Showing papers in "Advances in Experimental Medicine and Biology in 2008"

Epidemiology of melanoma and nonmelanoma skin cancer--the role of sunlight.

Abstract: Melanoma and nonmelanoma skin cancer (NMSC) are now the most common types of cancer in white populations. Both tumor entities show an increasing incidence rate worldwide but a stable or decreasing mortality rate.1,2 The rising incidence rates of NMSC are probably caused by a combination of increased sun exposure or exposure to ultraviolet (UV) light, increased outdoor activities, changes in clothing style, increased longevity, ozone depletion, genetics and in some cases, immune suppression. A dose-dependent increase in the risk of squamous cell carcinoma (SCC) of the skin was found associated with exposure to Psoralen and UVA irradiation. An intensive UV exposure in childhood and adolescence was causative for the development of basal cell carcinoma (BCC) whereas for the aetiology of SCC a chronic UV exposure in the earlier decades was accused.

Spermatogenesis and cycle of the seminiferous epithelium.

Abstract: Spermatogenesis is a complex biological process of cellular transformation that produces male haploid germ cells from diploid spermatogonial stem cells. This process has been simplified morphologically by recognizing cellular associations or ‘stages’ and ‘phases’ of spermatogenesis, which progress through precisely timed and highly organized cycles. These cycles of spermatogenesis are essential for continuous sperm production, which is dependent upon numerous factors, both intrinsic (Sertoli and germ cells) and extrinsic (androgens, retinoic acids), as well as being species-specific.

Interaction between the coagulation and complement system.

Abstract: The complement system as a main column of innate immunity and the coagulation system as a main column in hemostasis undergo massive activation early after injury. Interactions between the two cascades have often been proposed but the precise molecular pathways of this interplay are still in the dark. To elucidate the mechanisms involved, the effects of various coagulation factors on complement activation and generation of anaphylatoxins were investigated and summarized in the light of the latest literature. Own in vitro findings suggest, that the coagulation factors FXa, FXIa and plasmin may cleave both C5 and C3, and robustly generate C5a and C3a (as detected by immunoblotting and ELISA). The produced anaphylatoxins were found to be biologically active as shown by a dose-dependent chemotactic response of neutrophils and HMC-1 cells, respectively. Thrombin did not only cleave C5 (Huber-Lang et al. 2006) but also in vitro-generated C3a when incubated with native C3. The plasmin-induced cleavage activity could be dose-dependently blocked by the serine protease inhibitor aprotinin and leupeptine. These findings suggest that various serine proteases belonging to the coagulation system are able to activate the complement cascade independently of the established pathways. Moreover, functional C5a and C3a are generated, both of which are known to be crucially involved in the inflammatory response.

Trans fatty acids and bioactive lipids in ruminant milk.

Abstract: There is increasing evidence that nutrition plays an important role in the development of chronic diseases in the human population, including cancer, cardiovascular disease, insulin resistance, and obesity Developing foods that enhance human health is central to dietary approaches for preventing and reducing the economic and social impacts of chronic disease Numerous studies in human subjects have implicated a high consumption of saturated fatty acids (SFA) and trans fats as risk factors for cardiovascular disease risk, with evidence that high-SFA intakes may also be related to lowered insulin sensitivity, which is a key factor in the development of themetabolic syndromeWhile it is generally accepted that SFA raise plasma total and low-density lipoprotein cholesterol concentrations, atherogenic effects are confined to 12:0, 14:0, and 16:0 Consistent with the effects of individual SFA, there is some evidence to suggest that physiological responses to trans fatty acids (TFA) may also be isomer-dependent National nutritional guidelines with the target of reducing the incidence of cardiovascular disease have advocated a population-wide reduction in the intake of total fat, SFA, and TFA Milk and dairy products are the major source of 12:0 and 14:0 in the human diet and also make a significant contribution to 16:0 and TFA intake However, developing public health policies promoting a decrease in milk, cheese, and butter consumption ignores the value of these foods as a versatile source of nutrients Furthermore, consumption of milk and dairy products may confer beneficial effects with respect to the prevention of osteoporosis, cancer, atherosclerosis, and other degenerative disorders (Heaney, 2000; Ness et al, 2001; Kalkwarf et al, 2003; Valeille et al, 2006) A number of minerals, proteins, peptides, and lipids in milk and fermented dairy products exhibit bioactive properties with the potential to

Nutrient and other environmental controls of harmful cyanobacterial blooms along the freshwater-marine continuum.

Abstract: Nutrient and hydrologic conditions strongly influence harmful planktonic and benthic cyanobacterial bloom (CHAB) dynamics in aquatic ecosystems ranging from streams and lakes to coastal ecosystems Urbanization, agricultural and industrial development have led to increased nitrogen (N) and phosphorus (P) discharge, which affect CHAB potentials of receiving waters The amounts, proportions and chemical composition of N and P sources can influence the composition, magnitude and duration of blooms This, in turn, has ramifications for food web dynamics (toxic or inedible CHABs), nutrient and oxygen cycling and nutrient budgets Some CHABs are capable of N2 fixation, a process that can influence N availability and budgets Certain invasive N2 fixing taxa (eg, Cylindrospermopsis, Lyngbya) also effectively compete for fixed N during spring, N–enriched runoff periods, while they use N2 fixation to supplant their N needs during N–deplete summer months Control of these taxa is strongly dependent on P supply However, additional factors, such as molar N:P supply ratios, organic matter availability, light attenuation, freshwater discharge, flushing rates (residence time) and water column stability play interactive roles in determining CHAB composition (ie N2 fixing vs non–N2 fixing taxa) and biomass Bloom potentials of nutrient–impacted waters are sensitive to water residence (or flushing) time, temperatures (preference for >15 °C), vertical mixing and turbidity These physical forcing features can control absolute growth rates of bloom taxa Human activities may affect “bottom up” physical–chemical modulators either directly, by controlling hydrologic, nutrient, sediment and toxic discharges, or indirectly, by influencing climate Control and management of cyanobacterial and other phytoplankton blooms invariably includes nutrient input constraints, most often focused on N and/or P While single nutrient input constraints may be effective in some water bodies, dual N and P input reductions are usually required for effective long–term control and management of blooms In some systems where hydrologic manipulations (ie, plentiful water supplies) are possible, reducing the water residence time by flushing and artificial mixing (along with nutrient input constraints) can be effective alternatives Blooms that are not readily consumed and transferred up the food web will form a relatively large proportion of sedimented organic matter This, in turn, will exacerbate sediment oxygen demand, and enhance the potential for oxygen depletion and release of nutrients back to the water column This scenario is particularly problematic in long–residence time (ie, months) systems, where blooms may exert a strong positive feedback on future events Implications of these scenarios and the confounding issues of climatic (hydrologic) variability, including droughts, tropical storms, hurricanes and floods, will be discussed in the context of developing effective CHAB control strategies along the freshwater–marine continuum

Cyanobacteria blooms: effects on aquatic ecosystems.

Abstract: Cyanobacteria become increasingly dominant as concentrations of TP and TN increase during eutrophication of lakes, rivers and estuaries. Temporal dynamics of cyanobacteria blooms are variable--in some systems persistent blooms occur in summer to fall, whereas in other systems blooms are more sporadic. Cyanobacteria blooms have a wide range of possible biological impacts including potential toxic effects on other algae, invertebrates and fish, impacts to plants and benthic algae due to shading, and impacts to food web function as large inedible algae produce a bottleneck to C and energy flow in the plankton food web. In lakes with dense blooms of cyanobacteria, accumulation of organic material in lake sediments and increased bacterial activity also may lead to anoxic conditions that alter the structure of benthic macro-invertebrates. Diffusive internal P loading may increase, and hypolimnetic anoxia may lead to a loss of piscivorous fish that require a summer cold water refuge in temperate lakes. Ecosystem changes associated with frequent blooms may result in delayed response of lakes, rivers and estuaries to external nutrient load reduction. Despite numerous case studies and a vast literature on species-specific responses, community level effects of cyanobacterial blooms are not well understood--in particular the realized impacts of toxins and changes in food web structure/function. These areas require additional research given the prevalence of toxic blooms in the nation's lakes, rivers and coastal waters--systems that provide a wide range of valued ecosystem services.

Lactoferrin structure and functions.

Abstract: Lactoferrin (Lf) is an iron binding glycoprotein of the transferrin family that is expressed in most biological fluids and is a major component of mammals' innate immune system. Its protective effect ranges from direct antimicrobial activities against a large panel of microorganisms, including bacteria, viruses, fungi, and parasites, to anti-inflammatory and anticancer activities. This plethora of activities is made possible by mechanisms of action implementing not only the capacity of Lf to bind iron but also interactions of Lf with molecular and cellular components of both host and pathogens. This chapter summarizes our current understanding of the Lf structure-function relationships that explain the roles of Lf in host defense.

Cyanobacterial poisoning in livestock, wild mammals and birds--an overview.

Abstract: Poisoning of livestock by toxic cyanobacteria was first reported in the 19th century, and throughout the 20th century cyanobacteria–related poisonings of livestock and wildlife in all continents have been described. Some mass mortality events involving unrelated fauna in prehistoric times have also been attributed to cyanotoxin poisoning; if correct, this serves as a reminder that toxic cyanobacteria blooms predate anthropogenic manipulation of the environment, though there is probably general agreement that human intervention has led to increases in the frequency and extent of cyanobacteria blooms. Many of the early reports of cyanobacteria poisoning were anecdotal and circumstantial, albeit with good descriptions of the appearance and behaviour of cyanobacteria blooms that preceded or coincided with illness and death in exposed animals. Early necropsy findings of hepatotoxicity were subsequently confirmed by experimental investigations. More recent reports supplement clinical and post–mortem findings with investigative chemistry techniques to identify cyanotoxins in stomach contents and tissue fluids.

Optimal Serum 25-Hydroxyvitamin D Levels for Multiple Health Outcomes

Abstract: Recent evidence suggests that higher vitamin D intakes beyond current recommendations may be associated with better health outcomes. In this chapter, evidence is summarized from different studies that evaluate threshold levels for serum 25(OH)D levels in relation to bone mineral density (BMD), lower extremity function, dental health, risk of falls, admission to nursing home, fractures, cancer prevention and incident hypertension. For all endpoints, the most advantageous serum levels for 25(OH)D appeared to be at least 75 nmol/l (30 ng/ml) and for cancer prevention, desirable 25(OH)D levels are between 90-120 nmol/l (36-48 ng/ml). An intake of no less than 1000 IU (25 mcg) of vitamin D3 (cholecalciferol) per day for all adults may bring at least 50% of the population up to 75 nmol/l. Thus, higher doses of vitamin D are needed to bring most individuals into the desired range. While estimates suggest that 2000 IU vitamin D3 per day may successfully and safely achieve this goal, the implications of 2000 IU or higher doses for the total adult population need to be addressed in future studies.

Expression and nutritional regulation of lipogenic genes in the ruminant lactating mammary gland.

Abstract: The effect of nutrition on milk fat yield and composition has largely been investigated in cows and goats, with some differences for fatty acid (FA) composition responses and marked species differences in milk fat yield response. Recently, the characterization of lipogenic genes in ruminant species allowed in vivo studies focused on the effect of nutrition on mammary expression of these genes, in cows (mainly fed milk fat-depressing diets) and goats (fed lipid-supple- mented diets). These few studies demonstrated some similarities in the regulation of gene expression between the two species, although the responses were not always in agreement with milk FA secretion responses. A central role for trans-10 C18:1 and trans-10, cis-12 CLA as regulators of milk fat synthesis has been proposed. However, trans-10 C18:1 does not directly control milk fat synthesis in cows, despite the fact that it largely responds to dietary factors, with its concentration being negatively correlated with milk fat yield response in cows and, to a lesser extent, in goats. Milk trans-10, cis-12 CLA is often correlated with milk fat depression in cows but not in goats and, when postruminally infused, acts as an inhibitor of the expression of key lipogenic genes in cows. Recent evidence has also proven the inhibitory effect of the trans-9, cis-11 CLA isomer. The molecular mechanisms by which nutrients regulate lipogenic gene expression have yet to be well identified, but a central role for SREBP-1 has been outlined as mediator of FA effects, whereas the roles of PPARs and STAT5 need to be determined. It is expected that the development of in vitro functional systems for lipid synthesis and secretion will allow future progress toward (1) the identifica- tion of the inhibitors and activators of fat synthesis, (2) the knowledge of cellular mechanisms, and (3) the understanding of differences between ruminant species.

UV Damage and DNA Repair in Malignant Melanoma and Nonmelanoma Skin Cancer

Abstract: Exposition of the skin with solar ultraviolet radiation (UV) is the main cause of skin cancer development. The consistently increasing incidences of melanocytic and nonmelanocytic skin tumors are believed to be at least in part associated with recreational sun exposure. Epidemiological data indicate that excessive or cumulative sunlight exposition takes place years and decades before the resulting malignancies arise. The most important defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The important function of nucleotide excision DNA repair (NER) to protect against skin cancer becomes obvious by the rare genetic disease xeroderma pigmentosum, in which diverse NER genes are mutated.

Global warming and cyanobacterial harmful algal blooms

Abstract: The Earth and the oceans have warmed significantly over the past four decades, providing evidence that the Earth is undergoing long-term climate change. Increasing temperatures and changing rainfall patterns have been documented. Cyanobacteria have a long evolutionary history, with their first occurrence dating back at least 2.7 billion years ago. Cyanobacteria often dominated the oceans after past mass extinction events. They evolved under anoxic conditions and are well adapted to environmental stress including exposure to UV, high solar radiation and temperatures, scarce and abundant nutrients. These environmental conditions favor the dominance of cyanobacteria in many aquatic habitats, from freshwater to marine ecosystems. A few studies have examined the ecological consequences of global warming on cyanobacteria and other phytoplankton over the past decades in freshwater, estuarine, and marine environments, with varying results. The responses of cyanobacteria to changing environmental patterns associated with global climate change are important subjects for future research. Results of this research will have ecological and biogeochemical significance as well as management implications.

Sunlight, UV Radiation, Vitamin D, and Skin Cancer: How Much Sunlight Do We Need?

Abstract: Vitamin D is the sunshine vitamin for good reason. During exposure to sunlight, the ultraviolet B photons enter the skin and photolyze 7-dehydrocholesterol to previtamin D3 which in turn is isomerized by the body’s temperature to vitamin D3. Most humans have depended on sun for their vitamin D requirement. Skin pigment, sunscreen use, aging, time of day, season and latitude dramatically affect previtamin D3 synthesis. Vitamin D deficiency was thought to have been conquered, but it is now recognized that more than 50% of the worlds population is at risk for vitamin D deficiency. This deficiency is in part due to the inadequate fortification of foods with vitamin D and the misconception that a healthy diet contains an adequate amount of vitamin D. Vitamin D deficiency causes growth retardation and rickets in children and will precipitate and exacerbate osteopenia, osteoporosis and increase risk of fracture in adults. The vitamin D deficiency has been associated pandemic with other serious consequences including increased risk of common cancers, autoimmune diseases, infectious diseases and cardiovascular disease. There needs to be a renewed appreciation of the beneficial effect of moderate sunlight for providing all humans with their vitamin D requirement for health.

Compstatin: a complement inhibitor on its way to clinical application.

Abstract: Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic.

Probiotics, Immunomodulation, and Health Benefits

Abstract: Probiotics are defined as live microorganisms that, when administered in adequate amount, confer a health benefit on the host. Amongst the many benefits associated with the consumption of probiotics, modulation of the immune system has received the most attention. Several animal and human studies have provided unequivocal evidence that specific strains of probiotics are able to stimulate as well as regulate several aspects of natural and acquired immune responses. There is also evidence that intake of probiotics is effective in the prevention and/or management of acute gastroenteritis and rotavirus diarrhoea, antibiotic-associated diarrhoea and intestinal inflammatory disorders such as Crohn's disease and pouchitis, and paediatric atopic disorders. The efficacy of probiotics against bacterial infections and immunological disorders such as adult asthma, cancers, diabetes, and arthritis in humans remains to be proven. Also, major gaps exist in our knowledge about the mechanisms by which probiotics modulate immune function. Optimum dose, frequency and duration of treatment required for different conditions in different population groups also remains to be determined. Different probiotic strains vary in their ability to modulate the immune system and therefore efficacy of each strain needs to be carefully demonstrated through rigorously designed (randomised, double-blind, placebo-controlled) studies. This chapter provides an over view of the immunomodulatory effects of probiotics in health and disease, and discusses possible mechanisms through which probiotics mediate their disparate effects.

Obesity and diabetes epidemics: cancer repercussions.

Abstract: The prevalence of overweight (body mass index, BMI, between 25 and 30 kg/m2) and obesity (BMI of 30 kg/m2 or higher) is increasing rapidly worldwide, especially in developing countries and countries undergoing economic transition to a market economy. One consequence of obesity is an increased risk of developing type II diabetes. Overall, there is considerable evidence that overweight and obesity are associated with risk for some of the most common cancers. There is convincing evidence of a positive association between overweight/obesity and risk for adenocarcinoma of the oesophagus and the gastric cardia, colorectal cancer, postmenopausal breast cancer, endometrial cancer and kidney cancer (renal-cell). Premenopausal breast cancer seems to be inversely related to obesity. For all other cancer sites the evidence of an association between overweight/obesity and cancer is inadequate, although there are studies suggesting an increased risk of cancers of the liver, gallbladder, pancreas, thyroid gland and in lymphoid and haematopoietic tissue. Far less is known about the association between diabetes mellitus type I (also called insulin dependent diabetes mellitus or juvenile diabetes), type II diabetes (called non-insulin dependent diabetes mellitus or adult onset diabetes mellitus) and cancer risk. The most common type of diabetes mellitus, type II, seems to be associated with liver and pancreas cancer and probably with colorectal cancer. Some studies suggest an association with endometrial and postmenopausal breast cancer. Studies reporting on the association between type I diabetes mellitus, which is relatively rare in most populations and cancer risk are scanty, but suggest a possible association with endometrial cancer. Overweight and obesity, as well as type II diabetes mellitus are largely preventable through changes in lifestyle. The fundamental causes of the obesity epidemic-and consequently the diabetes type II epidemic-are societal, resulting from an environment that promotes sedentary lifestyles and over-consumption of energy. The health consequences and economic costs of the overweight, obesity and type II diabetes epidemics are enormous. Avoiding overweight and obesity, as well as preventing type II diabetes mellitus, is an important purpose to prevent cancer and other diseases. Prevention of obesity and type II diabetes should begin early in life and be based on the life-long health eating and physical activity patterns. Substantial public investments in preventing overweight, obesity and type II diabetes mellitus are both appropriate and necessary in order to have a major impact on their adverse health effects including cancer.

Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitor-induced apoptosis.

Abstract: Epigenic modifications, mainly DNA methylation and acetylation, are recognized as the main mechanisms contributing to the malignant phenotype. Acetylation and deacetylation are catalyzed by specific enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. While histones represent a primary target for the physiological function of HDACs, the antitumor effect of HDAC inhibitors might also be attributed to transcription-independent mechanisms by modulating the acetylation status of a series of non-histone proteins. HDAC inhibitors may act through the transcriptional reactivation of dormant tumor suppressor genes. They also modulate expression of several other genes related to cell cycle, apoptosis, and angiogenesis. Several HDAC inhibitors are currently in clinical trials both for solid and hematologic malignancies. Thus, HDAC inhibitors, in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, could be promising candidates for cancer therapy. Here, we review the molecular mechanisms and therapeutic potential of HDAC inhibitors for the treatment of cancer.

The GNAS locus and pseudohypoparathyroidism.

Abstract: Pseudohypoparathyroidism (PHP) is a disorder of end-organ resistance primarily affecting the actions of parathyroid hormone (PTH). Genetic defects associated with different forms of PHP involve the alpha-subunit of the stimulatory G protein (Gsalpha), a signaling protein essential for the actions of PTH and many other hormones. Heterozygous inactivating mutations within Gsalpha-encoding GNAS exons are found in patients with PHP-Ia, who also show resistance to other hormones and a constellation ofphysical features called Albright's hereditary osteodystrophy (AHO). Patients who exhibit AHO features without evidence for hormone resistance, who are said to have pseudopseudohypoparathyroidism (PPHP), also carry heterozygous inactivating Gsalpha mutations. Maternal inheritance of such a mutation leads to PHP-Ia, i.e., AHO plus hormone resistance, while paternal inheritance of the same mutation leads to PPHP, i.e., AHO only. This imprinted mode of inheritance for hormone resistance can be explained by the predominantly maternal expression of Gsalpha in certain tissues, including renal proximal tubules. Patients with PHP-Ib lack coding Gsalpha mutations but display epigenetic defects of the GNAS locus, with the most consistent defect being a loss of imprinting at the exon A/B differentially methylated region (DMR). This epigenetic defect presumably silences, in cis, Gsalpha expression in tissues where this protein is derived from the maternal allele only, leading to a marked reduction of Gsa levels. The familial form of PHP-Ib (AD-PHP-Ib) is typically associated with an isolated loss of imprinting at the exon A/B DMR. A unique 3-kb microdeletion that disrupts the neighboring STX16 1ocus has been identified in this disorder and appears to be the cause of the loss of imprinting. In addition, deletions removing the entire NESP55 DMR, located within GNAS, have been identified in some AD-PHP-Ib kindreds in whom affected individuals show loss of all the maternal GNAS imprints. Mutations identified in different forms of PHP-Ib thus point to different cis-acting elements that are apparently required for the proper imprinting of the GNAS locus. Most sporadic PHP-Ib cases also have imprinting abnormalities of GNAS that involve multiple DMRs, but the genetic lesion(s) responsible for these imprinting abnormalities remain to be discovered.

Endogenous hormone levels and risk of breast, endometrial and ovarian cancers: prospective studies.

Abstract: Multiple lines of evidence support a central role of hormones in the etiology of breast, endometrial and ovarian cancers. Evidence of an association between circulating hormones and these cancers varies by both hormone and cancer site, with the most consistent associations observed for sex steroid hormones and breast cancer risk among postmenopausal women. Recently, evidence has begun to accumulate suggesting an important role for endogenous hormones in premenopausal breast cancer, endometrial cancer and possibly ovarian cancer. In this chapter, prospective epidemiologic studies, where endogenous hormones are measured in study subjects prior to disease diagnosis, are summarized. Overall, a strong positive association between breast cancer risk and circulating levels of both estrogens and testosterone has now been well confirmed among postmenopausal women; women with hormone levels in the top 20% of the distribution (versus bottom 20%) have a two-to-three-fold higher risk of breast cancer. Evidence amongpremenopausal women is more limited, though increased risk associated with higher levels of testosterone is consistent. Evidence to date of hormonal associations for endometrial cancer is limited, though a strong association with sex steroid hormones is suggested. Studies of ovarian cancer have been few and small with no consistent associations observed with endogenous hormones. Clearly more evaluation is needed to confirm the role of endogenous hormones in premenopausal breast cancer, endometrial cancer and ovarian cancer.

Antihypertensive Peptides Derived from Bovine Casein and Whey Proteins

Abstract: Peptides play an important primary role as a supply of essential amino acids and a source of nitrogen. Recent studies have reported on another role of peptides: having specific amino acid sequences that can express some biological functions in vivo. For an exhaustive study and supply of biologically active peptides, a large-scale screening of protein sources is necessary. Various physiologically functional peptides, such as opioid, immunostimulating, mineral carrier, ACE inhibitory, antihypertensive, and antimicrobial peptides, have been derived from milk protein: both caseins and whey proteins (Meisel, 1998; Korhonen & Pihlanto-Leppala, 2001). Milk is known to be a rich source for the supply of bioactive peptides compared to other protein sources such as animal and fish meat, wheat, and soybean proteins. Among the bioactive peptides, ACE inhibitory peptides and antihypertensive peptides have been extensively researched worldwide, because hypertension is a major risk factor in cardiovascular disease, such as heart disease (FitzGerald & Meisel, 2000; Kitts & Weiler, 2003). We discuss the isolation, utilization, and application of bioactive peptides, especially ACE inhibitory peptides and antihypertensive peptides including our recent human studies on their use as a functional food material.

Regulation of Programmed Cell Death by NF-κB and its Role in Tumorigenesis and Therapy

Abstract: The Rel/NF-kappaB transcription factors are key regulators of programmed cell death (PCD). Their activity has significant physiological relevance for normal development and homeostasis in various tissues and important pathological consequences are associated with aberrant NF-kappaB activity, including hepatocyte apoptosis, neurodegeneration, and cancer. While NF-kappaB is best characterized for its protective activity in response to proapoptotic stimuli, its role in suppressing programmed necrosis has come to light more recently. NF-kappaB most commonly antagonizes PCD by activating the expression of antiapoptotic proteins and antioxidant molecules, but it can also promote PCD under certain conditions and in certain cell types. It is therefore important to understand the pathways that control NF-kappaB activation in different settings and the mechanisms that regulate its anti- vs pro-death activities. Here, we review the role of NF-kappaB in apoptotic and necrotic PCD, the mechanisms involved, and how its activity in the cell death response impacts cancer development, progression, and therapy. Given the role that NF-kappaB plays both in tumor cells and in the tumor microenvironment, recent findings underscore the NF-kappaB signaling pathway as a promising target for cancer prevention and treatment.

Cyanobacterial toxins: a qualitative meta-analysis of concentrations, dosage and effects in freshwater, estuarine and marine biota

Abstract: This paper reviews the rapidly expanding literature on the ecological effects of cyanobacterial toxins. The study employs a qualitative meta–analysis from the literature examining results from a large number of independent studies and extracts general patterns from the literature or signals contradictions. The meta–analysis is set up by putting together two large tables – embodying a large and representative part of the literature (see Appendix A). The first table (Table A.1) reviews the presence (concentrations) of different cyanobacterial toxins in the tissues of various groups of aquatic biota after exposure via different routes, experimentally in the lab or via natural routes in the environment. The second table (Table A.2) reviews the dose dependent effect of toxins on biota. The great majority of studies deal with the presence and effects of microcystin, especially of the MC–LR congener. Although this may partly be justified – MC–LR is an abundant and highly toxic protein – our review also emphasizes what is known about (i) other MC congeners (a number of studies showed a preferred accumulation of the less toxic variant MC–RR in animal tissues), (ii) nodularin (data on a range of biota from studies on the Baltic Sea), (iii) neurotoxins like anatoxin–a(s), which are conspicuously often present at times when mass mortalities of birds occur, (iv) a few studies on the presence and effects of cylindrospermposin, as well as (v) the first examples of ecological effects of newly identified bioactive compounds, like microviridin–J. Data were reorganized to assess to what extent bioconcentration (uptake and concentration of toxins from the water) or biomagnification (uptake and concentration via the food) of cyanobacterial toxins occurs in ecosystems. There is little support for the occurrence of biomagnification, and this reduces the risk for biota at higher trophic levels. Rather than biomagnification biodilution seems to occur in the foodweb with toxins being subject to degradation and excretion at every level. Nevertheless toxins were present at all tropic levels, indicating that some vectorial transport must take place, and in sufficient quantities for effects to possibly occur. Feeding seemed to be the most important route for exposure of aquatic biota to cyanobacterial toxins. A fair number of studies focus on dissolved toxins, but in those studies purified toxin typically is used, and biota do not appear very sensitive to this form of exposure. More effects are found when crude cyanobacterial cell lysates are used, indicating that there may be synergistic effects between different bioactive compounds. Aquatic biota are by no means defenseless against toxic cyanobacteria. Several studies indicate that those species that are most frequently exposed to toxins in their natural environment are also the most tolerant. Protection includes behavioral mechanisms, detoxication of MC and NODLN by conjugation with glutathione, and fairly rapid depuration and excretion. A common theme in much of the ecological studies is that of modulating factors. Effects are seldom straightforward, but are dependent on factors like the (feeding) condition of the animals, environmental conditions and the history of exposure (acclimation and adaptation to toxic cyanobacteria). This makes it harder to generalize on what is known about ecological effects of cyanobacterial toxins. The paper concludes by summarizing the risks for birds, fish, macroinvertebrates and zooplankton. Although acute (lethal) effects are mentioned in the literature, mass mortalities of – especially – fish are more likely to be the result of multiple stress factors that co–occur during cyanobacterial blooms. Bivalves appear remarkably resistant, whilst the harmful effects of cyanobacteria on zooplankton vary widely and the specific contribution of toxins is hard to evaluate.

A world overview — One-hundred-twenty-seven years of research on toxic cyanobacteria — Where do we go from here?

Abstract: CyanoHABs are an intermittent but repeated occurrence throughout the world. They have been documented to impact water quality through production of compounds affecting taste and odor. Selected species within about 40 genera can produce potent toxins that can cause chronic, acute and acute lethal poisonings to wild and domestic animals and humans. Direct and indirect evidence indicates that the incidence, duration and intensity of CyanoHABs is increasing throughout the world, due largely to a decline in the quality of water supplies. While significant effort has gone into defining the chemistry and toxicology of cyanotoxins, a worldwide effort from scientists and environmental agencies to map their occurrence and environmental health risk is needed. An unprioritized listing for those efforts is suggested below (Ramsdell et al. (eds.) 2005): 1. Improved Ability to Detect HAB Species and Analyze CyanoHAB Toxins. 2. Improved Capability for Monitoring and Forecasting CyanoHABs in a Cost Effective and Timely Manner. 3. Improved Protection of Human Health. 4. Improved Protection of Endangered Species and Improved Ecological Health. 5. Improved Prevention and Mitigation Strategies. 6. Improved Economic Cost Estimates of CyanoHAB Events. 7. Improved Economics for Aquaculture and Shellfish Safety. 8. An Educated and Informed Public.

The commensal microbiology of the gastrointestinal tract.

Abstract: The gastrointestinal (GI) tract is a dynamic environment and therefore the stability of the commensal community, or microbiota, is under constant challenge. Microscopic observations have revealed that the majority of bacteria present in the GI tract are not detected using standard culturing techniques, however with the application of culture-independent techniques it has been estimated that between 500 to 1000 bacterial species inhabit the human GI tract. Numerically predominant organisms in the microbiota belong to two eubacterial divisions, the Cytophaga-Flavobacterium-Bacteroides (CFB) and the Firmicutes, and fall into three main groups; Clostridium rRNA subcluster XIVa, Clostridium rRNA subcluster IV and Bacteroides. The prevalence and diversity of bacteria in different areas of the GI tract is influenced by the different conditions at these sites and thus the microbiota of the stomach and jejunum varies with that of the large intestine. Additionally, host genotype, age and diet have all been shown to affect microbial diversity in the GI tract. The distal intestine harbours the highest bacterial cell densities for any known ecosystem. Characterizing the species composition of the healthy microbiota may be a key step in identifying bacterial or associated physiological conditions that are present or absent in an unhealthy microbiota.

Quorum sensing and biofilm formation by Streptococcus mutans.

Abstract: Streptococcus mutans is the primary causative agent involved in dental caries in humans. Among important virulence factors of this pathogen, its ability to form and sustain a polysaccharide-encased biofilm (commonly called dental plaque) is vital not only to its survival and persistence in the oral cavity, but also for its pathogenicity as well. This chapter focuses on the S. mutans’ biofilm phenotype and how this mode of growth is regulated by its density-dependent quorum sensing (QS) system primarily comprised of the Competence Stimulating Peptide (CSP) and the ComD/ComE two-component signal transduction system. In addition to biofilm formation, the CSP-mediated QS system in S. mutans also affects its acidogenicity, aciduricity, genetic transformation and bacteriocin production. Interestingly, it has also been discovered that these properties are optimally expressed in cells derived from a biofilm as opposed to a free-floating planktonic mode of growth. Hence, strategies targeting S. mutans’ QS system to attenuate biofilm formation and/or virulence are currently being used to develop therapeutic or preventative measures against dental caries. Recently, it was discovered that the addition of CSP in large concentrations (relative to amounts used for normal competence development) resulted in growth arrest and eventual cell death, thus paving way for CSP-mediated targeted killing of S. mutants. In addition to the QS system, effects of other two-component signal transduction systems on the biofilm phenotype of S. mutans are also discussed.

The PhoQ/PhoP Regulatory Network of Salmonella enterica

Abstract: The PhoQ/PhoP two-component regulatory system is a major regulator of virulence in the enteric pathogen Salmonella enterica serovar Typhimurium It also controls the adaptation to low Mg2+ environments by governing the expression and/or activity of Mg2+ transporters and of enzymes modifying the Mg2+-binding sites on the bacterial cell surface The regulator PhoP modifies expression of ≈3% of the Salmonella genes in response to the periplasmic Mg2+ concentration detected by the PhoQ protein Genes that are directly controlled by the PhoP protein often differ in their promoter structures, resulting in distinct expression levels and kinetics in response to the low Mg2+ inducing signal PhoP regulates a large number of genes indirectly: via other transcription factors and two-component systems that form a panoply of regulatory architectures including transcriptional cascades, feedforward loops and the use of connector proteins that modify the activity of response regulators These architectures confer distinct expression properties that may be important contributors to Salmonella’s lifestyle

Modifying insect population age structure to control vector-borne disease.

Abstract: Age is a critical determinant of the ability of most arthropod vectors to transmit a range of human pathogens. This is due to the fact that most pathogens require a period of extrinsic incubation in the arthropod host before pathogen transmission can occur. This developmental period for the pathogen often comprises a significant proportion of the expected lifespan of the vector. As such, only a small proportion of the population that is oldest contributes to pathogen transmission. Given this, strategies that target vector age would be expected to obtain the most significant reductions in the capacity of a vector population to transmit disease. The recent identification of biological agents that shorten vector lifespan, such as Wolbachia, entomopathogenic fungi and densoviruses, offer new tools for the control of vector-borne diseases. Evaluation of the efficacy of these strategies under field conditions will be possible due to recent advances in insect age-grading techniques. Implementation of all of these strategies will require extensive field evaluation and consideration of the selective pressures that reductions in vector longevity may induce on both vector and pathogen.