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The Science of Phytochemical

Essay 2019 64 Seiten

Biologie - Botanik


Table of Contents

I. Introduction

II. 3,3'-Diindolylmethane or DIM Health Benefits
1. Anti-Inflammation
2. Arthritis
3. Autoimmune Encephalitis
4. Cancers
5. Chronic Diseases
6. Colitis
7. Delayed-Type Hypersensitivity
8. Heart Muscle
9. Hyperglycemia
10. Hypoxia
11. Hematopoiesis
12. Liver Fibrosis
13. Liver Protection
14. Non-alcoholic steatohepatitis (NASH)
15. Osteoporosis
16. Oxidative Stress
17. Radiation Intestinal Injury
18. Renal Fibrosis
19. Wound Healing

III. Summary


The Science of Phytochemical: The Health Benefits of 3,3'-Diindolylmethane (DIM)

I. Introduction

Phytochemicals, the nonnutritional parts are natural chemical constituents in plants to protect against diseases and to form color as well as other organoleptic properties(1). Study of Phytochemicals has emerged as a potential source to find a better treatment or cure some diseases with little or side effects or to create a synthetic equivalence for commercial profits(2).

Secondary metabolites are chemical compounds produced by bacteria, fungi, particularly in plants involved in the protection of the survival of the organism(3).

Most common secondary metabolites are flavonoids, phenolic and polyphenolic compounds, terpenoids and sulfur-containing compounds(4).

3,3'-Diindolylmethane or DIM is phytochemicals derived from the digestion of indole-3-carbinol, belongings to the group of Indoles, found abundantly in broccoli, Brussels sprouts, cabbage, and kale(5), etc.

A recent study from the US suggested that DIM may be a potent phytochemical for the prevention or treatment of the adverse effects caused by radiation and chemotherapy in breast cancer patients(6).

Intake of DIM as a form of supplement should be taken with extreme care to prevent overdose toxicity(7).

II. 3,3'-Diindolylmethane or DIM Health Benefits

1. Anti-Inflammation

Inflammation is a natural response of the immune system which tries to protect our body by destroying the harmful pathogens before they cause damage(8).

In the acute phase of infection, the immune system white blood cells in the first line defense stimulate the production of blood palette to cover the wound and the production of inflammatory cytokines to kill off micro-organisms, leading to symptoms of fever, redness and swelling(8).

Overproduction of proinflammatory cytokines in some cases have been found to damage nearby healthy cells and tissues, causing the formation of scars(9).

In severe cases, a protein with duo functions in the production of pro and anti- inflammatory cytokines which produce anti-inflammatory cytokines under normal condition also switch to produce pro-inflammatory cytokines(9).

Most harmful pathogens are stopped at the acute phase of infection(9). However, if the immune first line of defense can not completely destroy the invaders within a period of 3 to 8 weeks, it will compromise, leading to low-grade chronic inflammation(9).

Diseases associated with low-grade chronic inflammation include diabetes, cardiovascular disease, and cancer(9).

Conventional treatment of acute phase inflammation is to manage inflammation and prevent the risk of long-term damage, including anti-inflammatory nonsteroidal anti- inflammatory drugs (NSAIDs) which can be bought without a prescription(10).

In the urgency of finding a potential compound which processes a strong anti- inflammatory activity, researchers examined the effects of 3,3'-Diindolylmethane (DIM), a condensation product of indole-3-carbinol, and a glucosinolate naturally occurring in Brassica genus vegetables(11).

The study carried out by differentiated the 3T3-L1 adipocytes in the co-cultured with RAW 264.7 macrophages and exposed to 20 µM, 40 µM and 60 µM DIM for 24 h followed by 100 nM insulin for 20 min(11).

According to the tested assays, DIM significantly (p<0.05) reduced the production and mRNA expression of proinflammatory cytokines (MCP-1, IL-6, and TNFα) in a concentration-dependent manner(11).

Injection of DIM was found to increase the expression of proteins involved in the positive regulation of metabolism and proliferation (IRS-1 pY612 and Akt-1/PKB pT308) through its anti-inflammatory properties(11).

In other words, DIM influences the glucose metabolic pathway by exerting an anti- inflammatory effect.

Dr. Lopez-Vazquez A, the lead scientist said, "The potential therapeutic benefits of DIM in the treatment of glucose metabolic disorders deserve further studies".

In order to reveal more information about DIM anti-inflammatory effects, researchers examined the dietary components found in cruciferous vegetables, on brain inflammation(12).

Administration of DIM suppressed lipopolysaccharide (LPS)-induced expression of reactive oxygen species and promoted the production of antioxidant enzymes in the host through inhibiting the microglial hyperactivation by attenuating inflammatory transcription factor NF-κB(12).

Furthermore, DIM protected primary cortical neurons from inflammatory toxicity induced by LPS.

In vivo model of neuroinflammation, DIM also suppressed LPS-induced brain inflammation in the mouse hippocampus(12).

Based on the findings, Dr. Kim HW, the lead researchers said, "DIM may have beneficial potential against brain inflammation and neurodegenerative diseases through the negative regulation of the NF-κB signal pathway in microglia"(12).

2 . Arthritis

Arthritis is a group of diseases associated with the inflammation of the joints. According to the epidemiological studies osteoarthritis (OA) and rheumatoid arthritis (RA) are 2 most common types of arthritis(13).

According to the information provided by the Arthritis Foundation, arthritis affects over 54 million people in adults of which diagnosed by doctors. Osteoarthritis is the most prevalent type in the US, affecting 31 million Americans(14).

Depending on types and the location affected, arthritis can be classified into over 100 conditions(15), but the most common types of arthritis include - Osteoporosis is a condition of thinning of bone and bone tissues as a result of the loss of bone density over a long period of time. (16)

- Osteoarthritis (OA), is a condition caused by the wear and tear on a joint due to aging, affecting over 25 million people in the United States alone(15).
- Rheumatoid Arthritis is a chronic disorder as a result of inflammation, affecting mostly the flexible (synovial) joints and tissues and organs in the body(15).
- Polymyalgia arthritis is a condition of inflammatory rheumatic disease-induced pain, stiffness, and tenderness in large muscles, including muscles shoulders and pelvic girdle(17).
- Fibromyalgia in the newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites(a) as a result in responding to pressure(18).

As of today, there is no cure for arthritis, medications used in conventional medicine are to reduce pain, and symptoms and improve quality of life for patients to carry out the daily activity(15).

In the urgency to discover a natural compound for the treatment of diseases associated with(19) osteoclastogenesis, researchers investigated the therapeutic efficacies of DIM on experimental arthritis.

The study included a rat model of adjuvant-induced arthritis (AIA), with daily AIA paw swelling(19).

According to the clinical and histologic indices of inflammation and tissue damage, administration of DIM attenuated AIA in animal models(19).

Furthermore, DIM also reduced the expression of several inflammatory cytokines, associated with the onset of arthritis. However, the anti-inflammatory function of DIM could not prevent the development of arthritis(19).

Moreover, in the differentiation of the DIM effect on activation-induced cytokine, researchers found that the bioactive compound effectively inhibits the expression of RANKL, leading to the blockade of osteoclastogenesis and consequently an alleviation of experimental arthritis(19).

Where Receptor activator of nuclear-factor-kappa-Β ligand (RANKL) is a protein involved the activation-induced cytokine, osteoprotegerin ligand, and osteoclast differentiation factor.

Dr. Dong L the lead researcher wrote, "DIM has shown anti-arthritis activity in animal models via inhibiting the expression of RANKL, and thus may offer potential treatments for arthritis and associated disorders"(19).

3 . Autoimmune Encephalitis

Autoimmune encephalitis is a group of conditions caused by the body's immune system mistakenly attacks healthy brain cells (20).

Autoimmune encephalitis has been found to induce neurologic symptoms such as impaired memory and cognition, abnormal movements, seizures, and/or psychiatric symptoms such as aggression, inappropriate sexual behaviors, panic attacks(20).

Autoimmune encephalitis can be classified into

- Post-infectious encephalitis or acute disseminated encephalomyelitis (ADEM) are the conditions caused by an infection. In these cases, the immune system not only attacks the pathogens which cause infection it also destroys mistakenly the healthy cells in the brain(22).

Methylprednisolone is the first line of drug for the treatment of post-infectious encephalitis, if it failures, plasma exchange or intravenous immunoglobulin may be used(21).

- Other forms of autoimmune encephalitis are caused by the specific antibodies in the blood produced by the immune system that attack the brain cells(22).

According to the Autoimmune Encephalitis Alliance, a number of options are available to treat AE, the first-line option include including medication that decreases the inflammatory response to antibodies, and intravenous immunoglobulin (IVIG); to increase the removal of antibodies, inhibit binding of the harmful antibodies(23).

If the first line option failure, immune-suppressive medicine may be used as a second line of treatment, including Rituximab, CellCept, and Cytoxan (Cyclophosphamide)(23).

With an aim to find a potential ingredient for the treatment of autoimmune encephalomyelitis, researchers evaluated the 3,3'-Diindolylmethane (DIM) effects on the regulation of activated T cells during the development of experimental autoimmune encephalomyelitis (EAE)(24).

During the experiment, administration of DIM 10 days after EAE was effective in ameliorating disease parameters, including inflammation and central nervous system cellular infiltration(24).

According to the microRNA (miRNA) microarray analysis, post-treatment of DIM alter the expression of miRNA profile in brain infiltrating CD4(+) T cells, an indication of autoimmune dysfunction on EAE mice(24).

Observed by the bioinformatics analysis, the efficacy of DIM-altered the miRNAs expression associated with pathways that halt cell cycle progression and promote apoptosis(24).

Particularly, DIM impacted these cellular processes in activating the T cells(24).

More precisely, DIM protected the brain against the immune dysfunction in attacking the brain cell in the forming of autoimmune encephalomyelitis, by activating and suppressing the micro genes- induced immune dysfunction of EAE(24).

Dr. Rouse M, the lead scientist, after taking into account co and confounders wrote, "these studies demonstrate that DIM post-treatment leads to the amelioration of EAE development by suppressing T-cell responses through the induction of select miRNAs that control cell cycle progression and mediate apoptosis"(24).

4. Cancers

Cancer is a group of diseases characterized by the cell growth uncontrollably in the tissue of certain organs, due to the alternation of cell DNA(25).

Epidemiologically, researchers do not the exact causes of cancer. They cannot explain why people with the same health conditions in the same family, some are prone to the disease while others do not(25).

Most cases of cancer start in the cells on the surface of the inner lining tissue of an organ and at the advanced stage, cancer cells can travel a distance away from the original site to infect other tissues and organs through the circulation of blood and fluids, leading to secondary metastasis(25).

Cancer diagnosed at the early stage can have a survival rate up to 100%, depending on the type of cancer(25).

All cancers shared the general symptoms of unintended weight loss, loss of appetite, fatigue, and tiredness and gastrointestinal discomforts(26).

Furthermore, most cancers at the early stage do not induce any symptoms, however, at the later stage, the overgrowth tumor may press on the nearby blood vessels and nerve cells, leading to severe bleeding and pain(26).

Although there are several risk factors associated with the onset of cancer, some researchers suggested the increased in aging that leads to a number of abnormal alternations may be one of the major causes(26).

Dr. Jan R. Aunan, the lead scientist wrote in the study of the biological role of age and cancer, "Aging is the inevitable time-dependent decline in physiological organ function and is a major risk factor for cancer development"(27).

And, "Mechanisms of aging are also found to occur in carcinogenesis, albeit with shared or divergent end-results. It is now clear that aging and cancer development either share or diverge in several disease mechanisms. Such mechanisms include the role of genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, decreased nutrient sensing and altered metabolism, but also cellular senescence and stem cell function"(27).

4.1. Bladder Cancer

Bladder cancer is a medical and chronic condition characterized by irregular cell growth in the bladder tissues(28).

Most cases of bladder cancer begin in the cells on the surface of the inner lining of the bladder tissue before penetrating into the deeper layers of the bladder(28).

There are three types of bladder cancer classified depending on their origination(29).

- Transitional cell carcinoma(29)

Transitional cell carcinoma starts in the innermost tissue layer of the bladder which can change shape and stretch without breaking apart. In other words, they are able to stretch when the bladder is full and shrink when it is emptied(29).

More than 90 percent of bladder cancers begin in the transitional cells(29)

- Squamous cell carcinoma(29)

Cancer begins in squamous cells found in the tissues of the surface of the bladder, caused by long-term infection or irritation(29).

About 8 percent of people with bladder cancers begin squamous cells(29).

- Adenocarcinoma(29)

The cancer is originated from the glandular tissue of the bladder, including the surface layer of skin, glands and a variety of other tissue, due to long-term irritation and inflammation(30).

Only 2 percent of people with the condition have a third bladder cancer type(29).

Regardless of the types of cancer originated, bladder cancer shares the general symptoms of other types of cancer accompanied by specific symptoms such as bladder spasms, blood in urine, frequent urination, pain or burning sensation during urination, pain in lower back and/or abdomen, inability to urinate, urinary urgency, reduced bladder capacity, and difficulty in urination(28).

If you have some of the aforementioned symptoms, please make sure that you talk to your doctor to rule out the possibility of bladder cancer.

Out of many risk factors associated with the onset of the diseases, smoking has been associated with most of the patients(30).

Dr. Neal D Freedman, wrote, "...the population attributable risk of bladder cancer for tobacco smoking is 50–65% in men and 20–30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking"(30).

And, "Over the last 30 years, incidence rates have remained stable in the United States (men: 123.8/100,000 person-years to 142.2/100,000 person-years; women: 32.5/100,000 person-years to 33.2/100,000 person-years), yet changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer in more recent data"(30).

In other words, if you are smokers, your risk of bladder cancer is substantially higher compared to never smoking individuals.

On finding a natural ingredient for the treatment of bladder cancer, researchers investigated the antiproliferative and anti-inflammatory potential effects of diindolylmethane (DIM) and lupeol on the experimental bladder cancer.

The study included 60 healthy male Wistar rats were selected and randomly divided into six groups, with 10 rats in each group(31).

- Group I: control(31).
- Group II: N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN; 150 mg/gavage/twice a week) for 8 weeks, and then they were given 100 ppm concentrations of dimethyl arsenic acid (DMA) in the drinking water for 28 weeks(31).
- Group III: BBN + DMA + DIM (5 mg/kg body weight (b.w.)/day) treatment was started after BBN treatment, and it was orally administered for 28 weeks)(31)
- Group IV: BBN + DMA + lupeol (50 mg/kg b.w./day) treatment was started after BBN treatment, and it was orally administered for 28 weeks)(31); and
- Groups V and VI: DIM and lupeol treatment alone for 36 weeks(31).

At the final day of the experiment, DIM and lupeol treatment showed the inhibition of tumor growth in the bladder by histopathological confirmations and increased the expression of a protein associated with tumor suppression(31).

According to the Western blot analysis, the inhibition of bladder cancer also was accompanied by decreasing the production of proinflammatory cytokines(31).

Furthermore, DIM and lupeol treatment significantly decreased the levels of an enzyme associated with a mediator of tumor repopulation (Cox-2) in bladder tissue samples and NMP 22 in urine samples(31).

Moreover, in order to reveal more information of DIM anti-bladder cancer property, researchers to investigate the apoptotic properties of Diindolylmethane (DIM) and Lupeol on N-Butyl-N-(4-hydroxybutyl) Nitrosamine (BBN) initiated and Dimethylarsinic Acid (DMA) in the promotion of urinary bladder cancer(32).

The experiment included 60 male Wistar rats divided into 6 groups. Group I: Control. Group II: Rats were experimentally developed bladder carcinogenesis with BBN and DMA. Group III and IV: DIM and lupeol were administered after BBN treatment for 28 weeks. Group V and VI: DIM and lupeol alone treatment for 36 weeks(32).

During the study, DIM and lupeol induced cancer cell apoptosis and inhibited cell proliferation by activated the stimulation of proteins associated with cell death programming and deactivated the gene associated with cell differentiation and division(32).

In other words, administration of DIM and lupeol inhibited the progression of bladder cancer, by promoting the expression of apoptotic Bax, caspase-3, caspase-9 and inhibiting the expression of anti-apoptotic Bcl-2, PCNA in the urinary bladder of rats(32).

Dr. Prabhu B, the lead scientist wrote in the final report, "Administration of diindolylmethane and lupeol treatment induces apoptosis and cellular proliferation by its anti-carcinogenic properties. From our results, DIM and lupeol would be the agent or adjunct for the treatment of bladder carcinogenesis"(32).

4.2. Breast Cancer

Breast cancer is a chronic and a medical condition characterized cell growth irregularly in the breast tissue(33).

Breast cancer is the most common cancer in American women, besides skin cancers. Most cases of breast cancer begin in the cells of the surface of the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk(33).

In 2010, over 250,000 new cases of breast cancer were diagnosed in women in the U.S. alone, leading to the death of over 41,000 women(34).

The risk of getting invasive breast cancer during the lifetime of a woman is 1/8. As of today, there are more than 3.1 million breast cancer survivors in the US(34).

The 5 years of the survival rate of localized breast cancer is closed to 100%(34).

The risk factors of breast cancer can be divided into 2 groups

- Preventable risk factors include exposure to ionizing radiation, hormone replacement therapy, use of oral contraceptives, alcohol, being obese and physical inactivity(35).
- Unpreventable risk factors include family and personal history, age, race, genetic preposition, dense breast, and reproductive history(35).

If you are at the higher risk of breast cancer, please make sure that you self-check your breast every month for preventive measure.

Since breast cancer is so sensitive to levels of the hormone, some scientists suggested that hormonal changes may have a critical impact on the disease(36).

Dr. Hindle WH in the examination of the hormonal changes in the risk of breast cancer wrote, "Nearly a dozen hormonal hypotheses of breast cancer causes have been proposed -- among them estrogen excess, low luteal-phase progestational activity, adrenal androgen deficiency, ovarian androgen excess, melatonin deficiency, prolactin excess, and thyroid insufficiency"(36).

And, The androgen deficiency hypotheses, however, may have some bearing on premenopausal breast cancer, and the ovarian dysfunction hypothesis may have some bearing on postmenopausal breast cancer"(36).

The results strongly indicated that the risk of breast cancer is associated with the decline production of hormones due to aging(36).

Researchers on finding a natural compound for the treatment of cancer without the development of toxic side effects and resistance to chemotherapy examined the effect of 3,3'-Diindolylmethane (DIM) on the enhancement of docetaxel (DOC) on breast cancer(37).

The study included the selected MDA-MB231 and Sk-BR-3 cells treated with and without 25 or 50 µM of DIM and 1 nM of DOC for 48 and 72 h(37).

Combining 25 µM of DIM with 1 nM DOC showed a significantly decreased cell survival by 42% in MDA-MB231 cells and 59% in Sk-BR-3 cells compared to control and the use of DIM or DOC alone(37).

The combination treatment increased apoptosis over 20% (p ≤ 0.01) in both cell lines, associated with decreased of proteins involved cell proliferation and survival and activation of JNK involved in the cancer cells apoptosis(37).

ROS production induced cancer cells cytotoxicity were increased by 46.5% in the MDA-MB231 and 29.3% in Sk-BR-3 cells with the combination compared to DIM or DOC alone(37).

The overexpression of ROS was correlated with a 54% decrease in antioxidant MnSOD and 47% increase of free radicals NOX2 protein compared to the other groups(37).

Dr. Lanza-Jacoby S, the lead scientist concluded, "DIM enhances the sensitivity of breast cancer cells to DOC treatment by increasing ROS, which led to decreased cell survival and apoptosis"(37).

Furthermore, in order to reveal more information about the DIM, researchers investigated the bioactive compound against HER2/neu positive breast tumors(38).

The differentiation included MDA-MB-435eB1 human Her2/neu breast cancer cells treated with varying concentrations of DIM and paclitaxel(38).

Both DIM and paclitaxel exhibited time and concentration-dependent inhibition of cell proliferation(38).

The combination also increased the number of apoptotic cells more than either agent alone, according to tested assays(38).

Moreover, the combined treatment exerted breast cancer cells apoptosis by inhibiting the proteins associated with cancer cell proliferation and survival and exhibiting the function of enzymes associated with cell death programming(38).

Additionally, DIM alone inhibited the cancer expression by decreasing the activation of the Her2/neu receptor and the combination decreased the activation of ERK1/ERK2 associated with cancer cell proliferation(38).

The results suggested that DIM enhanced the function of chemo medicine against the development and progression of breast cancer(38).

4.3. Colorectal cancer

Colorectal cancer is a medical condition caused by cell growth irregularly in the tissue of the colon or rectum due to the alternation of cells DNA(39).

According to the statistics provided by the American Cancer Society, in the US, colorectal cancer is the third most common cancer diagnosed in both men and women compared to other types of cancer(39).

The lifetime risk of colorectal cancer is 1 in 22 (4.49%) for men and 1 in 24 (4.15%) for women(40).

Approximately, 140,000 cases of colorectal cancer were diagnosed in the US in 2018. Cancer also causes of death of over 50, 000 people, representing 8.3% of total cancer death(40).

Being overweight or obese. smoking, physical inactivity, excessive alcohol drinking, the increased in age, family and personal history, genetic preposition are some of the prevalent risks of the disease(41).

Some researchers suggested that unhealthy diet such as the promotion of the Western diet over the past few decades may be one of the major causes of colorectal cancer(42).

Dr. Alan Moss, the lead scientist in the evaluation of the association of between diet and colorectal cancer risk, wrote, "Studies that examined dietary factors and various cancers showed that one of the strongest associations is between CRC and meat consumption"(42).

And "Recently, global publicity was generated by the World Health Organization International Agency for Research on Cancer consensus statement regarding the increased risk of CRC with consumption of processed or red meat.4 The 2015 statement notes that processed meat is carcinogenic to humans and lists processed meat as a group 1 substance. Processed meats result from salting, smoking, fermenting, or curing the meat, and common examples include ham, bacon, and sausage"(42).

The results clearly suggested that by changing your diet pattern from the Western diet to a traditional diet with high fruits and vegetables, your risk colorectal can be reduced substantially(42).

Researchers in the concern of the slow growth of colorectal cancer and the prognosis in colorectal cancer patients examined the effects of 3,3'-Diindolylmethane (DIM) on cyclin D1, which was aberrantly overexpressed in colorectal cancer cells and tumors(43).

Where cyclin D1 is a protein needed for cellular proliferation in the G1 phase of the cell cycle(43).

Injection of DIM inhibited the cyclin D1 expression in colorectal cancer cells (CRC), without affecting the PPARγ expression and protease activity in regulating the process of cell differentiation(43).

Moreover, DIM inhibition of the cell cycle in the G1 phase of colorectal cancer cells (CRC) without alternating the cyclin D1 mRNA expression. The results suggested DIM modulated cyclin D1 expression at the translational level through some unknown mechanisms(43).

Dr. Zhang X and colleagues wrote in the final report, "the present study demonstrates that DIM downregulates cyclin D1 through triggering ER stress in human colorectal cancer cells"(43).

In other words, DIM-induced cell cycle arrest of the colorectal cancer cells by modulating the G1 phase of the cell cycle(43).

Additionally, in order to reveal more information about the DIM anti-colorectal cancer activity, researchers elucidated the molecular mechanism of ATF3 induction by DIM in human CRC cells(44).

The DIM treatment induced apoptosis and induced ATF3 gene expression at protein and messenger RNA levels, involving the DNA repair of the damaged cells(44).

However, in colorectal cancer cells, deletion and point mutation of the ATF binding site (-23 to -16) abolished ATF3 promoter activation by DIM, leading to overexpression of ATF4 associated with the promotion metabolic homeostasis and cancer cell survival(44).

4.4. Gastrointestinal (GI) Cancer

Gastrointestinal (GI) cancer is a group of cancers, affecting the digestive system, including esophagus, gallbladder & biliary tract, liver, pancreas, stomach, small intestine, bowel, and anus(45).

The digestive system consists of the gastrointestinal tract and other parts of the accessory organs of digestion including the tongue, salivary glands, pancreas, liver, and gallbladder), involved in the function of breaking down food into smaller and smaller components then absorbed before passing them as nutrients and fluids to the body(46).

Most cases of gastrointestinal cancer start in the cells on the surface of the inner lining tissues, depending on the location of the affected organs(45).

At the early stage, most patients are asymptomatic due to the small size of the tumor. However, at the later stage, after penetrating into deeper layers of the organ, cancer cells can travel through blood and fluids circulation to infect other healthy tissues or organs, leading to secondary metastasis(45).

At this stage, besides sharing the general symptoms of other types of cancer, gastrointestinal cancer also cause symptoms of severe pain and bleeding due to the overgrowth tumor size have suppressed the nearby blood vessels and nerve cells(45).

The exact causes of gastrointestinal cancer are not identified. However, genetic preposition, unhealthy lifestyle and medical conditions are some of the prevalent risks of the disease(45).

Some researchers suggested that a poor diet may have a strong implication on the incidence of gastrointestinal cancer(47).



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Titel: The Science of Phytochemical