of oxygen in physiological processes result in the production of ROS. The production of energy in mitochondria is dependent upon the metabolism of oxygen since oxygen gets reduced to water. During the transfer of electrons through a pathway, incomplete reduction of oxygen can result in the production of highly damaging and reactive ROS, such as hydroxyl radical, hydrogen peroxide, singlet oxygen and superoxide radicals The toxicity of superoxide radicals can be diminished with the help of metalloenzyme SOD which catalyzes the reduction of O2•- to O2 and H2O2. Other antioxidant agents such as green tea extract are also capable of reducing the damage resulting from superoxide radicals. Hydroxyl radicals are generally formed from the Cu+/H2O2 or Fe2+ Fenton reaction system via incubation of H2O2 and FeSO4 in an aqueous solution. These radicals are found to be toxic to macromolecules such as proteins, lipids, and DNA. The application of various polyphenol and polyene from different vegetables and fruits protect against the damaging effect of hydroxyl radicals (Lipinski, 2011). Large numbers of metals are responsible for inducing carcinogenicity and toxicity in the animal body. An excessive amount of iron in the body leads to cancer, vascular diseases and other neurological complications. Copper at higher concentrations is known to result in metastasis. The complexes of cobalt ion led to the production of ROS which cause heart complications. Research showed that Se can chelate copper ions efficiently and prevent the damage caused to DNA by hydroxyl radicals. The component of red wine binds to high-density lipoprotein (HDL) and low-density lipoprotein (LDL) and protect lipoproteins from metal-independent and meta-dependent lipid and protein oxidation (Ivanov et al., 2001). According to some studies, melanoidin possessed better scavenging and metal-ion chelating activity which were due to its molecular weight (Wu et al., 2021). It has been determined that the major source of free radicals in diverse pathological and physiological circumstances is related to the enzyme number. The enzymes that lead the generation of superoxide include NADPH-dependent oxidase, cyclooxygenase, lipoxygenase, and xanthine oxidase. The production of hydrogen peroxide is catalyzed by the superoxide dismutase enzyme. Various enzymes of peroxisomes such as D-aspartate oxidase, xanthine oxidase, urate oxidase, D-amino acid oxidase and acyl CoA oxidase direct the production of different ROS. Many natural agents have revealed their potential to restrict the enzymes that direct the generation of free radicals as well as in the development of novel therapeutics agents against oxidative stress-induced diseases (Phaniendra et al., 2015). Plant alkaloids such as berberine carried out the inhibition of NADPH oxidase activity via reducing the mRNA expression‎ of gp91phox in macrophages. Similar results were obtained by the treatment with dihomo-γ-linolenic (ω-6) acid, ellagic acid (from nuts and fruits), and 3-(4′-hydroxyl-3′,5′-dimethoxyphenyl) propionic acid (HDMPPA) (from kimchi), (Maraldi, 2013). Eugenol obtained from Ocimum sanctum showed 97% inhibition in the activity of cyclooxygenase at 1000-microM concentration (Kelm et al., 2000).

5.3 Prevention of lipid peroxidation

Lipid peroxidation is damaging due to the production of products which leads to the spread of free radical reactions. The potent function of lipids in the cellular system emphasizes the need to understand the consequences and mechanism of lipid peroxidation in the human body. Polyunsaturated fatty acids (PUFAs) are utilized as the substrate for the peroxidation of lipids due to the presence of active bis-allylic methylene groups. The hydrogen-carbon bonds on these methylene units have very low bond-dissociation energy, making the hydrogen atom to be abstracted easily in the radical reactions (Davies and Guo, 2014). It has been determined that the a-tocopherol is the most suitable antioxidant and protect the membrane from oxidation by reacting with the various lipid radicals generated in the peroxidation chain reaction of lipid. It carried out the removal of free radical intermediates and prevents the continuation of the propagation reaction (Mostafa Abd El-Aal, 2012). Antioxidants such as t-butyl hydroxy anisole (BHA), t-butylhydroxyl toluene (BHT), and vitamin E inhibited the Fe2+/ascorbate-induced peroxidation of lipids in the liver microsome of rats (Reddy and Lokesh, 1992). The natural agent, rosmarinic acid spontaneously penetrates the cell membrane to inhibit the peroxidation of lipids in situ as reported by Fadel et al. (2011).

5.4 Prevention of DNA damage

Oxidative stress is the major reason behind the majority of DNA damage in the case of human beings. Various factors are responsible for the production of free radicals and ROS. The major factors are smoking, junk foods/fried foods, restless life, and lifestyle change (Kaur et al., 2019). Antioxidant agents include external antioxidants and internal antioxidants that can be consumed through a diet to fulfil the natural need of the human body. These agents can scavenge free radicals and prevent further damage (Jamshidi et al., 2018). The fraction obtained from normal and transformed roots of Rhaponticum carthamoides provides DNA repair and antioxidant effect against oxidative stress-induced DNA damage in Chinese hamster ovary (CHO cells); (Skala et al., 2016). The methanolic fraction of Tamarind indica, Adhatoda vasica, Centella asiatica, Pseudomugii furcatus, and Kocuria indica protect against DNA damage. Trans-resveratrol and p-coumaric acid extracted from the ethanolic fraction of germinated peanut also protect against DNA damage (Limmongkon et al., 2019).

5.5 Prevention of protein modification

The oxidation of protein can be induced by several radical species such as hydroperoxyl, alkoxyl, peroxyl, •OH, O2•-, and by some non-radical species as well like OONO−, singlet oxygen, HOCl, O3, and H2O2. The reactive species oxidize the different types of amino acids present in the protein and result in the generation of the protein-protein cross linkage which further results in the denaturation, loss of protein functioning, loss of transport protein and receptor functioning, and loss of enzymatic activity. Hydroxyl radicals are reactive, they can further react with both inorganic and organic molecules like carbohydrates, lipids, proteins, and DNA and results in severe damage to cells (Phaniendra et al., 2015). Both biliverdin and bilirubin exhibited greater antioxidant activity than alpha-tocopherol against peroxynitrite and peroxyl-radical-induced protein oxidation in the brain microsome of rats in vitro (Mancuso et al., 2012).

5.6 Antioxidants’ protective effect against cancer

Chemoprevention of cancer is defined as the reverse process or inhibition of carcinogenesis by the administration of synthetic and natural agents as shown in Table 3. These agents have helped to understand the molecular and cellular levels of carcinogenesis. The chemopreventive agents can be divided into three wide categories.

(i) Those which prevent the generation of procarcinogens from the precursor components e.g., Vit. C, which avoids nitroso compounds formation (Landis-Piwowar and Iyer, 2014).

(ii) Blocking agents: These prevent the cancer casing compounds from interacting with the cellular target e.g., flavones, isothiocyanates, and phenols. Further, blocking agents are sub-categorized into three major categories: those which restrict the activation of carcinogen to its carcinogenic form; those which induce the enzyme system capable of carcinogen detoxification, and those which can react with cancer-causing species and prevent their reaction with the cellular targets (Steward and Brown, 2013; Landis-Piwowar and Iyer, 2014).

(iii) Suppressing agents: These restrict carcinogenesis by suppressing their activity e.g., protease inhibitors, sea salt, and retinoic acid (Usman et al., 2022).

TABLE 3

TABLE 3. Role of antioxidants in the chemoprevention of other diseases.

Antioxidant defence such as the enzymes involved in the DNA damage repair cannot counteract all the oxidants and this results in damage which may lead to mutation and further contribute to carcinogenesis. Dietary antioxidants are ubiquitous and protect plants against oxidative assault and this property of them may be found to be useful in humans in terms of decreasing the risk of cancer. ROS are involved at all stages of tumor development, consequently, dietary agents are found to be protected throughout the stages of carcinogenesis. Citrus fruit is also reported to be beneficial in about 65% of investigational studies. The tumour-inhibitory effects imparted by these plant foods are due to the presence of various antioxidants such as carotenoids, polyphenolics, selenium, vitamin C, vitamin E, and provitamin A, respectively. It is determined that various constituents contribute to the overall protective effect (Bouayed and Bohn, 2010). Lung tumor risk has been reported to be decreased by the consumption of high vegetables and fruits in both retrospective epidemiological and prospective studies (Dela Cruz et al., 2011). Efficient inactivation of both endogenous and xenobiotics toxins results in the restriction of several cytotoxic events, and in the prevention of cellular integrity, which may lead to various diseases. The equilibrium between the phase II detoxifying enzyme and phase I carcinogen-activating enzyme is important to determine an individual’s risk of cancer disease (Wilkinson and Clapper, 1997). The contribution of various families of enzymes such as conjugation catalyzing transferase, hydrolases, peroxidases, reductases, dehydrogenases, and monooxygenases results in protection against different hazardous components like N-nitroso compounds, which are very different in their cellular defense mechanism. Some carcinogens act directly while others need activation (Rendic and Guengerich, 2012). The metabolism of the xenobiotic component is carried by many enzymes that are included in Phase II and I reactions (Jančová and Šiller, 2012). Phase I reactions include hydrolysis, reduction, hydroxylation, and oxidation, which results in water-soluble metabolites and further facilitate their excretion and conjugation. Cytochrome P450-dependent monooxygenase is the broadly studied phase I enzyme that is responsible for xenobiotic metabolism. These enzymes are encoded by the superfamily of CYP genes. In the NADPH monooxygenase system: P450 oxidoreductase transfer the electrons from NADPH to P450 and results in the formation of ferrocytochrome P450 which carried out molecular oxygen activation and one of the atoms of oxygen is added to the substrate molecule (Riddick et al., 2013). Other enzymes of phase I include: reductase, aromatase, dehydrogenase, monoamine oxidase, hydrolase, lipoxygenase, cyclooxygenase, and monooxygenase. The products of phase I reactions act as a substrate for the phase II enzymes but some of the xenobiotics are conjugated directly bypassing the metabolism of phase I. Cytochrome b5 is one of the competitive inhibitors of CytP450 phosphorylation by protein kinase. Thus, b5 has a key role in the activity of cytP450. Mixed function oxidase is the flavin comprising monooxygenase present in the ER and contains one FAD molecule. The endogenous substrate for this is cysteamine and it can oxidize the nucleophilic sulphur and nitrogen atom (Porter, 2002). Detoxification enzymes of phase II compete with the activating enzymes of phase I to restrict the generation of electrophiles and catalyze the conversion of these electrophilic molecules to inactivate conjugates, making them more soluble in water and more easily get excreted from the body. Some of the conjugating reactions are glutathione conjugation, sulfation, and glucuronidation, respectively (Hodges and Minich, 2015).

5.7 Antioxidant’s protective effects against other diseases

The consumption of antioxidants through vegetables and fruits that are determined to be the better source of antioxidants helping in the treatment of cardiovascular diseases. These antioxidants are also utilized in the prevention of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Excessive production of reactive species leads to various pathological diseases such as ulcerogenic, depression, cardiovascular disorders, and rheumatoid arthritis. Antioxidants have been considered to play an important role in the prevention of these diseases. It has been found that antioxidants have a better potential for the treatment of problems related to sexual maturity, male infertility, and nephrolithiasis (Sindhi et al., 2013), (Table 3). Despite of various outcomes reported in vitro and in animal models, some studies are concentrated to humans and the results obtained are represented below in Table.

6 Therapeutic limitations

Natural antioxidant agents have many modes of action and can be useful in preventing diseases without side effects (Chaudhary and Janmeda, 2022b). The availability of antioxidants should be regulated by a prescription from a healthcare professional. Consumers should be advised about the health benefits of antioxidants and be encouraged to eat foods rich in vegetable oils, nuts, seeds, leafy vegetables and fresh fruits, which are the main sources of antioxidants. The main therapeutic limitation is the excessive consumption of antioxidant supplements that can cause side effects because in high concentrations antioxidants can act as pro-oxidants. There is also a significant difference between taking antioxidants from food and administering an isolated substance as a supplement. Many substances that show beneficial effects in the laboratory do not work when they are introduced into the human body. Many antioxidants do not have good bioavailability. The concentration of antioxidants such as polyphenols is sometimes so low in the blood that no significant effect is observed (Del Rio et al., 2013).

7 Conclusion and future perspectives

Free radicals-directed oxidative stress is known to be harmful to the health of a human being. Various experimental studies determine that free radicals contribute towards the progression and inhibition of various pathologies, ranging from cardiovascular disease to cancer. Antioxidants can counteract oxidative stress and mitigate all the effects on human health. These compounds gained a lot of attention from the field of biomedical research as they showed a better degree of efficacy in terms of the cure and prevention of various diseases. Synthetic antioxidants are found to be detrimental to the health of an organism. Therefore, the search for a non-toxic and natural compound with greater antioxidant activity has increased in the last few years. Through the literature survey, we can conclude that oxidative stress should be exploited as a tool for the treatment when and if we would be able to understand the fine-tuning of this phenomenon inside a living body. Newer approaches that utilise modern technology and collaborative research in combination with established conventional health practices can be used in near future for the improvement of health status, especially among individuals who do not have access to costlier therapeutic drugs.

Author contributions

Conceptualization and design were performed by PC, PJ, and JS-R; investigation, data curation, and writing were performed by PC, AD, and BM; validation, review and editing were performed by PJ, BY, AA, DC, and JS-R; supervision PJ, DC, and JS-R; All the authors contributed equally, read and approved the final manuscript. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

We acknowledge the Bioinformatics Centre, Banasthali Vidyapith, supported by DBT and DST for providing computation and networking support through the FIST and CURIE programs at the Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be eval‎uated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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