Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on
Degenerative diseases occur due to the continuous deterioration of cells and tissues that ultimately affects major organs. Both oxidative stress and inflammation are considered major role players in the pathogenesis of chronic degenerative diseases including cardiovascular diseases (CVDs) [
Over the last two decades, tremendous experimental advancements have been made in the use of natural products against different types of degenerative diseases targeting oxidative stress and inflammation [
In this review, we discussed the pathogenesis of CVDs, DM, and RA, which involve the heart, metabolism and the joints, respectively, and we discussed the use of phytochemicals (which are synthesized by fruits, vegetables, and spices) in attenuating the oxidative stress and inflammation associated with these chronic diseases.
The PubMed database was systematically searched to retrieve evidence of potential dietary natural products (fruits, vegetables, and spices) and their active substances (antioxidants, polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) for use against CVDs, DM, and RA by attenuating oxidative stress and inflammation (see Appendix). To retrieve clinical and experimental evidences of dietary phytochemicals associated with CVDs, DM, and RA, only papers published in English between January 2000 and March 2016 were considered.
CVDs are a group of diseases associated with complications of the heart and blood vessels; most are associated with coronary heart disease. Major risk factors of CVDs include hypertension (HTN), hypercholesterolemia, diabetes, obesity, inflammation, smoking, consumption of alcohol, lack of exercise, and a familial history of heart diseases [
CVD is believed to be the major contributor to worldwide mortality and morbidity in both developed and developing countries. In 2012, it was estimated that 17.5 million people died from CVDs, which represents 31% of all global deaths. Among these deaths, it was estimated that 7.4 million were due to coronary heart disease. It has also been predicted that, by 2030, over 28 million people will die from CVDs [
The pathogenesis of CVDs is multifactorial, resulting from the interplay of genetic and environmental factors. However, atherosclerosis, which occurs due to the accumulation of atherosclerotic plaques within the walls of the arteries (Figure
Inflammation and oxidative stress-mediated pathogenesis of (a) cardiovascular disease, (b) diabetes mellitus, and (c) rheumatoid arthritis.
Plaque formation is initiated by endothelial damage and is followed by the adherence of circulating monocytes and subsequent exposure to homocysteine, inflammation, increased platelet aggregation, and higher levels of oxidized low density lipoprotein (LDL-ox) and reactive oxygen species (ROS) [
Additionally, although intact endothelium can prevent smooth muscle proliferation by releasing nitric oxide (NO) when the endothelium is damaged, smooth muscle proliferation and migration are observed from the tunica media into the tunica intima in response to damaged endothelial cell-secreted cytokines. This activity induces the formation of a fibrous capsule covering the fatty streak. Due to calcification in the smooth muscle cells and on the unstable fatty streak, plaque hardening occurs, which further blocks the coronary arteries [
Further, genetic alterations can adversely promote the development of CVDs. Some examples include mutations or allelic variations of the renin-angiotensin pathway, endothelial NO synthase, coagulation factors, and fibrinogen, which can lead to the development of atherosclerosis [
Although there are several synthetic regimens available for treating CVDs, none are free of side effects and limitations (Table
Mechanism of action and side effects of some synthetic regimens used in the treatment of CVD, DM, and RA.
Number | Drugs |
Mechanism | Side effects | Structure |
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1 | Aspirin |
(i) Inhibiting the production of TXA2 by inactivation of COX-1 and COX-2 enzymes | (i) Stomach bleeding |
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2 | Quinapril |
(i) Inhibiting ACE which catalyzes the formation of angiotensin II (a strong vasoconstrictor) | (i) Dizziness |
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3 | Digoxin |
(i) Inhibiting the Na-K-ATPase membrane pump resulting in an increase in intracellular sodium | (i) Dizziness |
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4 | Amlodipine |
(i) Decreasing arterial smooth muscle contractility and vasoconstriction by inhibiting the influx of calcium ions through calcium channels | (i) Dizziness |
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5 | Isosorbide dinitrate |
(i) It is converted into NO which activates the enzyme guanylate cyclase that stimulates the synthesis of cGMP which then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells eventually resulting in vasodilation | (i) Headache |
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1 | Metformin (Glucophage®) | (i) Activating AMPK to inhibit hepatic glucose production |
(i) Lactic acidosis |
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2 | Pioglitazone |
(i) Activating PPAR |
(i) Weight gain |
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3 | Glibenclamide |
(i) Binding and inhibiting the ATP-sensitive potassium channels SUR1 receptor on the pancreatic cell surface, which causes membrane depolarization and opens the calcium channels for insulin exocytosis | (i) Nausea |
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4 | Acarbose |
(i) Reversibly binding to pancreatic |
(i) Diarrhea |
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5 | Human insulin |
(i) Binding to the IR and stimulating the downstream signaling molecules which regulates the GLU4 and PKC activity | (i) Pain |
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1 | Methotrexate |
(i) Inhibiting dihydrofolate reductase which is involved in purine metabolism |
(i) Nausea |
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2 | Hydroxychloroquine |
(i) Inhibiting stimulation of the TLR-9 |
(i) Nausea |
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3 | Sulfasalazine (Azulfidine®) | (i) Inhibiting NF- |
(i) Stomach upset |
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4 | Leflunomide |
(i) Inhibiting mitochondrial enzyme dihydroorotate dehydrogenase and thus inhibiting the reproduction of rapidly dividing cells, especially autoimmune lymphocytes | (i) Diarrhea |
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5 | Certolizumab |
(i) Binding and neutralizing the activity of TNF |
(i) Fever |
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AMPK: AMP-activated protein kinase; GLUT4: glucose transporter 4; SUR1: sulfonylurea receptor 1; IR: insulin receptor, PKC: protein kinase C; PPAR
Evidence of clinical trials with natural products attenuating oxidative stress and inflammation in patients with CVD, DM, and RA.
Number | Type of study | Number of participants | Age (years) | Intervention | Comparison/control | Period of intervention | Outcomes | Year [references] |
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1 | Randomized controlled crossover trial | 30 ( |
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Control, apple, spinach, and apple + spinach | Healthy control | 4 weeks | All treatments showed higher flow-mediated dilatation (FMD) ( |
2012 [ |
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2 | Double-blind randomized crossover trial |
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Two lyophilized apples (40 g), polyphenol-rich and polyphenol-poor, providing, respectively, 1.43 g and 0.21 g polyphenols per day | Hypercholesterolemic | 6 weeks | FMD did not differ between the polyphenol-rich and the polyphenol-poor apples, neither did the other cardiovascular disease risk factors (plasma lipids, homocysteine, and antioxidant capacity) | 2010 [ |
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3 | Open prospective randomized crossover controlled feeding trial | 40 ( |
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Raw tomatoes/kg (7.0 g), 3.5 g of tomato sauce/kg, 3.5 g of tomato sauce with refined olive oil/kg, and 0.25 g of sugar solved in water/kg | Healthy control | 12 days | Tomato sauce enriched with refined olive oil can regulate lipid profile and soluble inflammatory biomarkers better than raw tomatoes or tomato sauces | 2016 [ |
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4 | Double-blind controlled randomized trial |
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Genistein from soybeans (54 mg/day); estrogen/progestin therapy (1 mg/day); estrogen/progestin combined with norethisterone acetate (0.5 mg/day) | Healthy postmenopausal women | 1 year | Genistein therapy improved endothelium function similar to estrogen/progestin regimen | 2003 [ |
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5 | Double-blinded placebo-controlled crossover trial | 93 ( |
25–65 | Quercetin/day from fruits and vegetable sources (150 mg) | Overweight/obese | 6 weeks | Reduced SBP and plasma oxidized LDL level with a high-CVD risk phenotype | 2009 [ |
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6 | Double-blinded randomized placebo-controlled crossover trial |
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35–51 | Anthocyanins from fruits and vegetable sources (640 mg/day) | Prehypertensive | 4 weeks | HDL-C and blood glucose were significantly higher after anthocyanin versus placebo treatment ( |
2013 [ |
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7 | Randomized double-blind placebo-controlled clinical trial | 105 | 20–60 | One 350 mg whortleberry extract capsule every 8 hours | Hyperlipidemic | 2 months | Lowered total-C ( |
2014 [ |
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8 | Randomized double-blind placebo-controlled clinical trial | 50 | ≥18 |
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Hyperlipidemic | 4 weeks | Significantly reduced total-C ( |
2014 [ |
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9 | Randomized controlled investigator blinded parallel-group trial, |
44 ( |
56–73 | Dark chocolate (6.3 g/day) containing 30 mg of polyphenols | Stage-1 hypertensive | 18 weeks | Reduced mean (SD) SBP by 2.9 (1.6) mmHg ( |
2007 [ |
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10 | Randomized placebo-controlled single-blind crossover trial, |
45 ( |
30–75 | In phase 1, solid dark chocolate bar (containing 22 g cocoa powder) or a cocoa-free placebo bar. In phase 2, sugar-free cocoa (containing 22 g cocoa powder), sugared cocoa (containing 22 g cocoa powder), or a placebo | Healthy control | 1 week | The acute ingestion of both solid dark chocolate and liquid cocoa improved endothelial function and lowered blood pressure in overweight adults | 2008 [ |
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11 | Open label randomized clinical trial | 60 | 35–55 | Standard metformin therapy with turmeric (2 g) supplements | Standard metformin treatment | 4 weeks | Turmeric administered group significantly ( |
2015 [ |
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12 | Randomized double-blind controlled clinical trial | 70 | 30–70 | Powdered rhizome of ginger (1600 mg) | Wheat flour placebo (1600 mg) | 12 weeks | Ginger significantly reduced the fasting plasma glucose, HbA1c, insulin, triglyceride, total cholesterol, CRP, and PGE2 | 2014 [ |
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13 | Randomized triple-blind controlled trial |
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Capsule of 350 mg of RES enriched grape extract (GE) | 350 mg of capsules containing either maltodextrin (placebo) or RES lacking GE | 12 months | RES enriched GE downregulated the proinflammatory cytokines expression via involving the inflammation-related miRs in circulating immune cells | 2013 [ |
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14 | Randomized double-blind controlled trial | 36 ( |
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FDS beverage of 2 cups (50 g of FDS is equivalent to 500 g of fresh strawberries) | Placebo powder with strawberry flavor | 6 weeks | FDS significantly ( |
2013 [ |
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15 | Randomized double-blind controlled trial | 64 | 38–65 | Ginger supplementation | Placebo | 8 weeks | Ginger supplementation significantly reduced the TNF- |
2013 [ |
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16 | Randomized double-blind clinical trial | 81 | 18–60 | BSP at 10 g/day ( |
Placebo | 4 weeks | BSP significantly decreased the MDA, OSI, and oxidized low density lipoprotein cholesterol and increased the TAC | 2011 [ |
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17 | Double-blinded randomized crossover trial | 32 ( |
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GSE (600 mg/day) | Placebo | 4 weeks | GSE significantly improved the inflammatory markers (mainly CRP), glycemia, and oxidative stress | 2009 [ |
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18 | Randomized single-blind pilot study | 45 ( |
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Curcumin (500 mg) and diclofenac sodium (50 mg) alone or in combination | Diclofenac sodium (anti-inflammatory drug) | 8 weeks | Curcumin alone proved to be the most effective ( |
2012 [ |
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19 | Randomized double-blind placebo-controlled crossover study | 20 ( |
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Quercetin (166 mg/capsule) + vitamin C (133 mg/capsule); |
Placebo | 6 weeks | No significant difference was found among the proinflammatory cytokines; however quercetin tended to reduce VAS of RA | 2009 [ |
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20 | Randomized double-blind placebo-controlled study | 105 | 55–75 | Polyphenolic-rich olive extract | Placebo | 8 weeks | Significant ( |
2007 [ |
F: female; M: male; RA: rheumatoid arthritis; VAS: visual analogue scale; NR: not reported; CRP: C-reactive protein; RES: resveratrol; GE: grape extract; miRs: microRNAs; FDS: freeze-dried strawberry; MDA: malondialdehyde; GSE: grape seed extract; BSP: broccoli sprouts powder; OSI: oxidative stress index; TAC: total antioxidant capacity; PGE2: prostaglandin E2; HbA1c: glycosylated hemoglobin; CAD: coronary artery disease; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; SBP: systolic blood pressure.
A population-based prospective cohort study from nine areas in Japan (77,891 male and female subjects aged 45–74 years) suggested that fruit consumption protects against the risk of CVDs [
Apple is one of the most commonly consumed fruits, and its polyphenolic extract has a significant effect on decreasing the serum total-C and LDL-C levels in healthy individuals with relatively high body mass index (BMI), which consequently limits CVD risk [
Several studies have shown that citrus fruits such as mandarins, lemons, oranges, and grapefruits contain high quantities of flavanones (e.g., naringin and hesperidin) that improve significant vascular functions and the lipid profile in patients with coronary artery diseases [
The consumption of polyphenol-rich peach and plum juice showed preventive effects against risk factors for cardiometabolic disorders. This protection was largely achieved by decreasing the expression of plasma proatherogenic and proinflammatory molecules, intercellular cell adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1, and nuclear factor kappa B (NF-
A group of widely consumed flavonoids present in vegetables exhibit some protective activities against CVD progress [
Upaganlawar et al. [
Several studies have observed that the widely used spice ginger (
A meta-analysis reported that the consumption of 1 cup/day of green tea could decrease by 10% the chance of developing coronary artery disease due to the presence of polyphenols such as catechins, epicatechin 3-gallate (ECG), and epigallocatechin (EGC) and thereby prevent CVD; however, no significant relationship was found between black tea polyphenols and cardioprotective effects [
Chocolate, cocoa, and cocoa products provide a substantial quantity of dietary polyphenols. There is numerous evidence from
Because CVD is a multifactorial disorder, the consumption of fruits, vegetables, spices, green tea, red wine, or other polyphenol-rich phytochemicals is expected to decrease the risk of CVD via multiple mechanisms to ensure a healthy life.
DM is a group of metabolic diseases that are caused by overnutrition (mainly high-fat diet) and a lack of physical activity [
Worldwide, DM is the most common endocrine disorder; the reported prevalence in 2013 was 382 million people, which is anticipated to increase to as many as 592 million by 2035 [
Chronic low-grade inflammation and the activation of the innate immune system are considered to be closely involved in the pathogenesis of DM [
Both JNK and IKK
Increasing adiposity is reported to increase inflammatory gene expression in the liver [
Oxidative stress contributes to DM by modifying the enzyme systems, impairing glutathione metabolism and lipid peroxidation and reducing vitamin C levels [
Several groups of synthetic drugs and insulin possess antioxidative and anti-inflammatory potential that can be used in the treatment of DM. Unfortunately, none are free from adverse effects (Table
Numerous
Resveratrol, a naturally occurring polyphenol found in grapes and red wine, has recently been shown to exert potent antidiabetic, antioxidative, and anti-inflammatory activities. In the liver and spleen of STZ-induced male Long-Evans rats (type 1 diabetic animal models), resveratrol treatment (0.1 or 1.0 mg/kg/day) for 7 days significantly reduced oxidative stress (including superoxide anion content, protein carbonyl level, and manganese-superoxide dismutase expression) in hepatic and splenic tissues, and it reduced hepatic inflammation (NF-
Phlorizin (PZ) is a predominant phenolic compound that is found in apples. Preexposure to docosahexaenoic acid ester of PZ (PZ-DHA) in inflammation-induced macrophages [stimulated by lipopolysaccharide (LPS)] was effective in reducing the TNF-
Diabetes mellitus is associated with the reduction of glutathione levels, thus indicating the critical role of oxidative stress in its pathogenesis. In Ins-1E pancreatic
Pomegranate (
Anthocyanins can alter tissue PPAR activity, which further affects metabolism and inflammation. In the Zucker fatty rat model of obesity and metabolic syndrome, the effect of whole tart cherry powder (prepared from anthocyanin-rich tart cherries) was evaluated after 90 days’ treatment. The intake of tart cherry reduced retroperitoneal IL-6 and TNF-
Macrophage infiltration in adipose tissue due to increased adiposity can lead to T2DM. In an
T2DM is associated with chronic, low-grade, systemic inflammation accompanied by an increased production of adipokines or cytokines by obese adipose tissue. The treatment of diabetic db/db mice with grapefruit (0.5 g/kg) for six weeks produced antihyperglycemic effects that were accompanied by the reduced mRNA expression of proinflammatory genes such as COX-2, monocyte chemotactic protein-1, TNF-
In pancreas, liver, and adipose tissue, endoplasmic reticulum (ER) stress is an early event linked to T2DM pathogenesis. In the skeletal muscle of diabetic rats, 500 mg/kg of grape seed proanthocyanidin extract (GSPE) administration for 16 weeks decreased the plasma glucose levels and insulin resistance, restored the normal activities of antioxidant enzymes and ATPases, and partially alleviated severe ER stress, which suggests that GSPE could be a useful treatment strategy for T2DM [
Milk fat globule epidermal growth factor-8 (MFG-E8) is highly involved in the inflammatory response. In diabetic db/db mice, the administration of grape seed procyanidin B2 (a natural complex of polyphenol polymers) provided anti-inflammatory protection in pancreatic tissues by downregulating MFG-E8 and attenuating the levels of the proinflammatory cytokines IL-1
There is abundant
In STZ-induced diabetic rats, the administration of fermented carrot juice by
Sulforaphane (SFN) is an isothiocyanate that is naturally available in widely consumed vegetables, particularly broccoli. In diabetic male C57BL/6J mice, sulforaphane (0.5 mg/kg) treatment for four months significantly inhibited cardiac lipid accumulation and improved cardiac inflammation, oxidative stress, and fibrosis by downregulating diabetes-induced PAI-1, TNF-
Onion-derived quercetin derivatives have been regarded as the most important flavonoids for improving diabetic conditions in both
Cordycepin (3′-deoxyadenosine) is produced by a traditional medicinal mushroom known as
The administration of MT-
In an
A variety of spices also show potential for managing DM by reducing inflammation and oxidative stress. Turmeric (
Diabetic complications occur as a result of increased ROS due to long-term hyperglycemia. Honey and ginger have been shown to exhibit antioxidant activity by scavenging ROS. In STZ-induced Sprague Dawley rats, the combined administration of honey (2 g/kg body weight) and ginger (60 mg/kg body weight) for three weeks significantly (
In diabetic patients, diabetic encephalopathy is one of the more severe complications. In diabetic encephalopathy rats, saffron at 40 and 80 mg/kg significantly increased the body weight and serum TNF-
The protective effect of onion against oxidative stress was evaluated in an
Mustard leaf (
Sesame butter is a natural product produced by grinding sesame seeds and is thus free from any chemical or nonchemical additives. In STZ-induced male albino Wistar rats, oral treatment with sesame butter (1.25 g/kg) for six weeks significantly decreased the blood glucose, high density lipoprotein, and malondialdehyde levels and increased the total antioxidant capacity [
Eugenol (EU) is an active principle of cloves (
Cumin (
RA is an inflammatory, systemic autoimmune disorder with primary degenerating articular structures involving, in particular, the cartilage (movable synovial joints of knees, shoulders, and hands) and the bones (osteoarthritis and osteoporosis) as a result of pannus formation over the joint surfaces (abnormal layer of fibrovascular or granulation tissues) [
RA is the most common inflammatory arthritis and affects approximately 1% of the world population, with more than 3 million new patients being diagnosed yearly [
The pathogenesis of RA involves a complex interplay between genetic and environmental factors leading to autoimmune inflammatory responses against the connective and synovial tissues of the joints [
Oxidative stress was recently shown to be involved in the degeneration of cartilage due to the deregulation of Nrf2 or NFE2L2 [
Although synthetic regimens have been used to treat patients with RA, side effects are common and unavoidable (Table
Osteoclastogenesis (the process of destroying bone tissues by osteoclast cells) has been observed as a clinical phenomenon in patients with RA [
Anthocyanins from cherry can reduce both oxidative stress (increase superoxide dismutase and decrease serum malondialdehyde) and inflammatory mediators (decrease in TNF-
In 2015, resveratrol polyphenol found in red grape skin was reported to confer a significant protective effect against an aggressive RA rat model [
In an
Recently, Natarajan et al. [
Kaempferol (found especially in grapefruits) was shown to inhibit synovial fibroblast proliferation by suppressing inflammatory cytokines (inhibiting IL-1
An
Pattison et al. [
An
Cinnamon bark (
An
Methotrexate is an antirheumatic drug widely used to treat patients with RA [
Another recent
Extra virgin olive oil (EVOO) is consumed all over the world, especially in the Mediterranean countries [
A recent experiment in 2015 [
An
In LPS-stimulated macrophages, the secretion of IL-6 (found at elevated levels in patients with RA) was significantly reduced (by at least 25%) upon incubation with polyphenol-rich extracts of rooibos tea, black pepper, ginger, allspice, caraway, bay leaves, cinnamon, licorice, paprika, clove, nutmeg, and apples [
Dietary phytochemicals are some of the most potential natural sources for developing novel drugs with improved efficiency, efficacy, and safety. Well-designed clinical trials are warranted to address the safety issues and the concurrent utility of synthetic drugs and natural compounds in attenuating oxidative stress and inflammation-mediated degenerative diseases such as RA, DM, and CVD. In
To find appropriate literature, the following terms were used in combination with Boolean operators (AND and OR).
The authors declare that there are no competing interests.
Md. Asiful Islam and Fahmida Alam are equal contributors.
The authors would like to acknowledge the Universiti Sains Malaysia (USM) Vice-Chancellor Award (2015/2016) and the USM Global Fellowship (2014/2015) awarded to Md. Asiful Islam and Fahmida Alam, respectively, to pursue their Ph.D. degrees.