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).
Intake of DIM as a form of supplement should be taken with extreme care to prevent overdose toxicity(7).
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).
Dr. Reilly T. Enos, the leads scientist said, "High-fat-diet (HFD) consumption is associated with colon cancer risk"(47).
And, "HFDs with the highest SF content had the greatest concentration of Muc2. Our data suggest that high dietary SF is protective in the AOM/DSS model of colon cancer, which may be due, at least in part, to the ability of SF to maintain intestinal barrier integrity through increased colonic Mucin 2"(47).
With an aim to find a natural compound for the treatment of gastrointestinal cancers, researchers examined the 3,3'-Diindolylmethane (DIM) activity against effective gastrointestinal cancers(48).
In vivo and vitro, injection of the DIM acted upon several cellular and molecular processes in gastrointestinal cancer cells(48).
In cancer cells apoptosis, DIM initiated production reactive oxygen species (ROS) in generating stress, triggering DNA damage by increasing the cytotoxicity(48).
In angiogenesis, DIM inhibited the protein associated with the generation of a new blood vessel for cells survival and proliferation.
In cell cycle regulation, DIM deactivated the expression of protein kinases which play the critical roles in the cancer cells division(48).
Furthermore, DIM triggers cellular endoplasmic reticulum (ER) stress and apoptosis within the cancer cells(48).
In autophagy, DIM inhibited autophagy that leads to cell death(48).
In metastasis, DIM inhibited the growth of human cancer cells by interfering with multiple signaling pathways, involved restraining invasion, migration, and promoting apoptosis(48).
Furthermore, DIM used combined with conventional chemo drugs or therapeutic chemicals increased the efficacy of other drugs for the treatment of gastrointestinal cancer(48).
4.5. Glioblastoma
Glioblastoma is one of the most aggressive cancers that begins within the brain(49).
According to statistics, most patients diagnosed with cancer die within 12 to 15 months. Less than 5% of patients are survived longer than five years(49).
If you are male you are at 1.5 higher risks of glioblastoma, compared to the female's counterpart(50).
The causes of glioblastoma are unknown, some researchers suggested that genetic preposition and environmental factors, previous radiotherapy(49), a weakened immune system(52)may be some risk factors associated with the onset of the disease(49).
Most cases of GBM are diagnosed at an older age with a median age of 64(51). Some researchers suggested that aging with the change of body function may be one of the major risk factors that cause the incidence(51).
Dr. Judith Schwartzbaum, an associate professor of epidemiology and a member of The Ohio State University’s Comprehensive Cancer Center, in the study focused on the relationship between chemical signals from the immune system and the development of brain cancer uncovered the relationship between allergies, the immune system, and brain cancer(52). It appears that allergies may protect against the development of brain cancer.
She wrote, "It's important to identify the early stages of tumor development if we hope to intervene more effectively. " and "If you understand those early steps, maybe you can design treatments to block further tumor growth"(52).
The results strongly suggested that people with a weakened immune system such as the elderly may be at a higher risk of glioblastoma(52).
Researchers in the concern of current therapy deficits for treatment glioblastoma due to the limitation of limits the transport of essential drugs to the tumor sites. examined the effects of 3,3'-diindolylmethane by encapsulation in poly (lactic-co-glycolic acid) nanoparticles(53).
Nanoformulation loading of 27-87nm and encapsulation efficiency of 7.2% and 70% respectively showed to induce the glioma cells apoptosis internally(53).
Furthermore, in vivo, a bio-distribution study revealed the selective accumulation of the nanoformulation into rat brain tumor sites by crossing the blood-brain barrier(53).
Moreover, the nanoformulation also exhibited the abrogation of epidermal growth factor receptor pathway which has been found to that promote the growth and spread of glioblastoma cells(53).
Dr. Bhowmik A, the lead scientist after taking into account co and confounders, wrote, "Our novel nano preparation, therefore, shows great promise to serve as a template for targeted delivery of other therapeutics in treating GBM"(53).
In order to reveal more information about the prognosis for glioblastoma patients, researchers examined the 3,3'-diindolylmethane anti glioblastoma activity(54).
Indole-3-carbinol and related fragments, including 3,3'-Diindolylmethane exerted a potent anti glioblastoma activity with low micromolar activity, particularly resistant glioblastoma cell culture(54).
The finding clearly suggested that 3,3'-diindolylmethane alone or encapsulated in poly (lactic-co-glycolic acid) nanoparticles induced the glioblastoma cells and resistant glioblastoma cells death through a number of mechanisms(54).
4.6. Liver Cancer
The liver is the largest internal organs in the human body which plays a critical role for maintaining the integrity of cells wall, production of vitamin D and steroid hormone and aiding the digestive system in the absorption of nutrients, through the production of cholesterol(55).
Additionally, the liver also filters out waste from the blood coming from the digestive system before passing them to the other parts of the body(55).
Liver cancer is a medical condition caused by irregular cell growth in the tissues of the liver(56).
Most cases of liver cancer start in the cells on the surface of the inner lining of the liver tissues before penetrating into deeper layers of the liver(56).
At the early stage due to the small size of the tumor and lack of nerve tissues, most patients are asymptomatic(56).
However, at the advanced stage, cancer cells can travel a distance away from the liver to infect other healthy tissues and organs, leading to secondary metastasis(56).
Patients at this stage may experience the general symptoms of cancers such as gastrointestinal discomforts, unintended weight loss, loss of appetite and fatigue accompanied by the symptoms of persistent upper abdominal pain, abdominal swelling, jaundice, and chalky stools(56).
If you have some of the aforementioned symptoms, please make sure you check with your doctor to rule out the possibility of liver cancer.
Out of many risk factors associated with the onset of liver cancer, some researchers suggested that people who carry hepatitis viral may have a substantially higher risk of the disease(57).
Dr. Marc Ringehan, the lead researcher said, "Hepatitis B and C viruses are a global health problem causing acute and chronic infections that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). These infections are the leading cause of HCC worldwide and are associated with significant mortality, accounting for more than 1.3 million deaths per year"(57).
And, "The majority of viral-associated HCC cases develop in subjects with liver cirrhosis; however, hepatitis B virus infection can promote HCC development without prior end-stage liver disease"(57).
In two HCC cell lines SMMC-7721 and MHCC-97H, injection of DIM inhibited the proliferation, migration, and invasion of cancer cells(58).
In nude mice, DIM significantly decreased the volumes of SMMC-7721 orthotopic liver tumor and suppressed lung metastasis(58).
Furthermore, DIM decreased the level of phospho-FAK (Tyr397) which is found elevated in both vitro and in vivo(58).
The DIM anti-cancer cells efficacy on proliferation, migration, and invasion are probably due to the inhibition of the expression of matrixes (MMP2-9) associated with the promotion of cancer cells growth and invasion(58).
Dr. Li WX, the lead scientist wrote, "These results demonstrated that DIM blocks HCC cell metastasis by suppressing tumor cell migration and invasion"(58).
Moreover, in order to reveal more information about DIM anti-liver cancer activity, researchers investigated whether diindolylmethane effect on HA59T cells(59).
At concentrations of 10-75 μM, diindolylmethane killed cells in a concentration-dependent manner, particularly, in diindolylmethane (25-50 μM) induced apoptosis in a concentration-dependent manner.
The cytotoxic effect of diindolylmethane against the tested liver cancer cell line was not reversed by chelating cytosolic Ca(2+)(59).
Where Calcium (Ca2+) ions are important for cellular signaling. Its flow plays an essential role in regulating several secondary messenger systems in neural adaptation for visual, auditory, and the olfactory system.
The results suggested that DIM inhibited the onset and progression of liver cancer through a number of mechanisms, including proteins involved in anti-cell proliferation and migration, and promotion of apoptosis(59).
4.7. Lung Cancer
Lung cancer is a medical and chronic condition associated with the alternation of the cells in the lung tissue(60).
Most cases of lung cancer start in the cell on the surface of the inner lining of lung tissue before striking into deeper layers(60).
At the early stage, due to the small size of the tumor, most patients are asymptomatic. However, at the advanced stage, besides the common symptoms shared with other types of cancer, the patients may also experience symptoms of difficult breathing, persistent cough and hoarseness, and chest pain(60).
Some patients may also vomit blood caused by the oversize tumor-suppressing on the nearby blood vessels(60).
Lung cancer is diagnosed mostly in the elderly, particularly in people over 65 years of age.
The mortality rate of lung cancer is higher than the colon, breast, and prostate cancers combined(61).
According to the statistics, In Canada, the 5-year net survival for lung cancer is 17%(61).
In other words, on average, only 17% of people diagnosed with lung cancer will survive for at least 5 years after their diagnosis(61).
However, lung cancer at the early localized stage has 5 years of the survival rate of 60%(61).
Although there are many risk factors associated with the onset of lung cancer, smoking is considered epidemiologically a major cause of the disease onset(62).
Dr. Ozlü T, the lead scientist in the examination of smoking and lung cancer risk, "The association between cigarettes and lung cancer has been proven by large cohort studies. Tobacco use has been reported to be the main cause of 90% of male and 79% of female lung cancers. 90% of deaths from lung cancer are estimated to be due to smoking. The risk of lung cancer development is 20-40 times higher in lifelong smokers compared to non-smokers"(62).
And, "After smoking cessation, the cumulative death risk from lung cancer decreases. Patients who continue smoking experience greater difficulties during cancer treatment. Stopping smoking may prolong survival in cancer patients, and also decreases the risk of recurrent pulmonary carcinoma"(62).
Researchers in the concern about the risk of inflammatory conditions of the lung such as chronic obstructive pulmonary disease (COPD) that contributes to the onset of lung cancer risk, particularly lung squamous cell carcinoma (LSCC) examined the chemopreventive effects of BioResponse diindolylmethane (DIM))(63.
The study included a mouse model of inflammation-driven LSCC induced by N-nitroso-trischloroethylurea (NTCU) and enhanced by lipopolysaccharide (LPS), a potent pro-inflammatory agent contained in tobacco and tobacco smoke(63).
Before treatment of DIM, mice treated with the combination of NTCU and LPS had a 9-fold increase in the number of bronchioles with LSC(63).
Compared to mice treated with LPS alone, mice treated with NTCU plus LPS showed significantly increased expression of the pro-inflammatory cytokines, accompanied by the increased expression of proteins associated with the production of pro-inflammation and cancer cells initiation(63).
Pretreatment of DIM at a concentration of 0 μmol/g diet or 2,460 ppm) to mice treated with NTCU plus LPS reduced the incidence of LSCC by 2-fold and suppressed activation/expression of proinflammatory and procarcinogenic proteins without affecting the expression of cytokines and p53, a tumor-suppressive gene(63).
In other words, DIM blocked the development of LSCC through cytotoxicity and gene associated with tumor suppression(63).
In order to reveal more information about DIM anti-lung cancer property, researchers looked into the anticancer efficacy of 1,1-bis (3'-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC₆H₅) inhalation delivery alone and in combination with i.v. docetaxel in a murine model(64).
According to assays, the lung weight reduction in mice treated with the drug combination was 64% compared with 40% and 47% in mice treated with DIM-C-pPhC₆H₅ aerosol and docetaxel alone, respectively(64).
The combination treatment inhibited the lung cancer by decreased expression of proteins associated with the pro-inflammatory cytokines, cancer cells survival, and proliferation through stimulating the production of the new blood vessels(64).
Furthermore, the combination also increased expression of genes involved autophagy in the tumor formation, compared to the tumor cell counts from single-agent treatment and control groups(64).
Dr. Ichite N, the lead scientist said, "These results suggest that DIM-C-pPhC₆H₅ aerosol enhanced the anticancer activity of docetaxel in a lung cancer model by activating multiple signaling pathways"(64).
4.8. Melanoma
Melanoma is skin cancer caused by the alternation of melanocytes DNA in the skin pigment, leading to the formation of moles that change in the color, size or shape on the skin(65).
Most cases of melanoma start in the melanocytes or pigment-producing cells in the outer layer of the skin. However, at the later stage, the cancer cells can travel through the circulation of blood and fluids to infect other healthy cells and tissue, leading to secondary metastasis(65).
The liver, lungs, bones, and brain are most often affected by melanoma metastases(65).
According to statistic, the risk of melanoma is largely depended on the race. the lifetime risk of getting melanoma is about 2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for blacks, and 0.5% (1 in 200) for Hispanics(66).
The 5 years survival rate of melanoma is closed to 100% if the disease is diagnosed in the localized stages(66).
In the US, every year, approximately 96,480 new melanomas are diagnosed, leading to the death of 7,000 people(66).
In North America, most cases of melanoma are associated with UVB exposure, causing the alteration of cell DNA(67).
Dr. S A Oliveria, the lead scientist said, "Sun-sensitive phenotypes and reported sunburn were associated with an increased risk of melanoma" and "intense sun exposure is causal for melanoma in those prone to sunburn"(67).
Researchers on finding a natural compound for the treatment of melanoma compared the effects of
kaempferol (Kem), genistein (Gen), and 3'3-diindolylmethane (DIM) on melanoma cell viability(68).
Treatment of A375SM melanoma cells with the tested phytochemicals resulted in inhibition of cell growth(68).
DIM exerted the strong inhibition against the A375SM melanoma cells by increasing the tumor-suppressive gene expression, p21 and decreasing the gene expression associated with the cancer cell proliferation and survival(68).
Injection of DIM and other tested phytochemical also induced the expression of pro-apoptotic pathways against the tested cancer cell line and deactivated the anti-apoptotic pathways(68).
Furthermore, DIM and tested phytochemical also enhanced the activity of ROS in the induction of cytotoxicity without causing harm to the healthy cells(68).
Dr. Heo JR and colleagues said, "These results indicate that phytochemicals (kaempferol (Kem), genistein (Gen), and 3'3-diindolylmethane (DIM)) are potentially useful in treatments for melanoma due to their ability to inhibit melanoma cell growth and division"(68).
Taken altogether, 3,3'-Diindolylmethane may be considered a supplement for the prevention and combined with primary medicine for the treatment of melanoma, pending to the confirmation of large sample size and multicenter human study(68).
4.9. Mesothelioma
Mesothelioma is a medical condition characterized by irregular cell growth in the thin layer of tissue that covers the internal organs, due to cell DNA alternation(69).
However, according to the epidemiological studies, the most common area affected is the lining of the lungs and chest wall(69).
Most cases of mesothelioma start in the cell on the surface of the layered tissue. At the later stage, the cells of the larger size of the tumor can cause secondary tumors to develop in nearby organs and distant locations through the circulation of blood and fluids, leading secondary metastasis(69).
Most common symptoms of mesothelioma are persistent dry cough or wheezing, shortness of breath, pain in the chest or abdomen, fatigue and weakness(70).
In severe cases, patients may also experience symptoms of respiratory complications such as pleural effusion (fluid around the lungs)(70).
If you experience some of the above symptoms, please check with your doctor to rule out the possibility.
Most common causes of mesothelioma are due to long-term exposure to asbestos as the disease is found in 80% of the patients. However, suggested that genetic preposition may also be the prevalent risk factor of the disease(71).
Dr. Ombretta Melaiu, the lead scientist in the investigation of the genetic susceptibility in the development of malignant pleural mesothelioma (MPM), wrote, "Among asbestos-exposed workers, several studies reported familial cases of MPM, suggesting that heredity could be important in the tumor development,.... the risk of developing MPM is increased of a limited extent among people exposed to asbestos with a positive history of familial cancers"(71).
And, "In families and in animal models, mutations within BAP1 are strongly predisposing to develop MPM"(71).
The results clearly suggested that if you carry the mutation gene BAP1, you are at a higher risk of MPM and other types of cancer(71).
Scientists in the concern of the malignant mesothelioma (MM), a very aggressive, lethal cancer, and its incidence is increasing worldwide examined the dietary phytochemicals which may process the potential for the treatment of MM with no side effect(72).
The study included several bioactive ingredients such as curcumin, epigallocatechin gallate, quercetin, genistein, pterostilbene, resveratrol, capsaicin, ellagic acid, benzyl isothiocyanate, phenethyl isothiocyanate, sulforaphane, indole-3-carbinol, 3,3'-diindolylmethane (DIM), diallyl disulfide, betulinic acid, and oleanolic acid(72).
DIM was found to process the anti-MM activity by boosting the function microRNA in the regulation of the activities of the genes(72).
Where MicroRNAs (miRNAs) are a class of small noncoding RNAs of ∼22nt in length involved in the regulation of gene expression against the incidence of cancer. Increased expression of microRNAs is associated with numerous types of cancer(73). Overexpression of miR-132 in vivo was associated with the severity of cancer patients(73).
Injection of DIM exerted anti mesothelioma potentials, through the expression microRNA regulatory activities.was attributed to the suppression of macrophage infiltration and pro-inflammatory cytokines(72).
In other words, DIM modulated the immune response against the onset and progression of mesothelioma caused by the production of oxidative stress due to the overexpression of inflammatory cytokines in the initiation of the disease(72).
Dr. Sayeed MA the lead scientist wrote in the final report, "In addition to microRNA regulatory activities, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, phenethyl isothiocyanate, and sulforaphane have anti-mesothelioma potentials, and pterostilbene, capsaicin, ellagic acid, benzyl isothiocyanate, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulfide, betulinic acid, and oleanolic acid have potentials to inhibit cancer by regulating the expression of various genes which are also known to be aberrant in MM"(72).
4.10. Nasopharyngeal Cancer
The nasopharynx is the upper part of the pharynx, connecting with the nasal cavity above the soft palate that allows a person to breathe through the nose(74).
Nasopharyngeal cancer is a medical condition characterized by cells growth irregularly and disorderly in the tissues of the nasopharynx(75).
Most cases of nasopharyngeal cancer start in the cells on the surface of the inner lining of the nasopharynx. The early stage of nasopharyngeal cancer is asymptomatic due to the very small size of the tumor(76).
However, at the advanced stage, the oversize may suppress the nearby nerves and blood vessels, leading to severe throat pain and symptoms of a lump in your neck blood in the saliva, bloody discharged from your nose, particularly, persistent nasal congestion or ringing in your ears, accompanied with the general symptoms shared with other cancers(75).
According to the statistics provided by the American cancer society, nasopharyngeal cancer (NPC) is quite rare in the United States)(76). The risk of cancer is less than one case for every 100,000 people.
Epidemiologically, some patients at this stage may also experience symptoms of frequent ear infections, hearing loss and headaches(76).
If you have some of the aforementioned symptoms, please check with your doctor to rule out the possibility.
The exact causes of nasopharyngeal cancer are unknown. Gender, family history, ethnicity, where you live, poor diet, infected by the Epstein-Barr virus are some of the prevalent factors of nasopharyngeal cancer(77).
On finding potential and plant-based compound for the treatment of nasopharyngeal cancer, researchers examined the antitumor effects of DIM in a long-term low-dose manner in nasopharyngeal carcinoma (NPC)(78).
The study included NPC cells induced by 20 µmol/l DIM for over a month(78).
During the experiment, the injection showed significantly reduced the cell metastasis in vivo(78).
Furthermore, according to assays, DIM significantly reduced the proliferation and migration of without inducing apoptosis(78).
Long-term dose administration also exerted antitumor activity by altering the signaling pathways which are mutated in human cancer and protein associated with the anti-apoptosis, proliferation and cell survivals(78).
Moreover, in order to reveal more information about DIM antitumor efficacy, researchers launched an investigation of the pro-apoptotic and anti-proliferative effects of 3,3'-diindolylmethane (DIM) in various tumor cell types(79).
DIM-induced apoptosis and inhibited proliferation in nasopharyngeal carcinoma cells by inhibiting the activity of telomerase which is crucial for the survival of cancer cells, in a dose‑dependent manner(79).
The mRNA and protein expression of hTERT which is a catalytic component of human telomerase and used as a biomarker of a tumor was inhibited following treatment with DIM without causing a change of telomerase RNA (hTR)(79).
In other words, DIM-induced apoptosis and inhibited proliferation were attributed to its activity on telomerase by targeting the expression of hTERT(79).
The results indicated that DIM inhibited nasopharyngeal carcinoma cells by shortening the telomeres in a concentration‑dependent manner(79).
4.11. Ovarian Cancer
Ovarian cancer is the medical and chronic condition characterized by irregular cells growth in the tissues found either in at the tail ends of the fallopian tubes or the ovaries(80).
According to the statistics provided by the American Cancer Society, ovarian cancer is one of the dealy reproductive cancer in women. Every year, the disease causes more deaths than any other cancer of the female reproductive system(81).
The lifetime risk of a woman getting ovarian cancer is 1/78 compared to the lifetime dying risk of 1/108(81).
The 5-year relative survival of all stages of ovarian cancer is 47%. However, women with ovarian cancer diagnosed at the localized stage have a 5 years survival rate of over 92%(81).
The exact causes of ovarian cancer are not identified(82). However, epidemiological studies suggested that women who have endometriosis, genetic preposition such as BRCA1 and BRCA2 gene, acquired genetic mutation such as TP53 tumor suppressor gene are susceptible to the substantial risk of the development of the disease(82).
Besides sharing the common symptoms of other types of cancer, most ovarian cancer patients may experience symptoms of discomfort in the pelvic area, changes in bowel habits, such as constipation. and a frequent need to urinate(83).
In seeking a natural product which processes anti-ovarian cancer property, researchers examined the effects of 3,3'-diindolylmethane (DIM) on ovarian cancer cell viability, invasion, and sensitivity to chemotherapy(84).
According to the final results obtained by the ovarian cancer SKOV3 and A2780 cell lines treated by the 3,3'-diindolylmethane (DIM), DIM treatment not only potently suppressed the viabilities of ovarian cancer cells but also inhibited xenograft growth in nude mice(84).
Furthermore, according to the gene analysis, DIM inhibited phosphorylation of STAT3 and AKT proteins and proteins activated by STAT3 and AKT involved in cell growth and division and cell movement in the ovarian cancer SKOV3 and A2780 cell lines(84).
Moreover, DIM inhibited the production of protein and genes associated with the production of a new blood vessel for the cancer cells to growth, promotion of cancer cell survival and anti-apoptosis(84).
Additionally, in order to obtain more information about DIM anti-ovarian cancer effects, researchers examined the phytochemical activity on Interleukin (IL6) which has been found to be a major contributor to the initiation and progression of ovarian cancer(85).
During the experiment, human ovarian carcinoma-derived cell lines SKOV3 and A2780 treated with IL6 and/or DIM and subjected to in vitro proliferation, DIM inhibited the increase of ovarian cancer cell adhesion, migration, and invasion caused by the administration of IL-6 through deactivated the expression of protein STAT3 similar to that of the aforementioned study(85).
Importantly, DIM induced ovarian cancer cells apoptosis associated with the inhibition of the expression matrix metalloproteinases MMP-2 and MMP-9 associated with the pathologic relationship to cancer(85).
4.12. Pancreatic cancer
Pancreatic cancer is a chronic condition characterized by cell growth irregularly in the tissues of the pancreas(86).
According to statistics, every year, approximately, over 55,000 adults in the United States are diagnosed with pancreatic cancer, accounting to 3% of all cancers and 7% of all cancer deaths(87).
The survival rate of pancreatic cancer even diagnosed at the early is very low compared to other types of cancer. The 5-year survival rate at stage IA pancreatic cancer is only14%(87).
Researchers do not know what causes pancreatic cancer. They don't even know why people with the same health conditions in the same family, some are susceptible to pancreatic cancer, while others do not(88).
Most common risk factors of pancreatic cancer are similar to those of common cancers, including age, family history, gender, ethnicity, smoking, being overweight or obesity and certain medical conditions such as diabetes(88).
However, some researchers suggested that an unhealthy diet with high animal products such as the Western diet is associated with an increased risk of pancreatic cancer(89).
Dr. McCarty MF at the Pantox Laboratories, in the investigation of the insulin secretion as a determinant of pancreatic cancer risk, wrote, "In international ecologic epidemiology, pancreatic cancer rates correlate tightly with dietary intake of animal products; this may reflect the fact that vegan diets are associated with low diurnal insulin secretion"(89).
And, "There is also suggestive evidence that macrobiotic vegan diets, which are low in glycemic index, may increase mean survival time in pancreatic cancer. However, other types of diets associated with decreased postprandial insulin response, such as high-protein diets or 'Mediterranean' diets high in oleic acid, may also have the potential for pancreatic cancer prevention"(89).
The results clearly indicated a reduced risk of diets associated with less consumption of animal products and high fruits and vegetables such as traditional and vegan diet(89).
Researchers on finding a natural ingredient for the treatment of pancreatic cancer examined the function of dietary 3,3'-diindolylmethane (DIM) on the molecules of pancreatic cancer through the mechanistic underexpression of Krüppel-like factor 4 (KLF4) in pancreatic cancer(90).
Where Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor plays a critical role in the regulation of many cellular functions in both normal and neoplastic (benign or cancer) cells(90).
Injection of 3,3'-Diindolylmethane inhibited the overexpression of DNA methyltransferase 1 (DNMT1) in the promotion of cell cycle division, leading to the decreased KLF4 expression(90).
In other words, 3,3'-Diindolylmethane increased KLF4 expression in altering pancreatic cancer cells cycle progression by arresting the cells at the G2/M phase(90).
The findings indicated that DIM treatment caused significant inhibition of cell growth in vitro and tumorigenesis in animal models of pancreatic cancer(90).
Dr. Xie VK and colleagues said, "dysregulated KLF4 expression associated with poor differentiation of pancreatic cancer" and "dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells"(90).
In order to reveal more information about the effect of DIM against the progression pancreatic cancer, researchers investigated the overexpression of miR-221 in pancreatic cancer cell lines and tumor tissues compared to normal pancreatic duct epithelial cells and normal pancreas tissues(91).
Application of DIM exerted a significant effect in enhancing the transfection of miR-221 inhibitor in suppressing the proliferative capacity of pancreatic cancer cells accompanied by the activation of genes associated with tumor suppression(91).
Futhermore, injection of DIM alone or combined with isoflavone mixture (G2535), formulated 3,3'-diindolylmethane (BR-DIM), or synthetic curcumin analog (CDF) demonstrated a strong effect against the expression of miR-221 in pancreatic cancer cells, leading to the inhibition of cell proliferation and migration(91).
Dr. Sarkar S, the lead scientist wrote in the final report, "These results provide experimental evidence in support of the oncogenic role of miR-221 and also demonstrate the role of isoflavone, BR-DIM, and CDF as potential non-toxic agents that are capable of down-regulation of miR-221"(91).
4.13. Prostate cancer
Prostate cancer is a medical condition caused by cell growth disorderly in the tissue of the prostate glands. Prostate cancer is one of the most slow-growing cancers that take years to develop(92).
The disease often is discovered during the rectum examine annually. Most cases of prostate cancer start in the cells on the surface of the inner lining of prostate tissue(92).
In the early stage, patients may not experience any symptoms. However, at the advanced stage, prostate cancer can induce symptoms of blood in the urine and semen, disruption of urinary passing, frequent and urged urinary(93).
In severe cases, prostate cancer can also cause erectile dysfunction(93).
According to statistic, 1 man in 9 will be diagnosed with prostate cancer during his lifetime(94).
Most cases ( about 60%) of prostate cancer are found in older men, particularly in the African-American. The 5-year survival rate of local or regional prostate cancer is nearly 100(94).
Out of many risk factors, the unhealthy diet may be one of the major risk factors associated with the onset of the disease(95).
Some researchers in the study of the preventive diet against prostate cancer wrote, " Although the available data are not entirely consistent, possible preventative behavioral factors include increased physical activity, intakes of tomatoes, cruciferous vegetables, and soy. Factors that may enhance prostate cancer risk include frequent consumption of dairy products and, possibly, meat"(95).
" By comparison, alcohol probably exerts no important influence on prostate cancer development. Similarly, dietary supplements are unlikely to protect against the onset of prostate cancer in healthy men"(95).
"Several factors, such as smoking and obesity, show a weak association with prostate cancer incidence but a positive relation with prostate cancer mortality. Other factors, such as fish intake, also appear to be unassociated with incident prostate cancer but show an inverse relation with fatal prostate cancer"(95).
Researchers on finding a natural compound for the treatment of prostate cancer examined the effect of 3,3'-Diindolylmethane (DIM) as tumor inhibitors in multiple malignant tumors on microRNAs (miRNAs)(96).
Tetrachlorodibenzo-p-dioxin (TCDD) and 3,3'-Diindolylmethane (DIM) application showed a significant effect on the inhibition of proliferation and invasion of prostate cancer cells(96).
Furthermore, Tetrachlorodibenzo-p-dioxin (TCDD) and 3,3'-Diindolylmethane (DIM) treatment induced cancer death by inhibiting the expression level of CYP1A1, an enzyme associated with the activation of the compounds with carcinogenic properties(96).
In other words, Tetrachlorodibenzo-p-dioxin (TCDD) and 3,3'-Diindolylmethane (DIM) treatment activated the expression of MAP3K12 in the promotion of cancer cell by targeting the mRNA of miR-150-5p in prostate cancer cells(96).
Moreover, in order to reveal more information of DIM anti-prostate cancer activity, researchers examine the modulation of the immune system by cancer-protective food bioactives, indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM)(97).
Injection of indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM), exerted prostate cell protective effect by the regulation of inflammatory responses in monocytes and macrophages of the immune system(97).
In other words, I3C and DIM inhibited the lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria in the induction of IL-1β mRNA associated with the immune response to infection and protein in the monocyte form of the white blood cells(97).
I3C and DIM also exerted anti-inflammatory activity by inhibiting the expression of gene CD84 mRNA in signaling T-cell activation by regulating the proteins associated with the expression of the gene(97).
Dr. Wang TTY and colleagues after taking into account co and confounders, wrote, "cross-talk between AHR(protein associated with regulating gene expression) and inflammation-mediated pathways, but not CD84-mediated pathways, in monocytes but not macrophages may contribute to the modulation of tumor environments by I3C and DIM in prostate cancer(97)'.
The results strongly suggested that DIM modulated the immune function against the process of prostate cancer development and progression(97).
5. Chronic Diseases
Chronic diseases are a group of medical conditions most commonly associated with aging, including
arthritis, cardiovascular diseases such as heart attacks and stroke, cancer, diabetes, epilepsy and seizures, and obesity(98).
The exacted causes of chronic diseases are not identified(99). Aging, unhealthy lifestyle such as excessive alcohol drinking smoking, poor diet, lack of physical activity are the most common risk factors associated with the onset of the disease(99).
According to the article by the National Health Council, chronic diseases are among the most prevalent and costly health conditions in the US, affecting over 133 millions of the US population as many of them suffer from at least one chronic disease and the number is growing in the rapid rate(100).
Some chronic diseases such as cancer have been found to be the leading causes of hospitalization, long-term disability, reduced quality of life, and death(100).
According to the Centers for Disease Control, chronic diseases also are the major driver of health care costs accounted for nearly 75 percent of aggregate healthcare spending and increased absenteeism that impact workforce patterns(101).
Each chronic patient has cost the health care spending $5300 annually(101).
Believe it or not, chronic diseases in the US, chronic diseases are responsible for 7 out of 10 deaths yearly. In other words, chronic diseases kill more than 1.7 million Americans each year(101).
Some researchers suggested by changing unhealthy lifestyle pattern, chronic diseases may be preventable(102).
Dr. Walter C. Willett, the lead scientist in the concern about the risk chronic disease in poor lifestyle individuals wrote, "Several lines of evidence indicate that realistic modifications of diet and lifestyle can prevent most CAD, stroke, diabetes, colon cancer, and smoking-related cancers"(102).
And, "Among U.S. adults, more than 90 percent of type 2 diabetes, 80 percent of CAD, 70 percent of stroke, and 70 percent of colon cancer are potentially preventable by a combination of nonsmoking, avoidance of overweight, moderate physical activity, healthy diet, and moderate alcohol consumption"(102).
Researchers on finding a natural ingredient for the treatment of chronic diseases analyzed 3,3'-diindolylmethane (DIM) several biological activities on cellular and molecular levels against chronic diseases, including cancer(103).
DIM enhanced the function of the drug-metabolizing enzyme by blocking activity involved the promotion of cancer expression(103).
DIM affects multiple signaling pathways and target molecules which controls cell division, apoptosis, or angiogenesis deregulated in cancer cells(103).
DIM also prevented the development of hormone-dependent cancers(103).
Injection of DIM also was found to inhibit the onset of cardiovascular disease, obesity, and diabetes reduction through its antioxidant property in reducing oxidative stress caused by overexpression of free radical.
Dr. Licznerska B, the lead scientist after taking into account other factors wrote in the final report, "the current experimental data on the I3C and DIM activity and the results of clinical studies indicating their role in the prevention of chronic diseases"(103).
6. Colitis
Colitis is a class of conditions characterized by inflammation of the inner lining of the colon, including Crohn's disease, ulcerative colitis, ischemic colitis(104).
Most cases of colitis are caused by infection, chronic inflammation(104)(105).
Most common colitis can be classified into(105)
* Ulcerative colitis is a chronic disease that causes inflammation and ulcers within the inner lining of your large intestine. Most cases of ulcerative colitis start in the rectum and spread to the colon(105).
* Pseudomembranous colitis (PC) is a type of inflammation caused by the overgrowth of the bacterium Clostridium difficile. Most cases of PC are associated with the use of antibiotics that causes the imbalance of the ratio of bacterias in the digestive tract(105).
* Ischemic colitis (IC) is a type of inflammation of the large intestine or colon caused by interruption of blood flow in the colon. Most cases of IC occur in older adults over 60 years of age(105).
Most of the common symptoms of colitis are total depending on the causes of the disease including abdominal pain, cramping, diarrhea, and blood in the stool(104).
If you experience some of the above symptoms, please make sure to check with your doctor to rule out the possibility.
Although there are a number of risk factors associated with the onset of colitis, an unhealthy diet may be one of the major cause in the Western worlds coincidently with the promotion of such diet overpass few decades(106).
According to the University of Chicago Medical Center in the study of "Western diet changes gut bacteria and triggers colitis in those at risk" in vitro, wrote in the final report, "Certain saturated fats that are common in the modern Western diet can initiate a chain of events leading to complex immune disorders in those with a genetic predisposition"(106).
And, "This is the first plausible mechanism showing step-by-step how Western-style diets contribute to the rapid and ongoing increase in the incidence of inflammatory bowel disease" (106).
The results provide an explanation of the Western diet risk of inflammatory bowel disease, one many forms of colitis(106).
Researchers in the concerns of the chronic inflammation in ulcerative colitis (UC) associated with the risk of colon cancer (CAC) examined the effects DIM in inhibiting the microRNAs (miRNAs) expression against CAC pathogenesis(107).
Where MicroRNAs (miRNAs) are a class of small noncoding RNAs of ∼22nt in length involved in the regulation of gene expression including inflammation and angiogenesis(107).
The study included the use of 3,3'-diindolylmethane (DIM) to activate aryl hydrocarbon receptor (Ahr) in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC in mice(107).
Where aryl hydrocarbon receptor is a transcription factor associated with the regulation of gene expression(108).
Application DIM inhibited miR-132 expression and alleviated CAC severity by suppression of macrophage infiltration and pro-inflammatory cytokines(107).
DIM improved anti-inflammatory activity by suppressing the expression of the inflammatory cytokines, including the production of TNF-α, IL-1β, and IL-6(107).
Futhermore, before the injection of DIM, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC mice abrogated the cholinergic anti-inflammation and exacerbated CAC through silencing miR-132 in vivo(107).
In other words, the injection of TCDD on AChE also is found to exhibit miR-132 in vitro in CD4+ cells and macrophages, leading to the production of inflammatory cytokines(107).
Dr. Alzahrani AM and colleagues wrote in the final report, "miR-132 mediates the ameliorating effects of TCDD on CAC, suggesting miR-132 as a promising therapeutic candidate to control autoimmune inflammation and tumorigenesis in CAC patients"(107).
7. Delayed-Type Hypersensitivity
Delayed-type hypersensitivity is also known as type 4 hypersensitivity because the reaction takes several days to develop, including contact dermatitis(109).
Believe it or not, type IV hypersensitivity mediated by antigen-specific effector T cells is associated with the infection induced by slow-growing intracellular organisms, such as M. tuberculosis (tuberculosis), M. leprae (leprosy) and H. capsulatum(109).
Some researchers suggested that the delayed hypersensitivity is dependent on the presence of a significant number of prime antigen-specific T cells response which typically reaches its peak 24 to 48 hours after exposure to antigen(109).
Type IV hypersensitivity diseases although are common, but ranges second to type 1 hypersensitivity(110).
Many diseases are found to associate with delayed-type hypersensitivity include leprosy, tuberculosis, schistosomiasis, sarcoidosis and Crohn's disease(109).
* Leprosy is divided clinically into three essential types: tuberculoid, borderline, and lepromatous(111)(112).
* Schistosomiasis caused by schistosomes, once the body is sensitized by a granulomatous reaction developed in the parasitized tissue mediated by Th2 lymphocytes(112).
* Tuberculosis in the lungs caused by a granulomatous reaction that leads to cavitation and the spread of bacteria(112).
* Sarcoidosis is a chronic and idiopathic disease caused by the activated macrophage and granuloma accumulation in many tissues along with fibrosis(112).
* Crohn's disease is a granulomatous disease that is not caused by a microorganism(112).
On finding a potential ingredients for the prevention and treatment of the delayed-type hypersensitivity, researchers tested the ability of dietary AhR ligands (indole-3-carbinol [I3C] and 3,3'-diindolylmethane [DIM]) and an endogenous AhR ligand, 6-formylindolo(3,2-b)carbazole (FICZ), on the differentiation and functions of Tregs and Th17 cells(113).
Administration of indoles (I3C or DIM) in tested mice attenuated delayed-type hypersensitivity (DTH) response to methylated BSA, an antigen-specific inflammation in targeted organs(113) and generation of Th17 cells which play a critical role in the induction of the tissue inflammation and tissue destruction while promoting Tregs in the suppression of immune response(113).
Interestingly, the indoles inhibited the delayed-type hypersensitivity by causing the reciprocal induction of Tregs and Th17 cells only in wild-type (AhR(+/+)) but not in AhR knockout (AhR(-/-)) mice(113).
Additional analysis of the indoles anti-delayed-type hypersensitivity activity, researchers found that the efficacy of the indoles was associated with the promotion of protein (FoxP3) involved in immune system responses of the Tregs while decreasing the protein associated with pro-inflammatory expression(113).
In order to reveal more anti-inflammation about indole-3-carbinol (I3C) and diindolylmethane (DIM), researchers investigated the compounds in the exhibition of the characteristics of aryl hydrocarbon receptor (AhR) ligands, that was found to regulate the T cell differentiation(114).
In a murine model of multiple sclerosis (MS), retreatment with I3C or DIM completely prevented the clinical symptoms and cellular infiltration into the CNS through induction of inflammation(114).
Particularly, post-treatment of EAE with I3C or DIM proved highly effective in curtailing the overall severity of the disease(114).
Similar to that of aforementioned protection against delayed-type hypersensitivity, I3C or DIM promoted the generation of T-regs, while inhibited the induction of MOG-specific Th17 cells(114).
In other words, I3C or DIM inhibited delayed-type hypersensitivity through the promotion of T-regs and suppression of Th17 cells in vivo and in vitro were found to be AhR-dependent(114).
8. Heart Muscle
Heart muscle or myocardium is one of three types of muscles in human, that build the walls of the heart(115).
Most common diseases of heart muscle include angina pectoris and myocardial infarction, and other heart muscle disease caused by restricting blood supply to the muscle(115).
Most common symptoms of heart muscle diseases include tightness, pain, or swelling of the legs, ankles, and feet(116).
Some patients may also experience symptoms of gastrointestinal discomforts include bloating, abdominal pain and shortness of breath caused by the reduced blood supply(116).
Most common risk factors associated with heart muscle disease including high blood pressure, heart tissue damage, heart problems, metabolic syndrome, nutritional deficiencies, excessive alcohol drinking(116).
Some researchers suggested that genetic preposition may have a strong effect on the induction of heart muscle disease(117).
The Genetics Home Reference wrote, " mutations in more than 30 genes have been found to cause familial dilated cardiomyopathy. These genes provide instructions for making proteins that are found in cardiac muscle cells called cardiomyocytes"(117).
And, "Mutations in one gene, TTN, account for approximately 20 percent of cases of familial dilated cardiomyopathy"(117).
On finding a natural ingredient which protects the heart muscle against the onset of cardiovascular disease researchers examined the 3, 3'-Diindolylmethane (DIM) effects on cardiomyocytes(118).
Tested cell lines H9C2 used in the study was evaluated by DIM's influence on inflammation and apoptosis of cardiomyocytes induced by LPS. H9C2 cells incubated with DIM (10, 20 and 30 μM) with or without LPS for 24 h(118).
Treatment with various concentrations of DIM (10, 20 and 30 μM) inhibited the overabundance of pro-inflammatory cytokines (TNF-α and IL-6 mRNA expression) induced by LPS(118).
In other words, DIM normalized the levels of impaired TNF-α and IL-6 mRNA expression, in the LPS + DIM30(μM) group(118).
According to the tested assays, DIM treatment significantly blocked LPS-induced oxidative stress and inhibited LPS-induced apoptosis in H9C2 cardiomyocytes(118).
Furthermore, DIM significantly inhibited the LPS-induced expression of a protein associated with proapoptosis and enhanced the expression of a protein involved anti-apoptosis(118).
Dr. Luo Q, the lead scientist, wrote on the final report, "DIM may have a protective effect for H9C2 cardiomyocytes against LPS-induced inflammatory response and apoptosis. DIM may be a new insight into the treatment of septic cardiomyopathy"(118).
In order to find out more information about DIM anti-cardiovascular disease activity, researchers evaluated the function of DIM on the hypoxia‑induced cardiac injury(119).
The study included H9c2 cells pretreated with DIM (1, 5 and 10 µM) for 12 h and exposed to hypoxia for 12 h(119).
DIM with different doses extended markedly attenuated the increased transcription of pro-inflammatory cytokines (interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α) induced by hypoxia(119).
DIM also modulated the genes associated with transcription of autophagy, compared with the hypoxia group(119).
DIM also protected the cells against apoptosis through inhibiting and exhibiting the proteins associated with anti-apoptosis and pro-apoptosis, respectively(119).
9. Hyperglycemia
Hyperglycemia is a condition of abnormally high blood sugar in the bloodstream associated with diabetic complications in patients with type 2 diabetes(120).
In order words, hyperglycemia is a result of the body which isn't properly using or doesn't make the hormone insulin(120).
Hyperglycemia is also considered a hallmark of patients with type 2 diabetes. Another hallmark is insulin resistance(120).
The condition occurs mostly due to poor control and management in patients with diabetes such as
a poor diet, physical inactivity choices, symptoms of medicines intake(120).
Some patients with diabetes also experience symptoms of hyperglycemia due to skipping not taking enough glucose-lowering medication(121).
Most common symptoms of hyperglycemia are frequent urination, increased thirst, blurred vision, persistent fatigue, and headache(121).
If you are having some of the aforementioned symptoms, you may have hyperglycemia. Please make sure you check with your doctor to prevent the longer-term untreated complications.
According to the epidemiological studies, untreated or long term persistently hyperglycemia in patients with diabetes has been found to induce serious symptoms such as shortness of breath, confusion, and coma(121).
With an aim to find a natural ingredient for the treatment of hyperglycemia in patients with type 2 diabetes, researchers examined the effect of the nutritive phytochemicals, indole-3-carbinol (I3C) and its metabolite, 3, 3'- diindolylmethane (DIM) on oxidative stress developed in type 2 diabetes mellitus (T2DM)(122).
The study is carried out on the genetically modified mouse (C57BL/6J mice) similar to those of metabolic abnormalities of the human disease after the administration of a high-fat diet (HFD)(122).
Injection of DIM and I3C positively modulated the glucose, insulin, and hemoglobin (Hb), glycated hemoglobin (HbA1c) level, an indication of the hyperglycemically modulatory activities in the tested HFD mice(122).
Compared to the HFD group, treatment groups showed a decrease in the levels of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), conjugated dienes (CD associated with oxidative stress in lipid peroxidation(122).
Futhermore, DIM and I3C also improved the antioxidant enzymes produced by the host observed by the increasing SOD, CAT, GPx levels in the erythrocyte, liver, kidney, and heart(122).
Levels of free radical scavengers such as vitamin C, vitamin E, and GSH levels are also increased in the plasma, liver, kidney, and heart in diabetic mice(122).
In other words, DIM and I3C protected diabetic mice against diabetics complications by modulating blood glucose and lipid by balancing the ratio of free radicals and antioxidants in the tested subjects(122).
Based on the finding, researchers wrote in the final report, "the antioxidant-scavenging action was accelerated in mice treated with DIM than the I3C treatment group which was comparable with the standard drug metformin"(122).
10. Hypoxia
Hypoxia is a condition of deficiency in the amount of oxygen reaching the tissues, leading to permanent damage to the brain, liver, and other organs(123).
Most common symptoms of hypoxia include fast heart rate, rapid breathing, shortness of breath, slow heart rate and sweating(123).
Hypoxemia is a condition of the abnormally low level of oxygen in the blood(123).
There are many risk factors associated with the onset of hypoxemia, including reduced oxygen levels on the high altitude, damage of the lung that affects the breathing and exhaling function(124).
People with lung and heart disease such as asthma, poor blood circulation, and anemia are at a higher risk of hypoxemia(123).
In the searching for a potential compound against the onset of hypoxia, researchers examined the neuroprotective potential of 3,3'-diindolylmethane (DIM) in cellular and animal models of Parkinson's disease and lipopolysaccharide-induced inflammation(125).
In hypoxia-induced damage in mouse hippocampal cells in primary cultures, the 18 h of hypoxia-induced apoptotic processes in terms of the mitochondrial membrane potential, associated with the process of energy storage during oxidative phosphorylation. activation of a protein associated with cell death induced by fragmentation of cell nuclei(125).
Injection the DIM significantly demonstrated strong neuroprotective and anti-apoptotic actions in hippocampal cells exposed to hypoxia through decreasing the expression genes (Ahr and Arnt) involved the regulation of inflammatory signaling pathways and increasing the gene (Erβ) expression involved suppressing the inflammatory responses(125).
Futhermore, DIM decreased the expression of AhR-regulated CYP1A1 in stimulating the inflammatory response(125).
The results strongly suggested impairment of protein expression of AhR and ARNT, but not ERβ plays a key role in the neuroprotective action of DIM against hypoxia-induced cell damage(125).
Where aryl hydrocarbon receptor nuclear translocator (ARNT) is a component of the DNA binding form of the Ah receptor required for receptor function(108).
And aryl hydrocarbon receptor (AhR) is protein associated with the regulation of genes expression(108).
In other words, the mutation of genes aryl hydrocarbon receptor (AhR) or aryl hydrocarbon receptor nuclear translocator (ARNT) are the culprits in the induction of neuro oxygen deficiency(125).
Based on the findings, researchers wrote in the final report, "This study may have implication for identifying new agents that could protect neurons against hypoxia by targeting AhR/ARNT signaling"(125).
Furthermore, in hypoxia induces oxidative damage in retinal pigment epithelial cells (RPE cells) by cobalt chloride (CoCl2, 200 µM) and/or DIM (10 and 20 µM). DIM significantly attenuated the CoCl2-induced expression of a protein (VEGF) associated with the formation of blood vessels in the ARPE-19 cells compared to the lower levels under normal condition(126).
Similar to those of the aforementioned characteristics, DIM deactivated the genes which play an integral role in the body's response to low oxygen concentrations (HIF-1α) and pro-apoptosis (NF-κB, p38 MAPK) induced by CoCl2(126).
DIM also inhibited the induction of hypoxia by CoCl2 through the inhibition of oxidative stress detected by fluorescence microplate assay(126).
11. Hematopoiesis
Hematopoiesis is the process by which blood cells are formed, including the formation of all of the cellular components of blood and blood plasma.
1. Red blood cells with a function to transport oxygen and hemoglobin to the body(127).
2. White blood cells that form parts of the immune system(127), including
* T cells and B cells, that fight virus, and tumors(127).
* Neutrophils that fight bacteria and fungi(127).
* Eosinophils that fight some parasites and initiate an inflammatory response(127).
* Basophils that release the histamines necessary for the inflammatory response(127).
* Macrophages, the first line of the immune response in the acute phase of infection.
3. Platelets (thrombocytes) for coagulation(127).
Diseases of the bone marrow, spleen, lymph nodes, and thymus may affect the process of hematopoiesis, leading to various diseases of the hematopoietic system(128).
On finding a natural compound for the treatment of hematopoietic injury, researchers examined 3,3'-Diindolylmethane (DIM) effect on the hematopoietic system injury induced by total body irradiation (TBI) that leads to the generation of intracellular reactive oxygen species (ROS) and DNA damage(129).
In TBI-induced lethality mice, DIM ameliorated TBI-induced hematopoietic injury by inhibiting the production of ROS production in hematopoietic stem cells (HSCs)(129).
Furthermore, DIM improved the bone marrow (BM) HSC frequency, hematopoietic progenitor cell (HPC) clonogenic function, and multilineage engraftment after transplantation in tested mice(129).
Additional analysis of DIM anti hematopoietic injury, researchers found that DIM promotes the genes associated with the increased production of antioxidant enzymes (nuclear factor erythroid 2-related factor 2 (Nrf2)) in the hematopoietic stem cells (HSCs) and decreased the production of free radicals (NADPH oxidase 4 (NOX4))(129).
DIM also protected the cells against apoptosis by increasing the expression of the anti-apoptotic protein (Bcl-2) and decreasing expression of the pro-apoptotic protein (Bax)(129).
The results strongly suggested that DIM attenuates TBI-induced hematopoietic injury through the inhibition of both the oxidative stress in HSCs and hematopoietic cell apoptosis(129).
Dr. Lu L and colleagues wrote in the final report, "DIM protected BM hematopoietic cells against ionizing radiation and led to increased clonogenicity in vitro. Therefore, DIM has the potential to be used as an effective radioprotectant to ameliorate TBI-induced hematopoietic injury"(129).
12. Liver Fibrosis
Hepatic fibrosis is a condition caused by scars tissues buildup on the liver which limits the function of the liver(130).
Most cases of hepatic fibrosis is a result of an imbalance of production and dissolution of collagen in extracellular matrix caused by overproduction of proinflammatory cytokines in the acute phase of infection or interruption in the stages of healing(130).
Hepatic fibrosis is an early stage of cirrhosis, a leading cause of liver failure and liver cancer(131).
Patients with hepatic fibrosis are asymptomatic. However, long-term accumulated of liver scar induced cirrhosis can cause symptoms of jaundice, variceal bleeding, ascites, a condition of the accumulation of protein-containing fluid within the abdomen and portosystemic encephalopathy(131).
According to the statistics provided by the Medscape, cirrhosis and other chronic liver diseases are common disease-related causes of death in the U.S. Approximately 31,000 people in the U.S. die each year from cirrhosis(132).
In hepatitis C virus perspective, approximately 3.5 to 4.6 million people in the U.S. are chronically infected with the virus, leading to the death of 2,000 people annually(133).
Most cases of the advanced stages of liver fibrosis are treated by liver transplantation. However, according to the University of California in the development of new therapy for the treatment of liver fibrosis, targeting the steps in HSC activation may be a therapeutic target for liver fibrosis(134).
With an aim to find a potent natural ingredient for the treatment of hepatic fibrosis with no side effects, scientists evaluated the effects of 3,3'-Diindolylmethane (DIM) on excessive collagen deposition produced by activated hepatic stellate cells (HSCs)(135).
Both HSC-T6 cell line and primary HSCs included in the study were examined for the expression of α-smooth muscle actin and collagen I, after injection of DIM(135).
During the experiment, DIM inhibited the expression of miR-21 by deactivating the underlying HSC through suppressing the signaling pathway associated with cell differentiation linking to inflammation and autoimmunity(135).
Where overexpression of microRNA-21 (miR-21) has been found to play a crucial role in the biological functions and diseases, including development, cancer, cardiovascular diseases, and inflammation(136).
The inhibition of miR-21 overexpression was attributed to the effect of DIM in the modulation of the activity of the transcription factor, AP-1, a transcription factor that plays an essential role in the regulation of gene expression in response to a variety of stimuli, including cytokines, growth factors, stress(135).
The findings suggested that DIM in vivo process the potential in attenuating liver fibrosis induced by thioacetamide, according to the assessment of the collagen deposition and profiles of profibrogenic markers(135).
Dr. Zhang Z, the lead scientist wrote in the final report, "DIM shows potential as a therapeutic agent for the treatment of hepatic fibrosis"(135).
13. Liver Protection
Hepatic protection is an action in which substances including medicine and herbal remedy were used to protect the liver against damage(137).
The liver is the largest internal organ with a function which filters the blood from the intestinal tract before passing them to the heart and other parts of the body(138).
Additonally, the liver also produces bile to aid digestion and cholesterol to build strong cell membranes, production of vitamin D and steroid hormones(138).
Liver disease is a broad term included any problems that cause the reduced function of the liver(139).
There are many risk factors that liver problems. Most cases of liver disease are diagnosed in the advanced stage, it takes years to develop(139).
In other words, symptoms of liver disease can be felt only after more than 75% liver is damage(139).
Most common risk factors of liver disease are a genetic preposition, viruses, and long-term excessive alcohol drinking(140).
Non-alcoholic fatty disease (NAFLD), a leading cause of cirrhosis, is one of the most common liver disease found in the Western world, affecting up to 25% of people in the United States(140).
In the urgency of finding a natural compound with liver protective activity, researchers examined the pharmacokinetics of I3C and its derivatives, including 3,3'-Diindolylmethane or DIM multiple protective roles in the processes of chronic liver diseases(141).
Administration of I3C and its derivatives relieved liver oxidative stress by regulating transcriptional factors and their respective signaling pathways associated with the synthesis of DNA to influence the activation, proliferation, and apoptosis of target cells(141).
Furthermore, indoles not only modulated the enzymes that are relevant to hepatitis viral replication, lipogenesis, and the metabolism associated with liver function but also protected the liver against hepatotoxicity (ethanol and some hepatotoxic substances)(141).
In other words, the indoles exerted hepatoprotection by inhibiting pro-inflammatory cytokines and chemokines against microbial-induced liver injuries(141).
Based on the findings, Dr. Wang SQ, the lead scientist said, "Indoles, especially I3C and DIM as phytochemicals, exert anti-fibrosis, anti-tumor, anti-oxidant, immunomodulatory, detoxification and anti-inflammation effects on hepatic protection through pleiotropic mechanism"(141).
And, " I3C and DIM as phytochemicals, exert anti-fibrosis, anti-tumor, anti-oxidant, immunomodulatory, detoxification and anti-inflammation effects on hepatic protection through pleiotropic mechanism"(141).
14. Non-alcoholic steatohepatitis (NASH)
Non-alcoholic steatohepatitis (NASH) is an advanced form of inflammatory non-alcoholic fatty liver disease (NAFLD) caused by a buildup of fat in the liver(142).
NASH has been found to induce the formation of scars of the liver, a leading cause of cirrhosis associated with the onset of liver cancer and liver failure(142).
The progression of NASH has been a leading cause of liver transplant(142).
Patients with NASH are asymptomatic. However, some patients may experience vague pain and discomfort in the abdomen(142).
The causes of NAFLD are identified. Some researchers suspected that long-term unhealthy diet accompanied by physical inactivity may have a strong impact in accelerating the onset of the disease(143).
Dr. Kristen Stephenson in the investigation of the western diet in the risk NAFLD, wrote, "Nonalcoholic fatty liver disease (NAFLD) is a disease of increasing interest, as its prevalence is on the rise. NAFLD has been linked to metabolic syndrome, which is becoming more common due to the Western diet"(143).
And, "WD mouse models consisting of high fat, cholesterol, and a combination of high-fructose corn syrup, sucrose, fructose, or glucose not only lead to metabolic syndrome but also induce NAFLD"(143).
On finding the natural ingredient for the treatment of nonalcoholic steatohepatitis (NASH), researchers at the joint investigation led by the Fudan University examined the effects of 3, 3'-diindolylmethane (DIM) on methionine-choline-deficient (MCD)-diet induced mouse nonalcoholic steatohepatitis (NASH)(144).
NASH mice were administrated with or without DIM at different concentrations for 8 weeks(144).
In vivo, DIM treatment alleviated hepatic steatosis and inflammation and restored the Treg/Th17 imbalance from MCD diet-induced Th17 dominance to Treg dominance(144).
In-vitro, instead of suppressing the expression of Th17m, DIM not only significantly promoted the expression of the mRNAs that purify spleen CD4(+) T cells, but also enhanced the immunosuppressive function of these Treg cells(144).
In MCD-diet mice, DIM significantly exhibited the function of CYP1A1 and CYP1B1 in metabolizing liver toxicity, whereas down-regulated those of TLR4 on CD4(+) T cells in the promotion of autoimmune inflammation, leading to Treg/Th17 imbalance(144).
In other words, DIM treated NASH by dramatical induction of Treg dominance to alleviate intra-hepatic inflammation(144).
Dr. Liu Y, the lead scientist wrote, "dietary cruciferous vegetables (containing abundant DIM) might exist as a protective factor for patients with NASH-related liver diseases"(144).
15. Osteoporosis
Osteoporosis is a medical condition characterized by loss of bone density over time, caused by overexpression of bone loss compared to bone made(145).
In other words, 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, leading to an increased risk of fracture(145).
Most common fractures occurred in patients with OP are the hip, spine, wrist, and shoulder.
Most people with a risk of fracture do not know they have osteoporosis until the disease has advanced to the advanced stage(145).
Researchers do not know the exact causes of osteoporosis. Neither they know why some people with the same health condition in the same family, some are prone to the condition, while others do not(146).
However, according to the epidemiological studies, young age at diagnosis, male sex, aging, race, family history, body size, decreased lean mass, smoking and use of growth hormone replacement are some of the prevalent factors found in most patients with osteoporosis(146).
Most common symptoms of osteoporosis are loss of height over time, back pain, a stooped posture, neck, and low back pain, particularly bone break easily(146).
Recently, some scientists suggested that osteoporosis may also be associated with long term consumption of a poor diet(147).
Dr. Seon-Joo Park in the investigation of dietary patterns and osteoporosis risk wrote, "Three major dietary patterns were identified using factor analysis based on baseline intake data: traditional (high intake of rice, kimchi, and vegetables), dairy (high intake of milk, dairy products, and green tea), and western (high intake of sugar, fat, and bread)"(147).
And, ".., Western dietary pattern (p-trend = 0.043 in radius) demonstrated a higher risk of osteoporosis incidence than those in the lowest quintile"(147).
These results strongly suggested if you are Western diet follower, your risk of osteoporosis is increased substantially compared to other healthy diet pattern followers(147).
On finding the natural compound for the treatment of osteoporosis, researchers investigated the effect DIM on bone mass in mice under physiological and pathological conditions(148).
The study included 8-week-old female mice received injections of a vehicle or 0.1mg/g of DIM, twice a week for four weeks(148).
According to the dual-energy X-ray absorptiometry (DEXA) and micro-computed tomography (μCT) analysis, DIM treatment significantly increased bone mass(148).
Interestingly, treatment od DIM was found to significantly reduce bone resorption parameters but did not increase bone formation parameters(148).
In ovariectomized (OVX)-induced osteoporotic mouse model, administration of DIM effectively prevented OVX-induced bone loss resulting from increased bone resorption(148).
In other words, DIM increased bone mass by suppressing osteoclastic bone resorption in bone metabolism under both physiological and pathological conditions(148).
The results strongly suggested that DIM protect the bone integrity against the onset of osteoporosis in vivo and vitro(148).
Dr. Yu TY, the lead researcher, after taking other factors into account said, "DIM may be of value in the treatment and the possible prevention of bone diseases characterized by bone loss, such as postmenopausal osteoporosis"(148).
16. Oxidative Stress
Oxidative stress is a condition caused either by overexpression of free radicals or depletion of antioxidant enzymes produced by the host(149).
In other words, the condition of oxidative stress occurs only under imbalance of the ratio of free radicals and antioxidants(149).
Antioxidants can be either produced by the body or injected to the body from the outside sources such as consumptions of antioxidant-rich fruits and vegetables(150).
Free radicals are everywhere, including the air we breathe, the food we eat and the body daily functioning such as cell metabolism(150).
In other words, any chemical compound which has an oxygen molecule can become free radical after entering our body(150).
Most healthy individuals can produce enough amounts of antioxidant endogenously to counter the bombards of free radicals. However, for people with a weakened immune system such as elderly and immature immune system such as baby may need the injection of antioxidants from the outside sources(151).
More precisely, people with a weakened immune system do not produce enough antioxidant enzymes to inhibit the chain reaction of free radicals which occurs daily in the body due to the unstable nature of the molecules(151).
Believe it or not, our body needs limit levels of some free radicals to function better, including lower blood pressure, relax blood vessels to move blood, such as nitric oxide NO(150).
With an aim to find the natural ingredient for the treatment of diseases associated with oxidative stress, researchers investigated the effect of indole-3-carbinol (I3C) and its metabolite, 3, 3'- diindolylmethane (DIM) in type 2 diabetes mellitus (T2DM)(152).
The study included selected genetically modified mouse (C57BL/6J mice) similar to that of metabolic abnormalities of the human disease after the administration of a high-fat diet (HFD)(152).
Including indole-3-carbinol (I3C) and its metabolite, 3, 3'- diindolylmethane (DIM) into the diet showed a positively modulated the glucose, insulin, and Hb and HbA1c levels in HFD mice against the risk of diabetes complications(152).
Compared to the HFD group, injection of I3C and DIM protected the infected rat against the formation lipid peroxidation observed by levels of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), conjugated dienes (CD)(152).
Furthermore, levels of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were also increased, an indication of the balance of the ratio of antioxidants and free radicals(152).
Interestingly, I3C and DIM also improved the free radical scavengers such as vitamin C, vitamin E, and improved the reduced glutathione (GSH) levels in treated mice(152).
Based on the findings, researchers summarized, "From the study, it was clear that the antioxidant-scavenging action was accelerated in mice treated with DIM than the I3C treatment group which was comparable with the standard drug metformin"(152).
17. Radiation Intestinal Injury
Intestinal injury of small bowel, colon, or rectum can be due to blunt or penetrating trauma, and irradiation(153).
Intestinal injury can be minor which can be healed by its own or devascularization for blunt injuries and small perforations which may require surgery(153).
Most common symptoms of intestinal injury are totally depending on the severity of the damage, including abdominal tenderness or distension, mild, moderate or severe abdominal pain, forceful bowel movements, the urge to have a bowel movement(154).
Patients may also experience symptoms of blood in the stool and mental confusion(154).
If you have some of the aforementioned symptoms, please see your doctor immediately.
On finding a natural compound for the treatment of intestinal injury, researchers examined 3,3'-Diindolylmethane (DIM), a potent antioxidant agent in the amelioration of hematopoietic injury in a murine model of total body radiation injury(155).
In abdominal irradiation-induced intestinal injury in mice, administration of DIM ameliorated crypt-villus structural and functional injury of the small intestine(155).
DIM also protected the mice against whole abdominal irradiation (WAI)-induced lethality and weight loss(155).
Furthermore, MIC was found to promote the small intestine repair following WAI exposure(155).
MIC protected the intestinal cell against apoptosis caused by the injection of WAI by stimulating the production of proteins which protect the cells against oxidative damage triggered by injury and inflammation(155).
In other words, DIM protected human intestinal epithelial cell-6 (HIEC-6) against ionizing radiation, leading to increase cell vitality by protecting the cell DNA against damage caused by radiation.
The efficacy of the protective activity in the depth analysis was found to associate with the reduction of reactive oxygen species (ROS) levels and promotion of the production of antioxidant enzymatic in tested HIEC-6 cells(155).
Based on the results, researchers suggested DIM restores the WAI-shifted gut bacteria composition in mice in the exhibition of intestinal injury(155).
Dr. the lead scientists after taking other factors into accounts said, "the beneficial properties of DIM mitigate intestinal radiation injury, which provides a novel strategy for improving the therapeutic effects of irradiation-induced intestinal injury"(155).
18. Renal Fibrosis
Renal fibrosis is a progressive condition caused by excessive accumulation of extracellular matrix including collagen, enzymes, and glycoproteins which provided structural and biochemical support of surrounding the renal cells during aging and chronic kidney disease (CKD)(156).
According to the statistics, CKD and renal fibrosis affect approximately half of the adult's age 70 and over and 10% of the world's population(157).
In other words, renal fibrosis is a direct consequence caused by the inability of the kidney to regenerate after injury, leading to the formation of renal scars that results in a progressive loss of renal function(157).
Most cases of renal fibrosis ultimately lead to end-stage renal failure and a need for dialysis or kidney transplantation(158).
At the early stage of renal fibrosis, patients may experience symptoms of dull pain in the abdomen or back, pain on one side between your upper abdomen and back, leg pain. discoloration swelling in one or both legs(158).
If you have some of the aforementioned symptoms, you may have renal fibrosis, please make sure that you check with your doctor to rule out the possibility.
In dialysis point of view in patients with renal fibrosis, Dr. Menn-Josephy H in the examined the risk of dialysis in patients with renal fibrosis wrote, "Surprisingly, 13.9% of patients with normal renal function had 25-49% fibrosis and 5% had more than 50% fibrosis on biopsy, and 5 years after undergoing biopsy 21% of patients with >50% fibrosis still remained dialysis-free. Conclusion: Renal fibrosis is an imperfect prognostic indicator for the development of ESRD and caution should be exercised in applying it too rigidly, especially in elderly or diabetic patients"(159).
In the urgency to discover the potential compound for the treatment of renal fibrosis, researchers examined the effects of 3,3'-Diindolylmethane (DIM) a natural acid condensation extracted from cruciferous plants, on renal fibrosis(160).
Where DIM has been found to process anti-hepatic and cardiac fibrosis models in a number of studies.
The study included the established unilateral ureteral obstruction (UUO) and transforming growth factor (TGF)-β1-stimulated normal rat kidney (NRK)-49F fibroblast cell in mouse models(160).
Injection of DIM reduced kidney injury and production of interstitial collagens fibrosis(160).
In the UUO model, DIM inhibited expression of fibronectin, collagen-1 associated with the formation of scars but retain E-cadherin involved the formation of adherens junctions to bind cells with each other(160).
In other words, DIM protected the renal cells against the induction of renal fibrosis(160).
In vivo and in vitro, administration of DIM is also found to suppress local fibroblast activation observed by the levels of myofibroblast markers α-SMA and vimentin(160).
Most importantly, DIM significantly inhibited the levels of pro-inflammatory cytokine-induced abnormal proliferation of NRK49F cells, in a time- and dose-dependent manner(160).
Furthermore, DIM also inhibited the expression of Smad2 phosphorylation in the formation of renal scar tissue(160).
Based on the results, researchers concluded that DIM protects the renal cell integrity by inhibiting TGF-β/Smad2/3 signaling against the formation of renal fibrosis(160).
19. Wound Healing
Wound healing is a natural process to repair the wound or cut through a number of stages(161).
In the first stage, after receiving the message from the central nervous system, the immune first line of defense white blood cells stimulate the production of blood palettes to the site of damage to cover the wound and activate the protein associated with the production of pro-inflammatory cytokines to fight off the micro pathogens trying to enter the body(161).
Under normal condition, proteins associated with the production of anti-inflammation cytokines may also switch to proinflammatory cytokines, depending on the size and location of the wound(161).
Overproduction of pro-inflammatory cytokines in this phase can cause the death of nearby healthy cells, leading to the formation of a scar(161).
Most microbial invaders are stopped at the acute phase of infection(161).
The wound healing process is divided into four overlapping phases: hemostasis, inflammatory, proliferative, and maturation(162).
Any interruption of the stage of wound healing also can lead to imbalanced production and dissolving of collagens in the site, inducing the formation of scars(162).
In the urgency of finding a natural compound for speed-up wound healing without side effects, researchers evaluated 3,3'-diindolylmethane (DIM), a natural small-molecule compound involved in the repairing effects of hucMSCs on a deep second-degree burn injury rat model(163).
Where human umbilical cord-derived mesenchymal stem cells (hucMSCs) has been used in the laboratory as a promising therapeutic tool in regenerative medicine(163).
HucMSCs pretreatment of 50 μM of DIM exhibited desirable repairing effects compared to the untreated hucMSCs(163).
In vivo, DIM enhanced hucMSCs in tissue regeneration by activation of proteins that pass signals into a cell through cell surface receptors(163).
Furthermore, DIM-primed hucMSCs (DIM-hucMSCs) also promotes tissue regeneration by suppressing the inhibition of β-catenin that impairs the healing effects(163).
Moreover, DIM promoted the Wnt11 expression associated with all regeneration stages in hucMSC-derived exosomes(163).
Decreased expression of Wnt11 showed to inhibited β-catenin activation(163).
Based on the findings, DIM enhanced tissue regeneration after wound by promoting the genes associated with the healing process(163).
Dr. Shi H the lead scientist said, "DIM promotes the stemness of hucMSCs through increased exosomal Wnt11 autocrine signaling, which provides a novel strategy for improving the therapeutic effects of hucMSCs on wound healing"(163).
III. Summary
3,3'-Diindolylmethane derived from the indole-3-carbinol processes a number of health benefits, pending to the confirmation of the larger sample size and multicenter human study.
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