Convergence of Genetic, Nutritional and Inflammatory Factors in Gastrointestinal Cancers

Gastrointestinal cancers account for 20% of all cancer incidences worldwide. Colorectal cancer is the second most common cause of all cancer-related mortality and is increasing in Western societies. Infection and inflammation contribute to 15–20% of all malignancies, and are predisposing risk factors for gastrointestinal cancers. Helicobacter pylori infection is commonly associated with gastric cancers, and chronic inflammation increases the risk of colorectal cancer by 1% per year. Micronutrient status and common genetic variations in human populations modify risk for gastrointestinal cancer. Chronic inflammation promotes carcinogenesis by inducing gene mutations, inhibiting apoptosis, and stimulating an-giogenesis and cell proliferation. Inflammation also induces epigenetic alterations that are associated with cancer development. Two key genes in the inflammatory process, cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-kB), provide a mechanistic link between inflammation and cancer and are targets for chemoprevention. Dietary components, and human genetic variation that affects nutrient utilization, can directly modify inflammatory processes and/or suppress genomic alterations that are the molecular antecedents of cancers. The present report focuses on the convergence of genetic, nutritional, and inflammatory factors in the initiation and progression of gastrointestinal cancers, and the emerging dietary strategies for cancer prevention.     

Potential Nutrients from Natural and Synthetic Sources Targeting Inflammaging—A Review of Literature,Clinical Data and Patents

Inflammaging, the steady development of the inflammatory state over age is an attributable characteristic of aging that potentiates the initiation of pathogenesis in many age-related disorders (ARDs) including neurodegenerative diseases, arthritis, cancer, atherosclerosis, type 2 diabetes, and osteoporosis. Inflammaging is characterized by subclinical chronic, low grade, steady inflammatory states and is considered a crucial underlying cause behind the high mortality and morbidity rate associated with ARDs. Although a coherent set of studies detailed the underlying pathomechanisms of inflammaging, the potential benefits from non-toxic nutrients from natural and synthetic sources in modulating or delaying inflammaging processes was not discussed. In this review, the available literature and recent updates of natural and synthetic nutrients that help in controlling inflammaging process was explored. Also, we discussed the clinical trial reports and patent claims on potential nutrients demonstrating therapeutic benefits in controlling inflammaging and inflammation-associated ARDs.     

Inflammation and cardiovascular disease

Cardiovascular disease (CVD) has been associated with the so-called traditional risk factors, such as hypertension, hypercholesterolemia and cigarette smoking. Chronic inflammation, exemplified by elevated high sensitivity C-reactive protein, has been added to these risk factors for CVD as non-traditional risk factor. There are two aspects in this association. The first is whether inflammation plays a pathogenic role in traditional risk factors-mediated CVD or it is just an epiphenomenon. The second is whether chronic inflammation caused by an inflammatory disease has any impact on CVD. Accumulated data have shown that inflammation has a central and inciting role in the development of atherosclerosis leading to increased CVD risk. How inflammation contributes to CVD is a topic of continuous research where mechanisms involving both innate and adaptive immune pathways are involved. Endothelial dysfunction, oxidative stress in vascular endothelial cells, macrophage accumulation, formation of inflammasome, production of tumor necrosis factor (TNF)-a, IL-1 and IL-6 characterize the inflammatory process leading to atherogenesis. Recently clonal hematopoiesis of indeterminate potential represents a surprising and novel mechanism underlying atherogenesis. Data from chronic rheumatic inflammatory diseases exemplify the complexity of mechanisms leading to increased CVD, while they also provide evidence that anti-inflammatory biologic drugs, such as anti-TNF and anti-IL6 agents, could control atherogenesis and ameliorate CVD risk. Recent groundbreaking work using biologic anti-IL-1b therapy to treat men and women who have had a prior heart attack provides the best proof of the pathogenic contribution of inflammation in the development of CVD.     

Inflammaging as a Major Characteristic of Old People: Can It Be Prevented or Cured?

Widespread aging at the population level is a recent phenomenon that emerged in affluent societies. Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name "inflammaging". Centenarians are unique in that, despite high levels of pro-inflammatory markers, they also exhibit anti-inflammatory markers that may delay disease onset. The key to successful aging and longevity is to decrease chronic inflammation without compromising an acute response when exposed to pathogens.     

Curcumin from Turmeric Rhizome: A Potential Modulator of DNA Methylation Machinery in Breast Cancer Inhibition

One of the most systematically studied bioactive nutraceuticals for its benefits in the management of various diseases is the turmeric-derived compounds: curcumin. Turmeric obtained from the rhizome of a perennial herb Curcuma longa L. is a condiment commonly used in our diet. Curcumin is well known for its potential role in inhibiting cancer by targeting epigenetic machinery, with DNA methylation at the forefront. The dynamic DNA methylation processes serve as an adaptive mechanism to a wide variety of environmental factors, including diet. Every healthy tissue has a precise DNA methylation pattern that changes during cancer development, forming a cancer-specific design. Hypermethylation of tumor suppressor genes, global DNA demethylation, and promoter hypomethylation of oncogenes and prometastatic genes are hallmarks of nearly all types of cancer, including breast cancer. Curcumin has been shown to modulate epigenetic events that are dysregulated in cancer cells and possess the potential to prevent cancer or enhance the effects of conventional anti-cancer therapy. Although mechanisms underlying curcumin-mediated changes in the epigenome remain to be fully elucidated, the mode of action targeting both hypermethylated and hypomethylated genes in cancer is promising for cancer chemoprevention. This review provides a comprehensive discussion of potential epigenetic mechanisms of curcumin in reversing altered patterns of DNA methylation in breast cancer that is the most commonly diagnosed cancer and the leading cause of cancer death among females worldwide. Insight into the other bioactive components of turmeric rhizome as potential epigenetic modifiers has been indicated as well.     

Diet components can suppress inflammation and reduce cancer risk

Epidemiology studies indicate that diet or specific dietary components can reduce the risk for cancer, cardiovascular disease and diabetes. An underlying cause of these diseases is chronic inflammation. Dietary components that are beneficial against disease seem to have multiple mechanisms of action and many also have a common mechanism of reducing inflammation, often via the NFκB pathway. Thus, a plant based diet can contain many components that reduce inflammation and can reduce the risk for developing all three of these chronic diseases. We summarize dietary components that have been shown to reduce cancer risk and two studies that show that dietary walnut can reduce cancer growth and development. Part of the mechanism for the anticancer benefit of walnut was by suppressing the activation of NFκB. In this brief review, we focus on reduction of cancer risk by dietary components and the relationship to suppression of inflammation. However, it should be remembered that most dietary components have multiple beneficial mechanisms of action that can be additive and that suppression of chronic inflammation should reduce the risk for all three chronic diseases.     

低剂量电离辐射致眼晶状体混浊机制及遗传易感性研究现状

眼晶状体被认为是体内最具辐射敏感性的组织之一。0.5 Gy及更高的辐射剂量会诱发放射性白内障,但研究表明长期低剂量的辐射暴露也会增加眼晶状体混浊风险。目前关于低剂量电离辐射诱导眼晶状体混浊发生的具体生物学机制仍不明确,许多相互竞争的机制链可能独立或共同导致混浊的发生,如眼晶状体上皮细胞基因组损伤、氧化应激、细胞间通讯破坏和炎性反应等,遗传和表观遗传因素也可在其中发挥作用。本文旨在对低剂量电离辐射诱发眼晶状体混浊发生机制,及个体易感性在其发生和发展中的作用进行综述,以期对该病的预防和控制提供科学参考。     

n-3 Polyunsaturated Fatty Acids and Mechanisms to Mitigate Inflammatory Paracrine Signaling in Obesity-Associated Breast Cancer

Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA) may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.     

Twelve-Week Daily Consumption of ad hoc Fortified Milk with ω-3, D,and Group B Vitamins Has a Positive Impact on Inflammaging Parameters: A Randomized Cross-Over Trial

Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present in elderly people and represents a risk factor for all age-related diseases. Dietary supplementation with ad hoc fortified foods seems an appealing strategy to counteract inflammaging. The purpose of this study was to test the efficacy of elderly-tailored fortified milk on inflammaging and different health parameters. Methods: A double-blind randomized cross-over study was performed on forty-eight volunteers aged 63–80 years. The fortified milk was enriched with ω-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA), vitamins (25-hydroxyvitamin D, E, C, B6, B9, B12), and trace elements (zinc, selenium). The two intervention periods lasted for 12 weeks, with a 16-week washout intermission. Results: Compared to placebo, the consumption of fortified milk increased the circulating levels of different micronutrients, including vitamins and the ω-3 index of erythrocyte membranes. Conversely, it reduced the amount of arachidonic acid, homocysteine, and ω-6/ω-3 ratio. Conclusion: Twelve-week daily consumption of ad hoc fortified milk has an overall positive impact on different health parameters related to inflammaging in the elderly.     

Nutrition-Based Management of Inflammaging in CKD and Renal Replacement Therapies

Access to renal transplantation guarantees a substantial improvement in the clinical condition and quality of life (QoL) for end-stage renal disease (ESRD) patients. In recent years, a greater number of older patients starting renal replacement therapies (RRT) have shown the long-term impact of conservative therapies for advanced CKD and the consequences of the uremic milieu, with a frail clinical condition that impacts not only their survival but also limits their access to transplantation. This process, referred to as “inflammaging,” might be reversible with a tailored approach, such as RRT accompanied by specific nutritional support. In this review, we summarize the evidence demonstrating the presence of several proinflammatory substances in the Western diet (WD) and the positive effect of unprocessed food consumption and increased fruit and vegetable intake, suggesting a new approach to reduce inflammaging with the improvement of ESRD clinical status. We conclude that the Mediterranean diet (MD), because of its modulative effects on microbiota and its anti-inflammaging properties, may be a cornerstone in a more precise nutritional support for patients on the waiting list for kidney transplantation.     

Mediterranean Diet to Prevent the Development of Colon Diseases: A Meta-Analysis of Gut Microbiota Studies

Gut microbiota dysbiosis is a common feature in colorectal cancer (CRC) and inflammatory bowel diseases (IBD). Adoption of the Mediterranean diet (MD) has been proposed as a therapeutic approach for the prevention of multiple diseases, and one of its mechanisms of action is the modulation of the microbiota. We aimed to determine whether MD can be used as a preventive measure against cancer and inflammation-related diseases of the gut, based on its capacity to modulate the local microbiota. A joint meta-analysis of publicly available 16S data derived from subjects following MD or other diets and from patients with CRC, IBD, or other gut-related diseases was conducted. We observed that the microbiota associated with MD was enriched in bacteria that promote an anti-inflammatory environment but low in taxa with pro-inflammatory properties capable of altering intestinal barrier functions. We found an opposite trend in patients with intestinal diseases, including cancer. Some of these differences were maintained even when MD was compared to healthy controls without a defined diet. Our findings highlight the unique effects of MD on the gut microbiota and suggest that integrating MD principles into a person’s lifestyle may serve as a preventive method against cancer and other gut-related diseases.     

Inflammation in Pregnancy: Its Roles in Reproductive Physiology, Obstetrical Complications, and Fetal Injury

Fetal development and growth occur in a sterile amniotic cavity while first exposure to microorganisms happens at birth. However, at least 25% of all preterm births, the leading cause of perinatal morbidity and mortality worldwide, occur in mothers with microbial invasion of the amniotic cavity. Microbial attack of the fetus takes place in approximately 10% of pregnancies with intra-amniotic infection, and the human fetus is capable of deploying an inflammatory response (cellular and humoral) in the mid-trimester of pregnancy. The onset of premature labor in the context of infection is mediated by pro-inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α), as these cytokines are produced by intrauterine tissues in response to microbial products, can stimulate prostaglandin production, and induce labor in animals. Moreover, knockout experiments suggest that infection is less likely to lead to premature labor when the IL-1 and TNF signaling pathways are disrupted. A fetal inflammatory systemic response occurs in a fraction of fetuses exposed to microorganisms in utero, and is associated with the impending onset of labor as well as multisystem organ involvement. Neonates born with funisi-tis, the histologic marker of such inflammation, are at increased risk for neurologic handicap and cerebral palsy. Evidence has begun to accumulate that gene-environment interactions determine the likelihood of preterm labor and delivery and, probably, the risk of fetal injury. Fetal inflammation has emerged as a major mechanism of disease responsible for complications in the perinatal period (in utero and in the first 28 days of life), as well as in infancy. Moreover, reprogramming of the fetal immune response may predispose to diseases in adulthood.     

Obesity-Associated Inflammation: Does Curcumin Exert a Beneficial Role?

Curcumin is a lipophilic polyphenol, isolated from the plant turmeric of Curcuma longa. Curcuma longa has always been used in traditional medicine in Asian countries because it is believed to have numerous health benefits. Nowadays it is widely used as spice component and in emerging nutraceutical food worldwide. Numerous studies have shown that curcumin possesses, among others, potential anti-inflammatory properties. Obesity represents a main risk factor for several chronic diseases, including type 2 diabetes, cardiovascular disease, and some types of cancer. The establishment of a low-grade chronic inflammation, both systemically and locally in adipose tissue, occurring in obesity most likely represents a main factor in the pathogenesis of chronic diseases. The molecular mechanisms responsible for the onset of the obesity-associated inflammation are different from those involved in the classic inflammatory response caused by infections and involves different signaling pathways. The inflammatory process in obese people is triggered by an inadequate intake of nutrients that produces quantitative and qualitative alterations of adipose tissue lipid content, as well as of various molecules that act as endogenous ligands to activate immune cells. In particular, dysfunctional adipocytes secrete inflammatory cytokines and chemokines, the adipocytokines, able to recruit immune cells into adipose tissue, amplifying the inflammatory response also at systemic level. This review summarizes the most recent studies focused at elucidating the molecular targets of curcumin activity responsible for its anti-inflammatory properties in obesity-associated inflammation and related pathologies.     

Inflammation and cancer

Infection and inflammation account for approximately 25% of cancer-causing factors. Inflammation-related cancers are characterized by mutagenic DNA lesions, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-nitroguanine. Our previous studies demonstrated the formation of 8-oxodG and 8-nitroguanine in the tissues of cancer and precancerous lesions due to infection (e.g., Opisthorchis viverrini-related cholangiocarcinoma, Schistosoma haematobium-associated bladder cancer, Helicobacter pylori-infected gastric cancer, human papillomavirus-related cervical cancer, Epstein-Barr virus-infected nasopharyngeal carcinoma) and pro-inflammatory factors (e.g., asbestos, nanomaterials, and inflammatory diseases such as Barrett’s esophagus and oral leukoplakia). Interestingly, several of our studies suggested that inflammation-associated DNA damage in cancer stem-like cells leads to cancer development with aggressive clinical features. Reactive oxygen/nitrogen species from inflammation damage not only DNA but also other biomacromolecules, such as proteins and lipids, resulting in their dysfunction. We identified oxidatively damaged proteins in cancer tissues by 2D Oxyblot followed by MALDI-TOF/TOF. As an example, oxidatively damaged transferrin released iron ion, which may mediate Fenton reactions and generate additional reactive oxygen species. Dysfunction of anti-oxidative proteins due to this damage might increase oxidative stress. Such damage in biomacromolecules may form a vicious cycle of oxidative stress, leading to cancer development. Epigenetic alterations such as DNA methylation and microRNA dysregulation play vital roles in carcinogenesis, especially in inflammation-related cancers. We examined epigenetic alterations, DNA methylation and microRNA dysregulation, in Epstein-Barr virus-related nasopharyngeal carcinoma in the endemic area of Southern China and found several differentially methylated tumor suppressor gene candidates by using a next-generation sequencer. Among these candidates, we revealed higher methylation rates of RAS-like estrogen-regulated growth inhibitor (RERG) in biopsy specimens of nasopharyngeal carcinoma more conveniently by using restriction enzyme-based real-time PCR. This result may help to improve cancer screening strategies. We profiled microRNAs of nasopharyngeal carcinoma tissues using microarrays. Quantitative RT-PCR analysis confirmed the concordant downregulation of miR-497 in cancer tissues and plasma, suggesting that plasma miR-497 could be used as a diagnostic biomarker for nasopharyngeal carcinoma. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses. These changes may be useful biomarkers in liquid biopsy for early detection and prevention of cancer.     

Communicating clinical research to reduce cancer risk through diet: Walnuts as a case example

Inflammation is one mechanism through which cancer is initiated and progresses, and is implicated in the etiology of other conditions that affect cancer risk and prognosis, such as type 2 diabetes, cardiovascular disease, and visceral obesity. Emerging human evidence, primarily epidemiological, suggests that walnuts impact risk of these chronic diseases via inflammation. The published literature documents associations between walnut consumption and reduced risk of cancer, and mortality from cancer, diabetes, and cardiovascular disease, particularly within the context of the Mediterranean Diet. While encouraging, follow-up in human intervention trials is needed to better elucidate any potential cancer prevention effect of walnuts, per se. In humans, the far-reaching positive effects of a plant-based diet that includes walnuts may be the most critical message for the public. Indeed, appropriate translation of nutrition research is essential for facilitating healthful consumer dietary behavior. This paper will explore the translation and application of human evidence regarding connections with cancer and biomarkers of inflammation to the development of dietary guidance for the public and individualized dietary advice. Strategies for encouraging dietary patterns that may reduce cancer risk will be explored.     

Influence of Genetics on Disease Susceptibility and Progression

For many chronic diseases, the influence of genetics is complex and phenotypes do not conform to simple Mendelian patterns of inheritance. Discussed here are two types of genetic influences on healthy aging. The first involves variation in the gene sequence itself and how this may influence disease susceptibility, progression, and severity, interacting with other recognized risk factors. The second involves epigenetic regulatory mechanisms that may potentially provide insight into how environmental influences affect the expressed genome, thus improving our understanding of the genetic mechanisms underlying multifactorial diseases. The interleukin-1 family of cytokines can be used to illustrate how genetic sequence variation may affect such diseases. This cytokine family plays a key role in mediating inflammation, which is now understood to be a central component of a growing number of chronic diseases. Recent work has revealed many sequence variations in the regulatory DNA of genes encoding important members of the interleukin-1 family, and these variations are associated with differential effects on the inflammatory response. The interactions of environmental factors with both DNA sequence variations and epigenetic modifications are likely to determine the phenotypes of multifactorial diseases of aging as well as the phenotype of healthy aging.     

Effects of resistance training on the inflammatory response

Resistance training (RT) is associated with reduced risk of low grade inflammation related diseases, such as cardiovascular disease and type 2 diabetes. The majority of the data studying cytokines and exercise comes from endurance exercise. In contrast, evidence establishing a relationship between RT and inflammation is more limited. This review focuses on the cytokine responses both following an acute bout, and after chronic RT. In addition, the effect of RT on low grade systemic inflammation such as individuals at risk for type 2 diabetes is reviewed. Cytokines are secreted proteins that influence the survival, proliferation, and differentiation of immune cells and other organ systems. Cytokines function as intracellular signals and almost all cells in the body either secrete them or have cytokine receptors. Thus, understanding cytokine role in a specific physiological situation such as a bout of RT can be exceedingly complex. The overall effect of long term RT appears to ameliorate inflammation, but the specific effects on the inflammatory cytokine, tumor necrosis factor alpha are not clear, requiring further research. Furthermore, it is critical to differentiate between chronically and acute Interleukin-6 levels and its sources. The intensity of the RT and the characteristics of the training protocol may exert singular cytokine responses and as a result different adaptations to exercise. More research is needed in the area of RT in healthy populations, specifically sorting out gender and age RT acute responses. More importantly, studies are needed in obese individuals who are at high risk of developing low grade systemic inflammatory related diseases. Assuring adherence to the RT program is essential to get the benefits after overcoming the first acute RT responses. Hence RT could be an effective way to prevent, and delay low grade systemic inflammatory related diseases.     

Conditions in utero and cancer risk

There is increasing recognition that conditions in utero are of importance for later cancer risk in several organs, particularly the testis and breast. A review of the most recent literature on this topic is therefore warranted. The PubMed database was searched for relevant recent literature on intrauterine conditions associated with cancer risk later in life, with particular emphasis on the testis, breast, but also studies pertaining to other organs were included. Epidemiological and experimental data support the hypothesis that factors acting in utero play a role in the development of cancer in the testis and breast. For other organs, such as the prostate, urinary system and colorectum, the results are inconclusive. While conditions during foetal life are associated with later cancer risk in the testis and breast, the biological mechanisms are for the most part elusive. They are, however, likely to involve hormonal disturbances, number of cells at risk, and genetic or epigenetic events.     

Effect of Paternal Diet on Spermatogenesis and Offspring Health: Focus on Epigenetics and Interventions with Food Bioactive Compounds

Infertility is a growing public health problem. Consumption of antioxidant bioactive food compounds (BFCs) that include micronutrients and non-nutrients has been highlighted as a potential strategy to protect against oxidative and inflammatory damage in the male reproductive system induced by obesity, alcohol, and toxicants and, thus, improve spermatogenesis and the fertility parameters. Paternal consumption of such dietary compounds could not only benefit the fathers but their offspring as well. Studies in the new field of paternal origins of health and disease show that paternal malnutrition can alter sperm epigenome, and this can alter fetal development and program an increased risk of metabolic diseases and breast cancer in adulthood. BFCs, such as ascorbic acid, α-tocopherol, polyunsaturated fatty acids, trace elements, carnitines, N-acetylcysteine, and coenzyme Q10, have been shown to improve male gametogenesis, modulate epigenetics of germ cells, and the epigenetic signature of the offspring, restoring offspring metabolic health induced by stressors during early life. This indicates that, from a father’s perspective, preconception is a valuable window of opportunity to start potential nutritional interventions with these BFCs to maximize sperm epigenetic integrity and promote adequate fetal growth and development, thus preventing chronic disease in adulthood.