Showing papers in "Advances in Experimental Medicine and Biology in 2001"

Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines.

Abstract: Tumors expressing a high level of certain types of tumor-associated carbohydrate antigens (T ACAs) exhibit greater metastasis and progression than those expressing low level of TACAs, as reflected in decreased patient survival rate. Well-documented examples of such TACAs are: (i) H/Ley/ILea in primary non-small cell lung carcinoma; (ii) sialyl-Lex(SLex) and sialyl-Lea (SLea) in various types of cancer; (iii) Tn and sialyl-Tn in colorectal, lung, breast, and many other cancers; (iv) GM2, GD2, and GD3 gangliosides in neuroectodermal tumors (melanoma and neuroblastoma); (v) globo-H in breast, ovarian, and prostate cancer; (vi) disialylgalactosylgloboside in renal cell carcinoma.

Diabetes in sub-Saharan Africa.

Abstract: NCDs including diabetes, heart disease and stroke arc global epidemics of the 21 st century The greatest burden on health will be in developing countries and sub-Saharan Africa is an area of major challenge: We are concerned with planning for the adult victims of the new epidemic and this includes the development of appropriate treatment Therapy should be cost effective and evidence on the economics of treating chronic conditions in Africa is urgently required Finally, health promotion, primary prevention and health screening strategies for chronic diseases such as diabetes, stroke and coronary heart disease are required

Biology of erythropoietin

Abstract: Hypoxia induces tissue-specific gene products such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which improve the peripheral O2 supply, and glucose transporters and glycolytic enzymes, which adapt cells to reduced O2 availability. EPO has been the fountainhead in research on pO2-dependent synthesis of proteins. The EPO gene enhancer (like the flanking DNA-elements of several other pO2-controlled genes) contains a consensus sequence (CGTG) that binds the trans-acting dimeric hypoxia-inducible factor 1 (HIF-1alpha/beta). The alpha-subunit of HIF-1 is rapidly degraded by the proteasome under normoxic conditions, but it is stabilized on occurrence of hypoxia. HIF-1 DNA-binding is also increased by insulin, and by interleukin-1 and tumor necrosis factor. Thus, in some aspects there is synergy in the cellular responses to hypoxia, glucose deficiency and inflammation. In viewing clinical medicine recombinant human EPO (rHu-EPO) has become the mainstay of treatment for renal anemia. Endogenous EPO and rHu-EPO are similar except for minor differences in the pattern of their 4 carbohydrate chains. RHu-EPO is also administered to patients suffering from non-renal anemias, such as in autoimmune diseases or malignancies. The correction of anemia in patients with solid tumors is not merely considered a palliative intervention. Hypoxia promotes tumor growth. However, the benefits of the administration of rHu-EPO to tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo- and radiotherapy is still debatable ground.

Mechanisms by which garlic and allyl sulfur compounds suppress carcinogen bioactivation. Garlic and carcinogenesis.

Abstract: For centuries garlic has been revered as a plant with medicinal properties. During this past 20 years these beliefs have been reinforced by exciting evidence documenting that garlic and its allyl sulfur components can alter a host of physiological processes that potentially foster health (Fenwick and Hanley, 1985b, Milner, 1996, Orekhov and Grunwald, 1997). Garlic’s ability to reduce hyperlipidemia, hypertension, sterol synthesis and thrombus formation make it a strong candidate for lowering the risk of heart disease and stroke (Gebhardt, 1993, Orekhov and Grunwald, 1997, Abramovitz et al., 1999). In addition to antimicrobial properties (Adetumbi and Lau, 1983, Yoshida et al., 1999, Cellini et al., 1996, Dion et al., 1997), considerable evidence points to the ability of garlic and related components to serve as protectors of immunocompetence (Jeong and Lee, 1998, Morioka et al., 1993) and possibly mental function (Nishiyama et al., 1997). Garlic is a plant within the genus Allium. It along with onions, leeks and chives represent the major allium foods that are consumed by human beings. While it is possible that other allium foods possess similar health attributes, including a reduction in cancer risk, few comparative studies have been undertaken.

Survival of human milk oligosaccharides in the intestine of infants.

Abstract: Several human milk oligosaccharides inhibit human pathogens in vitro and in animal models. In an infant, the ability of these oligosaccharides to offer protection from enteric pathogens would require that they withstand structural modification as they pass through the alimentary canal or are absorbed and excreted in urine. We investigated the fate of human milk oligosaccharides during transit through the alimentary canal by determining the degree to which breast-fed infants’ urine and fecal oligosaccharides resembled those of their mothers’ milk Oligosaccharide profiles of milk from 16 breast-feeding mothers were compared with profiles of stool and urine from their infants. Results were compared with endogenous oligosaccharide profiles obtained from the urine and feces of age-, parity-, and gender-matched formula-fed infants. In all cases, oligosaccharides were extracted, purified, reduced, and separated into acidic and neutral species; the latter were perbenzoylated and subjected to reversed-phase high-performance liquid chromatography. Structures were determined by mass spectrometry after debenzoylation. Among breast-fed infants, concentrations of oligosaccharides were higher in feces than in mothers’ milk, and much higher in feces than in urine. Urinary and fecal oligosaccharides from breast-fed infants resembled those in their mothers’ milk Those from formula-fed infants did not resemble human milk oligosaccharides, were found at much lower concentrations, and probably resulted from remodeling of intestinal glycoconjugates or from intestinal bacteria. Most of the human milk oligosaccharides survived transit through the gut, and some were absorbed and then excreted into the urine intact, implying that inhibition of intestinal and urinary pathogens by human milk oligosaccharides is quite likely in breast-fed infants.

Characterization of oligosaccharides in milk and feces of breast-fed infants by high-performance anion-exchange chromatography.

Abstract: Human milk contains a large amount of oligosaccharides, which represent its third largest solute. Nevertheless, both the metabolism and the role of these substances are still largely unknown. A previous study we conducted documented that the amount of oligosaccharides excreted in the feces varies from 6% to 13% of the 24-hour ingested oligosaccharides. The aim of this study was to characterize the pattern of oligosaccharides in the feces compared with the pattern of the ingested milk Six term newborn infants were studied at the end of the first month of life. A 7:00 AM milk sample was obtained with an electric breast pump. Feces were collected during the day of milk sampling. Analyses of oligosaccharides were performed using high-pH anion-exchange chromatography with pulsed amperometer detection. Pure milk oligosaccharides were used as reference standards. The chromatographic profile of the oligosaccharides present in the feces and in the milk samples showed more than 40 peaks, 20 of which have been identified. The oligosaccharide profile observed in the feces was similar to the pattern of oligosaccharides present in the milk ingested. A significant difference was represented by the almost complete absence of lactose in the feces of all infants and of sialyllacto-N-tetraose a and disialyllacto-N-neotetraose in 3 samples. A substantial reduction of lacto-N-tetraose was observed in 5 samples. Our results demonstrate that the oligosaccharide profile in the feces is similar to that of the ingested milk. Approximately 40% to 50% of the total ingested oligosaccharides can be found in feces of breast-fed infants.

Proton-gated cation channels--neuronal acid sensors in the central and peripheral nervous system.

Abstract: Metabolic hyperactivity or limited oxygen supply can cause a decrease of tissue pH. Severe tissue acidosis that accompanies ischemia and most forms of inflammation is painful and sensory neurons respond to acidic tissue pH with increased firing. H+-gated cation channels in sensory nerve endings are thought to be responsible for the activation of nociceptive afferents by acid. The members of one family of recently identified H+-gated cation channels (ASICs, Acid Sensing Ion Channels) are candidates for the acid sensor in sensory nerve endings. Certain ASIC subunits are also or exclusively expressed in neurons of the central nervous system (CNS) where the role of those cation channels is as for yet unknown. Neuronal activity is accompanied by pH fluctuations and the widespread expression of ASIC channels throughout the CNS suggests that activation of those ion channels by local acidic transients might play a role in neurotransmission or neuromodulation.

The heme oxygenase system and cellular defense mechanisms. Do HO-1 and HO-2 have different functions?

Abstract: Heme oxygenase isozymes, HO-1, HO-2 and HO-3, are HSP32 protein cognates, with a known function of catalyzing the isomer specific oxidation of the heme molecule, including that of NO synthase Unknown until recent years was that the system is a central component of the cellular defense mechanisms; this can be attributed to a combination of many factors In biological systems HO activity is responsible for production of equimolar amounts of CO, biliverdin and free Fe The serine/threonine kinase, biliverdin reductase, catalyzes reduction of biliverdin to bilirubin Bilirubin is a potent antioxidant and CO is a signal molecule Although both active HO isozymes catalyze the same reaction, HO-1 and HO-2 may function in a rather distinct fashion in protection against tissue injury HO-1 is the stress responsive cognate that is rapidly induced by free and stable radicals as well as by hypoxia Supra induction of HO-1 completely protects ischemic kidney against tissue pathology This involves rapid inactivation of the pro-oxidant heme of denatured hemoproteins and converting it to bilirubin and CO In the case of severe tissue injury, such as compression injury, HO-1 is induced and colocalizes with cGMP and pro-apoptotic oncogenes HO-2, which is the constitutive form, in addition to maintaining cell heme homeostasis, inactivates NO derived radicals The isozyme binds the free radical at its “heme regulatory motifs” and is “suicide” inactivated at the protein and transcript levels Data are shown that provide evidence for role of the HO system in the cellular defense mechanism against free radical-mediated tissue damage, and are consistent with the forwarded concept that HO isozymes have common, as well as distinct, roles in cellular defense mechanisms

The world of resveratrol.

Abstract: Since the discovery of trans-resveratrol (3,5,4’-trihydroxystilbene) as a constituent of wine by Siemann and Creasy, first reported in 1992 (1), the possibility that this compound, almost unique to red wine among constituents of the human diet, may in large measure account for the putative health benefits of this beverage beyond its mere content of vulgar ethanol, excited the imagination of the scientific and medical communities, initiating a ferment of research and enquiry that continues to this day. Indeed, ripples of these activities from time to time flow into the pages of the lay press, so that resveratrol has become a molecule impacting the consciousness of many well-informed members of the lay public. In March, 1997 we published a major review incorporating 183 references forming the bulk of the world literature on resveratrol up to that time (2). Our bottom line was that the future of resveratrol did not look particularly promising given the reality that, despite its miraculous performances in the culture dish and the test tube, the intact bodies of mice and men proved to be an inhospitable millieu robbing it of its presumed powers. To us, it seemed to be a compound for whom the bell tolled , but others did not share this gloomy prognosis. In fact, so much new work on this topic has been published in a mere two years-and-a-bit that a reappraisal of the situation deserves a welcome and is mandated by the present Symposium. Resveratrol exists as trans and cis isomers. Very little is known about the latter. When the nature of resveratrol is not specified, the reader should assume that the text refers to the trans isomer.

Hypoxia-inducible factor in brain.

Abstract: HIF-1 is composed of HIF-1α and HIF-1s protein subunits. HIF-1 is induced by hypoxia and binds to promoter / enhancer elements and stimulates the transcription of hypoxia-inducible target genes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of stroke on the expression of HIF-1α, HIF-1s and several HIF-1 target genes in adult rat brain. After focal cerebral ischemia, mRNAs encoding HIF-1α, glucose transporter-1 and several glycolytic enzymes including lactate dehydrogenase were up-regulated in the areas around the infarction. HIF and its target genes were induced by 7.5 hours after the onset of ischemia and increased further at 19 and 24 hours. Since hypoxia induces HIF in other tissues, systemic hypoxia (6% O2 for 4.5h) was also shown to increase HIF-la protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2/3hrs), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1α and HIF-HIF-1β expression. We also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1α and HIF-HIF-1β protein levels were markedly increased after i.p. injection of CoCl2 and DFX. Preconditioning with CoCl2 or DFX 24 hours before the stroke decreased infarction by 75% and 56% respectively, compared with vehicle-injected, littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning.

The pVHL-hIF-1 system. A key mediator of oxygen homeostasis.

Abstract: Matching oxygen consumption and supply represents a fundamental challenge to multicellular organisms. HIF-1 is a transcription complex which is emerging as a key mediator of oxygen homeostasis. HIF-1 controls the expression of many genes, including erythropoietin, angiogenic growth factors, glucose transporters and glycolytic enzymes. The HIF-1 complex, which contains an alpha and beta subunit (both basic helix-loop-helix proteins of the PAS family) is formed in hypoxia and modulates gene expression through hypoxia response elements. Regulation involves ubiquitin-mediated oxygen-dependent destruction of the alpha subunit. Oxygen-regulated destruction of HIF-alpha requires the von Hippel Lindau tumour suppressor protein (pVHL). pVHL acts as the recognition component of a ubiquitin E3 ligase complex which binds HIF-alpha. Loss of pVHL function, which results in constitutive activation of the hypoxic response, is important in the development of clear cell renal cancer, where both copies of the gene are usually inactivated. The importance of the VHL-HIF system in multicellular organisms is supported by conservation in the nematode C. elegans. Understanding the events resulting in HIF activation should provide novel therapeutic targets. This would be useful in preventing angiogenesis in cancers and promoting adaptive changes in hypoxic/ischaemic tissue.

Cytotoxic reactions associated with insect immunity.

Abstract: Insects and other invertebrates lack the immunoglobulins and adaptive responses that characterize vertebrates yet possess efficient innate immune systems comprised of both cellular and humoral elements (Gillespie et al., 1997; Vilmos and Kurucz, 1998). The evolutionary origins and molecular basis for the various recognitive mechanisms remain among the most intriguing of immunological puzzles at all levels of biological organization (Ratcliffe, 1993; Ottaviani and Franceschi, 1998). Frequently, the first line of defense against potentially invasive organisms are integumental or midgut defenses, which may involve various cytotoxic proteins and antimicrobial peptides synthesized by epidermal cells and transported to the sites of wounding (Brey et al., 1993; Furukawa et al., 1999). Foreign organisms that breach integumental barriers or instead pass through the gut wall to invade the host’s hemocoel encounter reactive blood cells, and an array of both non-specific and specific inducible cytotoxic molecules.

Bioactive Components of Human Milk

Abstract: The growing number of bioactive substances being found in human milk suggest the need to attempt their categorization according to function. Two major themes that emerge from recent research on human milk and lactation are efficient nutrient transfer from mother to infant and protection of the infant from disease. Bioactive substances in human milk may be considered in terms of these themes.

Classification of plant lectins in families of structurally and evolutionary related proteins.

Abstract: The majority of plant lectins can be classified in seven families of structurally and lutionary related proteins. Within a given lectin family most but not necessarily all mbers are built up of protomers with a similar primary structure and overall 3-D fold. The rall structure of the native lectins is not only determined by the structure of the protomers depends also on the degree of oligomerization and in some cases on the post-nslational processing of the lectin precursors. In general, lectin families are fairly homogeneous for what concerns the overall cificity of the individuallectins, which illustrates that the 3-D structure of the binding site been conserved during evolution. In the case of the jacalin-related lectins the occurrence a mannose-and galactose-binding subfamily can be explained by the fact that a post-nslational cleavage of the protomers (of the galactose-binding subfamily) yields a slightly red binding site. Unlike the other families, the legume lectins display a wide range of cificites, which is clearly reflected in the occurrence of sugar-binding sites with a erent 3-D structure.

The Structural Basis for Carbohydrate Recognition By Lectins

Abstract: 1 Different carbohydrate-specific proteins, such as lectins, may combine with the same monosaccharide or oligosaccharide by different H-bonding and hydrophobic side chains. 2 Homologous proteins with distinct specificities may bind different monosaccharides (e.g., for glucose and galactose that differ in the configuration of a single hydroxyl) by the same set of invariant residues that are identically positioned in their tertiary structures. 3 The energetics of protein-carbohydrate interactions cannot be derived from structural in-formation. 4 Nature solves in a variety of different ways the problem of constructing combining sites for carbohydrates, just as it provides diverse solutions for other functions of proteins.

O-Linked N-Acetylglucosamine and Cancer: Messages from the Glycosylation of C-Myc

Abstract: Altered protein glycosylation is known to correlate with tumorigenesis, but its role remains enigmatic. Cells transformed by altered oncogene or twnor suppressor gene expression often also show changes of carbohydrate on cell surface glycoconjugates which correlate with the potential for twnor invasion and metastasis. In recent years, many oncogene and twnor suppressor gene products, such as c-Myc, SV40 large T antigen, and p53, were shown to be modified by O-G1cNAc. O-G1cNAc is a form of protein glycosylation found almost exclusively in the nucleus and cytoplasm of eukaryotic cells. The known O-G1cNAc-bearing proteins are phosphoproteins and form reversible multimeric complexes. O-G1cNAc modification is dynamic and appears to have a reciprocal relationship with protein phosphorylation.

Changes in lactoferrin and lysozyme levels in human milk during the first twelve weeks of lactation.

Abstract: Changes in the lactoferrin and lysozyme concentration of human milk during lactation were determined by microparticle-enhanced nephelometric immunoassays of 360 milk samples collected from 64 lactating volunteers. These 360 samples were colostrum from days 1 to 5 postpartum (142 samples), transitional milk from days 6 to 14 (106 samples), and 112 mature milk samples obtained from days 15 to 28 (34 samples), from days 29 to 56 (50 samples) and from days 57 to 84 postpartum (28 samples). The concentration and percentage of lactoferrin vs. total protein were found to be significantly higher in colostrum (5.8 g/L, 27%) than in transitional milk (3.1 g/L, 22%) or day 15 to 28 mature milk (2 0 g/L, 19%), then increased in day 29 to 56 mature milk (2 2 g/L, 22%) and day 57 to 84 mature milk (3 3 g/L, 30%). The concentration of lysozyme decreased from colostrum (0.37 g/L) to transitional milk (0.27 g/L) and day 15 to 28 mature milk (0.24 g/L), then increased in day 29 to 56 mature milk (0 33 g/L) and was highest in day 57 to 84 mature milk (0 89 g/L). The percentage of lysozyme vs. total protein was found to be always rising during lactation: colostrum, 2%; transitional milk, 2%; days 15 to 28, 2%; days 29 to 56, 3%; and days 57 to 84 mature milk, 8%.

Identification of hepatic protein targets of the reactive metabolites of the non-hepatotoxic regioisomer of acetaminophen, 3'-hydroxyacetanilide, in the mouse in vivo using two-dimensional gel electrophoresis and mass spectrometry.

Abstract: The hepatotoxicity observed following an overdose of acetaminophen is due to the excessive production of the reactive metabolite N-acetyl- p -benzoquinone imine (NAPQI) by cytochrome P4501–6. At therapeutic doses NAPQI is efficiently trapped by conjugation with glutathione; however, after a hepatotoxic dose, both cytosolic and mitochondrial glutathione pools in liver cells are depleted and NAPQI covalently binds to numerous liver proteins7 before centralobular liver cell necrosis develops via an unknown mechanism. Because NAPQI is a powerful electrophile as well as an oxidant, both protein covalent binding and oxidative stress hypotheses have been invoked to address the biochemical processes responsible for the hepatotoxicity of acetaminophen.

Detection of four human milk groups with respect to Lewis-blood-group-dependent oligosaccharides by serologic and chromatographic analysis.

Abstract: Oligosaccharides from human milk samples obtained from individual donors were analyzed using high-pH anion-exchange chromatography. Three patterns of neutral oligosaccharides were detected corresponding to milk groups already described. These oligosaccharide groups correspond to the Lewis blood types Lea-b+Lea+b-and Lea-b-. A new carbohydrate pattern was detected in a milk sample from a Lea-b-person in which only nonfucosylated oligosaccharides and compounds bearing al,3-linked fucosyl residues were found. This finding led to the hypothesis that there exist 4 different oligosaccharide milk groups that fit well to the genetic basis of the Lewis blood group system.

Skeletal muscle angiogenesis. A possible role for hypoxia.

Abstract: Skeletal muscle is one of the most plastic tissues in the body. Repeated exercise causes several muscle adaptations, among which the development of additional capillaries (angiogenesis) is prominent. Conversely, inactivity and some chronic diseases result in loss of muscle capillaries. Since (endurance) exercise depends on adequate O2 supply, it is reasonable to hypothesize that hypoxia occurring within muscle during exercise may provide the stimulus to angiogenesis. However, there are other potential stimuli including physical effects of increased muscle blood flow, or of muscle contraction; release of molecules such as NO that could transcriptionally activate angiogenic growth factors; and perhaps changes in the biochemical milieu of the muscle cell such as acidosis. This brief review will address evidence collected to date mostly at the molecular biological level that does in fact implicate reduced intracellular Po2 as a major stimulus to the angiogenic process resulting from exercise. In particular, it is shown that VEGF message and protein are increased in muscle with exercise, more so in hypoxia, and that HIF-1α correlates with VEGF as would be expected if hypoxia were the major stimulus. In addition, we show that muscle intracellular PO2 falls to very low levels during exercise (3–4 Torr), providing a degree of hypoxia compatible with a strong role for low Po2 in angiogenic growth factor response. However, the definitive experiments using acute gene manipulation to establish a cause and effect relationship between hypoxia and muscle angiogenesis remain to be performed.

Control of autoimmunity by regulatory T cells.

Abstract: The development of autoimmune disease involves a breakdown in the mechanisms that control self vs non-self discrimimation. The primary mechanism that leads to self tolerance is thymic deletion of autoreactive T cells, but thymic deletion is not perfect and autoreactive T cells do escape to the periphery. Cells that escape thymic deletion are then subject to mechanisms of peripheral tolerance including the induction of anergy t as well as T cell ignorance/indifference of the recognition of autoantigens. However, anergy can be reversed and ignorant T cell populations have the potential to be activated when their target self-antigens are released into the lymphoid system during the course of an infectious insult or when activated by cross-reactive antigens present on infectious agents. Passive mechanisms for the induction of self tolerance may therefore be insufficient to control the activation of autoreactive T cells. Evidence has recently been obtained for an active mechanism of immune suppression in which a distinct subset of T cells suppresses the activation of autoreactive T cells that have escaped the other mechanisms of tolerance induction. Two experimental models have been developed which have allowed the definition of unique populations of regulatory T cells. In one model, autoimmunity is induced by depletion of regulatory T cells from adult animals, while in the second model, the development of regulatory T cells is abolished in neonatal animals.

The strengths and weaknesses of the electronic nose.

Abstract: Arrays of electronic sensors, capable of detecting and differentiating complex mixtures of volatile compounds, have been utilized to differentiate aromas of food and related materials. These sensor arrays have been dubbed “Electronic Noses” and have been commercially available in the USA for the past 4-5 years. Electronic nose technology is still in its development phase, both in respect to hardware and software development. The instruments contain an array of from one to 32 sensors, using a variety of different sensor technologies—from organic polymers to metal oxides to micro-balances. Electronic noses are being widely used by some companies as a quality control instrument. Strengths include high sensitivity and correlation to human sensory panels for many applications. Limitations to their full potential includes loss of sensitivity in the presence of water vapor or high concentrations of a single component like alcohol; sensor drift and the inability to provide absolute calibration; relatively short life of some sensors; necessity to do considerable method development work for each specific application; and lack of being able to obtain quantitative data for aroma differences. They do have a high sensitivity (ppt to ppm) and are often more sensitive than the human nose. There is some evidence that sensors differentiate aromas on the basis of relatively few compounds and in the future a relationship between specific chemicals and a single flavor attribute may be achievable. Also, the possibility exists to differentiate between “top” and “middle” notes of aroma.

Chronic intermittent hypoxia enhances carotid body chemoreceptor response to low oxygen.

Abstract: Episodic or intermittent hypoxia occurs in many pathophysiological situations, including sleep apneas and recurrent apneas in premature infants. In addition, intermittent hypoxia is not all uncommon in humans who have lung diseases such as chronic obstructive pulmonary disease (COPD), asthma or pulmonary fibrosis. Thus mammals experience episodic hypoxia, often in life, even perhaps more so than sustained hypoxia that occurs in situations like high altitude.

Growth rates of a human colon adenocarcinoma cell line are regulated by the milk protein alpha-lactalbumin.

Abstract: The whey protein a-lactalbumin, derived from human milk, has been shown to inhibit proliferation of mammary epithelial cells and rat kidney cells. We have shown that bovine a-lactalbumin also has antiproliferative effects in human colon adenocarcinoma cell lines. During a 5-day dose-dependent growth study, bovine a-lactalbumin was added to Caco-2 or HT-29 monolayers in amounts from 5 to 35 µg/mL. Low concentrations of a-lactalbumin (10-25 µg/mL) stimulated growth during the first 3 to 4 days. After growing for 4 days, proliferation ceased and viable cell numbers decreased dramatically in the a-lactalbumin-treated cultures, suggesting a delayed initiation of apoptosis. This experiment demonstrates the acute bioactive effects of small concentrations of a-lactalbumin, compared with the high concentrations of other proteins in the media. These results suggest that a-lactalbumin in milk may promote health by inhibiting growth of potential cancer cells. Further studies will identify the role of calcium in the bioactivity of a-lactalbumin

Micro-FE analyses of bone: state of the art.

Abstract: The ability to provide a complete characterization of elastic properties of bone has vastly improved our understanding of trabecular bone mechanical properties. Based on this information, it was possible to validate several mechanical concepts related to the elastic behavior of trabecular bone that could not be validated earlier. With recently developed micro-CT scanners and the availability of large parallel computer systems, this technique has also enabled the determination of physiological bone tissue loading conditions from very large microFE models that can represent whole human bones in detail. Such analyses can provide the data needed for a better understanding of bone failure processes or cell mediated load adaptive remodeling processes. Computational demands for whole bone analyses, however, are still excessive. Unlike linear stress and strain analyses, the application of PFE to study non-linear processes, in particular bone failure mechanisms, is still in an early phase Results of recent studies, however, are promising and indicate that an accurate prediction of bone failure with these techniques is possible. Compelling features of such analyses are that they enable multi-axial failure criteria at the apparent level to be developed using primarily computational methods as well as that they can provide a basis for detailed analysis of micro-mechanics associated with trabecular failure at the apparent level. The application of microFE techniques to analyze bone in vivo is in an early stage as well. First results have indicated that, although the resolution of presently available in vivo imaging techniques (i.e. pQCT and MR) is much less than that of images used so far for uFE analyses, the technique can provide meaningful elastic properties of trabecular bone in vivo in most cases. It is expected that the remaining uncertainties in the microFE results can be eliminated as soon as the resolution of in vivo images is improved. With the fast developments in pQCT(47) and MR scanning, this will probably be in the near future.

Weight loss at high altitude.

Abstract: Loss of appetite and weight are frequently observed at altitudes above 5000m. However, the pathophysiology behind changes in body composition at extreme altitude is still not fully understood. Proper acclimatization to altitude and high caloric intake minimizes, but can not completely prevent significant weight loss under the influence of hypobaric hypoxia. The discovery of leptin in 1994 has initiated a new research area investigating molecular networks that connect peripheral organs with the central nervous system to sense and regulate energy intake as well as energy expenditure. Since then, a whole microcosm of new hormones, neurotransmitters and receptors has been discovered and studied with respect to body weight control. Those agents include neuropeptide Y (NPY), agouti-related protein (AGRP), melanocortin receptors (MC-R), cocaine-amphetamine regulated transcript (CART), proopiomelanocortin (POMC), orexin A and B (hypocretins), melanin-concentrating hormone (MCH) and ghrelin (endogenous ligand of the growth hormone secretagogue receptor). This overview will introduce the current concepts of the molecular control of energy homeostasis and attempt to reexamine the effects of altitude on appetite and body composition in light of these concepts. An overview of studies on changes of appetite and body composition at high altitude will be followed by the presentation of recent data on changes of endocrine parameters at hypobaric hypoxia that could be involved in the pathophysiology of weight loss.

Oral Immunization of Human with transgenic lettuce Expressing Hepatitis B Surface Antigen

Abstract: A number of reports for the past few years have shown that higher plants can be important and useful tools for production and delivery of viral antigens Oral route represents one of the most efficient and safe ways for administration of therapeutic proteins [1] Among protein antigens expressed in transgenic plants is hepatitis B surface antigen as reported by several laboratories

Leukocyte-endothelial interactions in environmental hypoxia

Abstract: Hypoxia induced by reducing inspired Po2 (PIo2) to 70 Torr, promotes a rapid microvascular response characterized by increased leukocyte rolling and adherence to the venular endothelium, leukocyte emigration to the perivascular space and increased vascular permeability. This appears to be a generalized response since it is observed in venules of the mesentery, cremaster muscle and pial microcirculations. After three weeks of acclimatization to hypoxia (barometric pressure 380 Torr, PIo2 70 Torr), the initial microvascular response resolves and exposure to even lower PIo2 (50 Torr) fails to elicit a microvascular response. The initial response is accompanied by a reversible increase in the generation of reactive oxygen species (ROS) and is blocked by antioxidants and by interventions that increase the tissue levels of nitric oxide (NO). In contrast to ischemia/reperfusion, ROS levels increase during hypoxia and return towards pre-hypoxic values after return to normoxia. Acclimatization involves upregulation of inducible NO synthase (iNOS): inhibition of iNOS using two different antagonists results in increased leukocyte-endothelial interactions and increased ROS generation. The results suggest that hypoxia initially leads to an alteration of the ROS/NO balance which is eventually restored during the acclimatization process. This phenomenon may have relevance to the microcirculatory alterations associated with hypoxic exposure, including acute mountain sickness and high altitude pulmonary and cerebral edema.

Mitochondrial Dysfunction in Neurodegenerative Disorders and Ageing

Abstract: In eukaryotic cells, mitochondria are the organelles that produce the majority of adenosine triphosphate (ATP) required for normal neuronal function and survival. ATP is generated by oxidative phosphorylation (OXPHOS) within mitochondria from intermediates, such as NADH and FADH2which are produced by s-oxidation and the Kreb’s cycle.