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Antioxidant Free Radical Aging and Disease

By @Entropy

Curcuminoids and Longevity

Introduction

Turmeric is derived from the roots of the tropical plant Curcuma longa. The bright yellow-orange color of turmeric is derived from fat-soluble, polyphenolic pigments known as curcuminoids. Of the well-characterized curcuminoids, curcumin is the most active and abundant. Curcuminoids comprise about 5% of turmeric. Curcumin comprises about 75% of the total curcuminoids. Curry powder contains turmeric along with other spices, but the amount of curcumin in curry powders is variable and often insignificant. Curcumin extracts are also used as food-coloring. In addition to its use as a spice and pigment, turmeric has been used in India for medicinal purposes for centuries. In Japan, it is a tea flavoring whereas in Thailand it is in both cosmetics and food. It is used as drink flavorant in Korea. Whereas thee the Malaysians use it as an antiseptic, the Pakistanis apply it to treat inflammatory conditions. The therapeutic properties of turmeric have been known for millennia and primarily attributable to its antioxidant, anti-inflammatory and anticancer properties. It, therefore, has potential application as a therapeutic agent against myriad disease conditions. Despite established benefits, gastrointestinal absorption is poor. An active ingredient in black pepper, piperine, increases absorption 20-fold 

Curcumin scavenges ROS/RNS free radicals and can be applied to allaying oxidative stress: an overload of free radical (ROS/RNS) accumulation in the system. In humans, oxidative stress is implicated in the development of ADHD, cancer, Parkinson’s disease, Lafora disease, Alzheimer’s disease, atherosclerosis, heart failure, heart attack, sickle-cell disease, vitiligo, autism, infection, chronic fatigue syndrome (CFS), metabolic syndrome (MetS) and depression. Oxidative stress causes several chronic diseases. Their pathologies are causally related to inflammation which demonstrably triggers conditions such conditions as Alzheimer’s disease (AD), Parkinson’s disease, colitis, arthritis, psoriasis, diabetes, obesity, multiple sclerosis, epilepsy, cardiovascular disease, allergy, asthma, bronchitis and fatigue. 

Being an antioxidant and an anti-inflammatory, enables curcumin to exert several therapeutic effects. Among some of the antioxidant effects are increasing the activity of three major enzymes. They are superoxide dismutase (SOD) catalase and glutathione peroxidase (GSH).  In concert with GSH, catalase and SOD, curcumin neutralizes ROS/RNS free radicals. Also inhibited by curcumin are the ROS-generating enzymes lipoxygenase/cyclooxygenase and xanthine hydrogenase/oxidase. In addition, curcumin is an efficient scavenger of peroxyl radicals including superoxide (O2-.) and hydroxyl (.OH) radicals. These potentially stimulate lipid peroxidation which is deleterious to proteins, DNA and cell membrane.[1],[2]

Anti-Inflammatory

Inflammatory cells are known to liberate free radicals at the site of inflammation suggesting a cause-effect relationship between oxidative stress and inflammation. In addition, a number of ROS/RNS free radicals stimulate the release of pro-inflammatory factors. Prominent among the pro-inflammatory factors is tumor necrosis factor α (TNF-α)[3] which activates NF-κB, another inflammatory factor. But NF-κB is also activated by a several other factors: namely, gram-negative bacteria, viral pathogens, environmental pollutants, psychological stress, high sugar levels, fatty acids, UVR and cigarette smoke. It is, therefore, logical to infer that suppression NF-κB would effectively alleviate inflammatory conditions.

Among naturally occurring compounds that has been shown to block NF-κB is curcumin.[4] Of the well-known chronic inflammatory diseases responsive to curcumin are osteoarthritis (OA) and rheumatoid arthritis. Besides its ability to increase resistance to invading organisms, NF-κB suppression reduces cell proliferation and induces death of cancer cells. Moreover, by reducing inflammatory factors TNF-α, IL-1β, prostaglandin E2 (PGE2) and reducing the secretion of matrix metalloproteins (MMPs), curcumin is able to alleviate arthritis symptoms in synovial joints: namely, shoulder, hip, elbow and knee joints.  Once considered degenerative and non-inflammatory, osteoarthritis is now recognized as an inflammatory condition having elevated cytokine levels, as well as being connected to systemic inflammation. Turmeric dosages of 1000 mg/day has been found to reduce arthritis symptoms. A comparative study of curcumin versus standard non-steroidal anti-inflammatory drugs (NSAID), like aspirin, found improvements in morning stiffness, walking time and joint swelling in patients with rheumatoid arthritis (RA). Moreover, supplementation with a mixture of all three major curcuminoids was found to be as effective as diclofenac (NSAID) in reducing joint tenderness and swelling. Studies have shown that oral curcumin supplementation is effective in reducing post-surgical swelling, tenderness and pain. As an active ingredient in mouthwash, curcumin was also found to be as effective as chlorhexidine in reducing inflammation.

Oral submucous fibrosis (OSMF) is premalignant condition characterized by inflammation and progressive scarring of the mucosal tissues. General symptoms are oral pain, inability to open the mouth, increased salivation and a burning sensation upon consumption of piquant foods. A change of taste sensation and hearing loss due to strictures in the tubes of the inner ear is also characteristic of OSMF. Although incurable, studies show that OSMF is responsive to curcumin. It improves some symptoms.

One of the consequences of DNA mutations is the development of cancer. Unlike normal cells which have a finite life span, cancer cells multiply indefinitely. Ingestion of curcumin, show promise as a deterrent of cancer cell proliferation. Although localized tumor is amenable to treatment, migration of cancer cells to distal sites pose an insurmountable challenge. Despite using several pathways, the dissemination of cancer cells can be controlled. One avenue of control being the inhibition of the pro-inflammatory protein NF-κB. Besides NF-κB, curcumin impedes the activity of IL-6 which boosts the proliferation, migration and invasiveness of small cancer cells. Because curcumin prevents inflammation, it reduces the risk of tumor initiation and therefore precludes the spread to adjoining tissues and distal secondary sites. Clusters of aberrant cells in smokers were reduced in response to increasing dosages of curcumin. The ability of curcumin to regulate cell growth, cell death, invasiveness and blood supply in preclinical investigations suggest a potential application as an anticancer therapeutic agent. By inhibiting the activity of multiple liver enzymes curcumin prevents chemical substances from being transformed into active carcinogens. For example, vinyl chloride is transformed in the liver to vinyl chloride epoxide which can cause cancer of the liver. Methanol is converted in the liver formaldehyde, a well-known carcinogen.

Studies on colon carcinogenesis have enabled researchers to link chronic inflammation as the primary risk factor for cancer and other serious health conditions. Ulcerative colitis (UC) is an inflammatory disease affecting the mucus membranes of the colon. Symptoms include bloody diarrhea, abdominal pain, rectal pain, rectal bleeding, urgency to ******** and the inability to ********. Sufferers are more than twice as likely to develop colorectal cancer than those without the disease. UC causes inflammation that can eventually turn normal colonic cells into malignant cells. Preliminary evidence suggests that curcumin might be a useful adjunctive agent to control this disease. Six months of curcumin enema treatment reduced symptoms and resulted in a lower relapse rate than subjects on standard medication of sulfasalazine or mesalamine. 

Metabolic Syndrome (MetS)

Metabolic syndrome (MetS) is a cluster of symptoms often manifested as cardiovascular diseases (CVDs), type 2 diabetes, hypertension, high blood sugar, excess visceral fat, high LDL and triglyceride levels but low HDL. People afflicted with this condition also suffer from excessive blood clotting and chronic low-grade inflammation. Associated conditions are fatty livers, polycystic ovarian syndrome, gallstones and breathing problems during sleep.[5] Because of its ability to neutralize oxidative stress, curcumin is capable of improving insulin sensitivity, suppressing fat-cell multiplication, reducing hypertension and inflammation. In addition, curcuminoids – the entire family of active compounds in turmeric – decreases circulating triglycerides and total cholesterol but elevate good cholesterol (HDL). MetS patients on diets supplemented with a curcuminoid-piperine[6] showed reduced levels of oxidative stress, inflammation and C-Reactive Protein (CRP). The latter is a marker of inflammation and indicative of several disease conditions including cancer. High CRP levels is also an indicator of inflammation in the arteries of the heart. Chronic low-grade inflammation is a common feature of overweight/obese people. Dietary intake of curcumin demonstrably reduces the secretion of pro-inflammatory factors. It raises good cholesterol (HDL) while diminishing bad cholesterol (LDL) triglycerides and lipoprotein a (Lp(a) – a risk factor for arterial hardening, coronary heart disease and stroke. In overweight/obese subjects treated with curcumin, significant reduction in malonaldehyde (MDA) and C-reactive protein (CRP) concentrations were observed. Under normal conditions, MDA readily interacts with proteins, lipoproteins, DNA, and RNA causing cellular injury. MDA is involved in the induction of type-2 diabetes, aging and neurodegenerative diseases. Excessive MDA reduces blood flow to the brain. This situation leads to poor oxygen supply causing death of brain tissue, impairment of vision, body movement and speech.[7] Because MDA interacts with collagen, it hastens skin-wrinkling and other aging features. Moreover, dietary supplementation with curcumin improves superoxide dismutase (SOD) activities which is known to diminish the accumulation harmful free radicals generated during normal metabolism.[8]

Type 2 diabetes mellitus

Studies have determined that curcumin intake diminishes inflammatory indicators including malondialdehyde (MDA), endothelin-1, TNFα and IL-6 suggesting that curcumin has the ability to prevent the development of inflammation. Both excessive accumulation of free radicals and inflammation have been causally linked to type 2 diabetes. The antioxidant, anti-inflammatory, and glucose-lowering properties of curcumin and other curcuminoids reveal their potential in preventing and/or treating type 2 diabetes. By increasing cell sensitivity to glucose, curcuminoid was found to delay the onset of full-blown diabetes. Clinical studies show that oral intake of curcumin for six months improved insulin sensitivity, plasma triglycerides, visceral fat and total body fat in participants with type 2 diabetes. Apart from glucose-lowering benefits, dietary curcumin was observed to be as effective as the cholesterol-lowering drug atorvastatin (Lipitor) – one of the many statin drugs. Furthermore, reduced urinary proteins and inflammation indicators suggests that curcumin might be helpful in slowing the progression of kidney damage associated with type 2 diabetes.

Neurological Conditions

In Alzheimer’s disease (AD), aggregates of amyloid β (beta) protein form plaques in the brain, but outside the nerve cell. Physiologically, amyloid β is vital to neural growth and repair. However, corrupted forms destroy the cells leading to the loss of thought and memory – characteristics of Alzheimer’s disease. Another structural feature of AD is the formation of intracellular misfolded and abnormally shaped tangles called Tau proteins. Both amyloid β and Tau proteins are responsible for brain atrophy. Curcumin has been found to inhibit amyloid β formation in vitro. Besides, the ability of curcumin to sequester zinc and copper prevents protein aggregation. In the mouse model of AD, curcumin was found to cross the blood-brain barrier and prevent the formation of amyloid β proteins. In other animal studies of AD, an abnormally high accumulation of ROS/RNS is associated with the progression of the disease. Dietary curcumin, however, is shown to decrease indicators of inflammation and oxidative damage caused by ROS/RNS free radicals. A test group, given curcumin, showed increased catalase activity which neutralizes free radicals.

Accumulation of inflammation causes nerve malfunction which, in turn, is linked to several neurological disorders. Major depressive disorder (MDD) is associated with aberrant nerve transmission. MDD influences feelings, thinking and behavior leading to a variety of emotional and physical problems. Often, MDD adversely affects daily routines and induces a sense of hopelessness. The underlying pathology include increased inflammation of the nerve cells. In mice subjected to brain trauma, inflammation of brain cells is alleviated by curcumin thereby increasing their survival rates. Retrospective studies have disclosed that curcumin reduced plasma concentrations of inflammatory markers such as C-Reactive Protein (CRP). 

Curcumin on Healthy Adults

In healthy adults, 80mg of curcumin/day has produced marked improvement nitric oxide (NO) profile: a vasodilator, causing the vessels to distend increasing blood flow and lowering blood pressure. In addition, curcumin intake decreased amyloid β which augurs well for those predisposed to Alzheimer’s disease. In an older group, over 60 years, 80mg of curcumin was shown to improve sustained attention and memory. Moreover, in healthy older adults, curcumin significantly induced higher levels of calmness, contentedness and mental alacrity. This dietary supplement is also potentially useful in sports medicine. Curcumin-piperine supplementation was found to reduce muscle soreness in rugby players. Players who received up to 1.0g of curcumin reported less muscular pain. MRI evidence support these findings. It revealed less muscle injury and inflammation in athletes taking this dosage. Of significance is that curcumin is found abundantly in beets, garlic, dark chocolate, leafy greens, citrus fruits and pomegranate.[9]

[1] https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/peroxy-radical

[2] https://en.wikipedia.org/wiki/Hydroperoxyl

[3] Tumor Necrosis Factor alpha (TNF-α): an inflammatory factor produced by macrophages/monocytes during acute inflammation leading to necrosis or apoptosis. It triggers the release of several immune factors, including interleukin-1 and interleukin-6 which can cause inflammatory diseases, including arthritis.

[4] Anlys Olivera, Terry W. Moore, Fang Hu, Andrew P. Brown, Aiming Sun, Dennis C. Liotta, James P. Snyder, Younghyoun Yoon, Hyunsuk Shim, Adam I. Marcus, Andrew H. Miller, and Thaddeus W. W. Pacea. 2012. Feb; 12(2): Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int. Immunopharmacol. 368–377.

[5] https://www.nhlbi.nih.gov/health-topics/metabolic-syndrome

[6] Piperine: The bioactive compound found in black pepper. It is also the active component found in chili powder and cayenne pepper. It has been shown to help relieve nausea, headaches and poor digestion. Of utmost significance is its ability to boost the absorption of curcumin.

[7] https://en.wikipedia.org/wiki/Brain_ischemia Retrieved October 29 2020

[8] https://www.sciencedirect.com/topics/medicine-and-dentistry/malonaldehyde Retrieved October 29 2020

[9] Susan J. Hewlings, and Douglas S. Kalman. 2017. Curcumin: A Review of Its’ Effects on Human Health. . Foods.

Oct; 6(10): 92.

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