Showing papers in "Frontiers in Bioscience in 2010"

Cancer associated fibroblasts (CAFs) in tumor microenvironment.

Abstract: Cancer associated fibroblasts (CAFs) is one of the most crucial components of the tumor microenvironment which promotes the growth and invasion of cancer cells by various mechanisms. CAFs demonstrate a high degree of heterogeneity due to their various origins; however, many distinct morphological features and physiological functions of CAFs have been identified. It is becoming clear that the crosstalk between the cancer cells and the CAFs plays a key role in the progression of cancer, and understanding this mutual relationship would eventually enable us to treat cancer patients by targeting CAFs. In this review, we will discuss the latest findings on the role of CAFs in tumorigenesis and metastasis as well as potential therapeutic implication of CAFs.

The circadian rhythm of body temperature.

Abstract: This article reviews the literature on the circadian rhythm of body temperature. It starts with a description of the typical pattern of oscillation under standard laboratory conditions, with consideration being given to intra- and interspecies differences. It then addresses the influence of environmental factors (principally ambient temperature and food availability) and biological factors (including locomotor activity, maturation and aging, body size, and reproductive state). A discussion of the interplay of rhythmicity and homeostasis (including both regulatory and heat-exchange processes) is followed by concluding remarks.

The evolution of thermal physiology in endotherms.

Abstract: Biologists usually refer to mammals and birds as homeotherms, but these animals universally experience regional and temporal variations in body temperature. These variations could represent adaptive strategies of heterothermy, which in turn would favor genotypes that function over a wide range of temperatures. This coadaptation of thermoregulation and thermosensitivity has been studied extensively among ectotherms, but remains unexplored among endotherms. In this review, we apply classical models of thermal adaptation to predict variation in body temperature within and among populations of mammals and birds. We then relate these predictions to observations generated by comparative and experimental studies. In general, optimality models can explain the qualitative effects of abiotic and biotic factors on thermoregulation. Similar insights should emerge when using models to predict variation in the thermosensitivity of endotherms, but the dearth of empirical data on this subject precludes a rigorous analysis at this time. Future research should focus on the selective pressures imposed by regional and temporal heterothermy in endotherms.

Beneficial effects of Bacteroides fragilis polysaccharides on the immune system.

Abstract: Bacterial colonization of the intestine is critical for the normal function of the mammalian immune system. However, the specific molecules produced by commensal bacteria that contribute to the modulation of the host immune system are largely uncharacterized. Polysaccharide A (PSA) produced by the ubiquitous human commensal, Bacteroides fragilis is a model symbiosis factor. PSA is capable of activating T cell-dependent immune responses that can affect both the development and homeostasis of the host immune system. Colonization of previously germ-free mice with B. fragilis alone is sufficient to correct the splenic Th1/Th2 imbalance found in germ-free mice. In addition, PSA can provide protection in animal models of colitis through repression of pro-inflammatory cytokines associated with the Th17 lineage. This review provides an overview of the immunologic properties of PSA including the mechanisms of immune system activation and the resulting immunomodulatory effects.

Replication protein A: directing traffic at the intersection of replication and repair.

Abstract: Since the initial discovery of replication protein A (RPA) as a DNA replication factor, much progress has been made on elucidating critical roles for RPA in other DNA metabolic pathways. RPA has been shown to be required for DNA replication, DNA repair, DNA recombination, and the DNA damage response pathway with roles in checkpoint activation. This review summarizes the current understanding of RPA structure, phosphorylation and protein-protein interactions in mediating these DNA metabolic processes.

Brain temperature homeostasis: physiological fluctuations and pathological shifts.

Abstract: Brain temperature is a physiological parameter, reflecting the balance between metabolism-related intra-brain heat production and heat loss by cerebral circulation to the rest of the body and then to the external environment. First, we present data on brain temperature fluctuations occurring under physiological and behavioral conditions and discuss their mechanisms. Since most processes governing neural activity are temperature-dependent, we consider how naturally occurring temperature fluctuations could affect neural activity and neural functions. We also consider psychomotor stimulants and show that their hyperthermic effects are state-dependent and modulated by environmental conditions. Since high temperature could irreversibly damage neural cells and worsen various pathological processes, we consider the situations associated with pathological brain hyperthermia and evaluate its role in acute perturbations of brain functions, neurotoxicity, and neurodegeneration. We also discuss the limitations in consideration of brain temperature within the frameworks of physiological regulation and homeostasis. While different adaptive mechanisms could, within some limits, compensate for altered intra-brain heat balance, these mechanisms could fail in real-life situations, resulting in life-threatening health complications.

Comparison of methods for evaluating drug-drug interaction.

Abstract: The goal of the present report is to compare several published methods of analyzing drug-drug interaction data. The compared methods are the curve-shift analysis, isobologram, combination index, and universal surface response analysis, and the comparison was based on analysis of published cytotoxicity data of combinations of two anti-folate agents. Major findings are as follows. The curve shift analysis enabled the inspection of the experimental data and visual evaluation of the approximate parallelism between the dose response curves. Isobologram analysis provided the range of concentration ratios where maximal synergy was obtained. The combination index analysis readily provided quantitative estimation of the extent of synergy or antagonism. The universal surface response method summarized drug-drug interaction in a single parameter, facilitating comparison of larger arrays of combinations. Only the curve shift analysis and the universal surface response method yielded a statistical estimate of differentiation between synergy, additivity, and antagonism. In summary, curve shift analysis, isobolograms, combination index analysis, and the universal response surface method are useful methods for analyzing drug-drug interaction, and provide complementary information.

Mechanisms and controllers of eccrine sweating in humans.

Abstract: Human body temperature is regulated within a very narrow range. When exposed to hyperthermic conditions, via environmental factors and/or increased metabolism, heat dissipation becomes vital for survival. In humans, the primary mechanism of heat dissipation, particularly when ambient temperature is higher than skin temperature, is evaporative heat loss secondary to sweat secretion from eccrine glands. While the primary controller of sweating is the integration between internal and skin temperatures, a number of non-thermal factors modulate the sweating response. In addition to summarizing the current understanding of the neural pathways from the brain to the sweat gland, as well as responses at the sweat gland, this review will highlight findings pertaining to studies of proposed non-thermal modifiers of sweating, namely, exercise, baroreceptor loading state, and body fluid status. Information from these studies not only provides important insight pertaining to the basic mechanisms of sweating, but also perhaps could be useful towards a greater understanding of potential mechanisms and consequences of disease states as well as aging in altering sweating responses and thus temperature regulation.

Chemokines and chemokine receptors in arthritis.

Abstract: Chemokines are involved in leukocyte recruitment to inflammatory sites, such as the synovial tissue in rheumatoid arthritis (RA). There is a structural and a functional classification of chemokines. The former includes four groups: CXC, CC, C and CX3C chemokines. Chemokines may also be either inflammatory or homeostatic, however, these functions often overlap. Anti-chemokine and anti-chemokine receptor targeting may be therapeutically used in the future biological therapy of arthritis. Most data in this field have been obtained from animal models of arthritis as only very few human RA trials have been completed. However, it is very likely that various specific chemokine and chemokine receptor antagonists will be developed and administered to RA patients.

Thermal comfort: research and practice

Abstract: Thermal comfort--the state of mind, which expresses satisfaction with the thermal environment--is an important aspect of the building design process as modern man spends most of the day indoors. This paper reviews the developments in indoor thermal comfort research and practice since the second half of the 1990s, and groups these developments around two main themes; (i) thermal comfort models and standards, and (ii) advances in computerization. Within the first theme, the PMV-model (Predicted Mean Vote), created by Fanger in the late 1960s is discussed in the light of the emergence of models of adaptive thermal comfort. The adaptive models are based on adaptive opportunities of occupants and are related to options of personal control of the indoor climate and psychology and performance. Both models have been considered in the latest round of thermal comfort standard revisions. The second theme focuses on the ever increasing role played by computerization in thermal comfort research and practice, including sophisticated multi-segmental modeling and building performance simulation, transient thermal conditions and interactions, thermal manikins.

Soluble form of a receptor for advanced glycation end products (sRAGE) as a biomarker.

Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) system are implicated in various disorders, including vascular complications in diabetes, cardiovascular disease, neurodegenerative diseases, inflammatory and autoimmune disorders, and cancer growth and metastasis. Indeed, the engagement of RAGE with AGEs elicits oxidative stress generation and evokes inflammatory and thrombogenic responses, thus playing an important role in these devastating disorders. Moreover, since administration of a recombinant soluble form of RAGE (sRAGE), has been shown to block the AGE-RAGE signaling pathway in animal models, exogenously administered sRAGE may capture and eliminate circulating AGEs, thus protecting against the AGE-elicited tissue damage by acting as a decoy receptor for AGEs. Recently, sRAGE has been identified in humans. However, there are a few comprehensive papers about the regulation and role of sRAGE in humans. Therefore, in this paper, we review the kinetics, regulation and pathophysiological role of sRAGE in humans. We further discuss the potential clinical utility of measuring sRAGE in various disorders as a biomarker.

Thermoregulatory and thermal control in the human cutaneous circulation.

Abstract: 1. ABSTRACT The past 10-15 years has been a time of focus on the mechanisms of control in the human cutaneous circulation. Methodological developments have provided powerful means for resolving the important contributors to the reflex control of skin blood flow (thermoregulatory control) and also for the equally impressive effects of direct heating and cooling of the skin (thermal control). This review is devoted largely to that recent literature. We treat the sympathetic vasoconstrictor system and its transmitters and modulatory factors and the sympathetic active vasodilator system and its abundant mysteries, with focus on the putative transmitters and cotransmitters, the involvement of nitric oxide and the relationship to sweating and modulatory factors. We also deal with the current understanding of the mechanisms of vasoconstriction and vasodilation that accompany direct skin cooling and heating, noting that adrenergic function, afferent nerve function and the nitric oxide system are involved in the vascular responses to both thermal stimuli.

Aging and the control of human skin blood flow.

Abstract: Human exposure to cold and heat stimulates cutaneous vasoconstriction and vasodilation via distinct sympathetic reflex and locally mediated pathways. The mechanisms mediating cutaneous vasoconstriction and vasodilation are impaired with primary aging, rendering the aged more vulnerable to hypothermia and cardiovascular complications from heat-related illness, respectively. This paper highlights recent findings discussing how age-related decrements in sympathetic neurotransmission contribute directly to thermoregulatory impairments, whereas changes in local intracellular signaling suggest a more generalized age-associated vascular dysfunction.

The interrelationship between sleep regulation and thermoregulation.

Abstract: The circadian distribution of vigilance states and body temperature changes are tightly coupled. The increase in heat loss at the end of the day is associated with increased ease to fall asleep. Experimental data show that warming the skin or the brain can increase sleep propensity, sleep consolidation, and the duration of sleep. Anatomical and neurophysiological studies show that the pre-optic-anterior-hypothalamus (POAH) is the main integrator of sleep and thermoregulatory information. It integrates information on vigilance states, body temperature, and environmental temperature and influences vigilance states and body temperature in response. Animals that display daily torpor may be a valuable model to investigate the relationship between sleep and thermoregulation. During torpor these animals seem to apply similar strategies and physiological processes as humans during entrance into sleep, but in a more extreme way, providing an excellent opportunity to investigate these processes in more detail. More systematic investigations are needed to further our understanding of the relationship between sleep and thermoregulation, and may provide the basis to treat sleep disturbances with thermal strategies.

Cardiovascular responses to cold exposure.

Abstract: The prevalence of hypertension is increased in winter and in cold regions of the world. Cold temperatures make hypertension worse and trigger cardiovascular complications (stroke, myocardial infarction, heart failure, etc.). Chronic or intermittent exposure to cold causes hypertension and cardiac hypertrophy in animals. The purpose of this review is to provide the recent advances in the mechanistic investigation of cold-induced hypertension (CIH). Cold temperatures increase the activities of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). The SNS initiates CIH via the RAS. Cold exposure suppresses the expression of eNOS and formation of NO, increases the production of endothelin-1 (ET-1), up-regulates ETA receptors, but down-regulates ETB receptors. The roles of these factors and their relations in CIH will be reviewed.

Role of myoepithelial cells in breast tumor progression.

Abstract: Myoepithelial cells form a semi-continuous protective sheet separating the human breast epithelium and the surrounding stroma. They suppress stromal invasion of tumor cells by the secretion of various anti-angiogenic and anti-invasive factors. The disruption of this cell layer results in the release of the growth factors, angiogenic factors, and reactive oxygen species causing an alteration in the microenvironment. This helps in the proliferation of surrounding cells and increases the invasiveness of tumor cells. Two theories are proposed for the mechanism of tumor epithelial cells progression from in situ to invasive stage. According to the first theory, tumor cell invasion is triggered by the overproduction of proteolytic enzymes by myoepithelial cells and surrounding tumor cells. The second theory states that tumor invasion is a multistep process, the interactions between damaged myoepithelial cells and the immunoreactive cells trigger the release of basement membrane degrading enzymes causing tumor progression. Further studies in understanding of molecular mechanism of myoepithelial cell functions in tumor suppression may lead to the identification of novel therapeutic targets for breast cancer.

The role of hypoxia and acidosis in promoting metastasis and resistance to chemotherapy.

Abstract: By a multiplicity of mechanisms, hypoxia and acidosis create a nurturing environment for tumor progression and the evolution of metastatic, drug-resistant cells. Acidosis drives mutagenesis and promotes the subversion of checkpoints and apoptotic mechanisms. Hypoxic tissues secrete cytokines that undermine normal anti-tumor surveillance by macrophages, turning them into accomplices and facilitators of invasion and angiogenesis. Invasiveness is also abetted by acidosis, the result of shifting to an anaerobic glycolytic metabolism. These factors explain the generally poor prognosis indicated by tumors expressing hypoxia-inducible factor-1 (HIF-1). However, these insights into the physiology of hypoxic tumors have inspired the development of new chemotherapeutic approaches directed at these tissues, including bioreductive drugs and gene therapies, some of which are in clinical trials. The ability to target the hypoxic compartment should allow longer progression-free survival and overall survival of patients bearing solid tumor malignancies.

Biomarkers of glial cell proliferation and differentiation in culture.

Abstract: The two major intermediate filament (IF) proteins of astrocytes are vimentin and GFAP. Early during development, radial glia and immature astrocytes express mainly vimentin. Towards the end of gestation, a switch occurs whereby vimentin is progressively replaced by GFAP in differentiated astroglial cells. The expression of vimentin and GFAP increased markedly after injury to CNS. GFAP has been widely recognized as an astrocyte differentiation marker, constituting the major IF protein of mature astrocyte. In our recent researches we investigated the interactions between growth factors and dexamethasone on cytoskeletal proteins GFAP and vimentin expression under different experimental conditions. In addition, nestin, a currently used marker of neural stem cells, is transiently co-expressed with GFAP during development and is induced in reactive astrocytes following brain injury. The role of S100B in astrocytes, neurons, and microglia is particularly studied in Alzheimer's disease. In conclusion, such glial biomarkers will help us to understand the more general mechanisms involved in CNS development and can open new perspectives for the control of the neurologic diseases.

Human thermoregulation: separating thermal and nonthermal effects on heat loss.

Abstract: Human thermoregulatory control during heat stress has been studied at rest, during exercise and more recently during exercise recovery. Heat balance in the body is maintained by changes in the rate of heat loss via adjustments in skin blood flow and sweating. Independent of thermal control, the actions of nonthermal factors have important consequences in the control of heat loss responses during and following exercise. While the effect of these nonthermal factors is largely considered to be an inhibitory or excitatory stimulus which displaces the set-point about which temperature is regulated, their effects on human thermoregulatory control are far reaching. Many factors can affect the relative contribution of thermal and nonthermal influences to heat balance including exercise intensity, hemodynamic status, and the level of hyperthermia imposed. This review will characterize the physiological responses associated with heat stress and discuss the thermal and nonthermal influences on sweating and skin blood flow in humans. Further, recent calorimetric evidence for the understanding of thermal and nonthermal contributions to human heat balance will also be discussed.

The effect of anesthesia on body temperature control.

Abstract: The human thermoregulatory system usually maintains core body temperature near 37 degrees C. This homeostasis is accomplished by thermoregulatory defense mechanisms such as vasoconstriction and shivering or sweating and vasodilatation. Thermoregulation is impaired during general anesthesia. Suppression of thermoregulatory defense mechanisms during general anesthesia is dose dependant and mostly results in perioperative hypothermia. Several adverse effects of hypothermia have been identified, including an increase in postoperative wound infection, perioperative coagulopathy and an increase of postoperative morbid cardiac events. Perioperative hypothermia can be avoided by warming patients actively during general anesthesia. Fever is a controlled increase of core body temperature. Various causes of perioperative fever are given. Fever is usually attenuated by general anesthesia. Typically, patients develop a fever of greater magnitude in the postoperative phase. Postoperative fever is fairly common. The incidence of fever varies with type and duration of surgery, patient's age, surgical site and preoperative inflammation.

Th 17 cells interplay with Foxp3+ Tregs in regulation of inflammation and autoimmunity

Abstract: T helper 17 cells (Th17) are a new CD4+ T helper subset that has been implicated in inflammatory and autoimmune diseases. Th17, along with CD4(+)CD25(high) Foxp3(+) regulatory T cells (Tregs) and other new T helper subsets, have expanded the Th1-Th2 paradigm. Although this new eight-subset paradigm significantly improved our understanding on the differentiation and regulation of CD4+ T helper subsets, many questions remain to be answered. Here we will briefly review the following issues: a) Old Th1-Th2 paradigm versus new multi-subset paradigm; b) Structural features of IL-17 family cytokines; c) Th17 cells; d) Effects of IL-17 on various cell types and tissues; e) IL-17 receptor and signaling pathways; f) Th17-mediated inflammations; and g) Protective mechanisms of IL-17 in infections. Lastly, we will examine the interactions of Th17 and Treg in autoimmune diseases and inflammation: Th17 cells interplay with Tregs. Regulation of autoimmunity and inflammation lies in the interplays of the different T helper subsets, therefore, better understanding of these subsets' interactions would greatly improve our approaches in developing therapy to combat inflammatory and autoimmune diseases.

Poloxamine-based nanomaterials for drug delivery.

Abstract: Poloxamines (Tetronic) are X-shaped amphiphilic block copolymers formed by four arms of poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) blocks bonded to a central ethylenediamine moiety Such a structure confers multi-responsive behaviour, namely temperature and pH-sensitiveness At relatively low concentrations but above the critical micellar concentration (CMC), poloxamines generate polymeric micelles Due to the presence of a hydrophobic core, these nanocarriers are useful in the solubilization and stabilization of poorly water-soluble drugs Moreover, chemical modification of the micellar core is feasible These remarkable and unique features, compared to the well-known linear poloxamers, have motivated an increasing interest in the study and application of the branched derivatives in different emerging disciplines The present review concisely overviews the most important developments comprising the application of poloxamines in drug delivery, mainly as micellar carriers capable of enhancing drug solubility and stability, and also as surface modifiers in the technology of stealth polymeric nanoparticles Their potential for the administration of drugs by different routes and the improvement of the drug bioavailability and therapeutic effect are discussed

Circadian clocks in crustaceans: identified neuronal and cellular systems.

Abstract: Circadian rhythms are known for locomotory and reproductive behaviours, and the functioning of sensory organs, nervous structures, metabolism and developmental processes. The mechanisms and cellular bases of control are mainly inferred from circadian phenomenologies, ablation experiments and pharmacological approaches. Cellular systems for regulation summarised here comprise the retina, the eyestalk neuroendocrine X-organ-sinus gland system, several neuropeptides such as red pigment concentrating, hyperglycaemic and pigment-dispersing hormones, and factors such as serotonin and melatonin. No master clock has been identified, but a model of distributed clockwork involves oscillators such as the retinular cells, neurosecretory systems in the optic lobes, putative brain pacemakers, and the caudal photoreceptor. Extraretinal brain photoreceptors mediate entrainment. Comparative analyses of clock neurons and proteins known from insects may allow the identification of candidate clock neurons in crustaceans as putative homologues in the two taxa. Evidence for the existence of "insect-like" intracellular clock proteins and (light sensitive) transcription factors is scarce, but clock-, period-, and cryptochrome-gene products have been localised in the CNS and other organs rendering further investigations into crustacean clockwork very promising.

Influence of obesity, physical inactivity, and weight cycling on chronic inflammation.

Abstract: Obesity prevalence continues to rise due to excessive caloric intake and sedentary behavior. Weight loss can be achieved through diet and/or exercise, but maintenance of a reduced weight is rare and relapse is prevalent. Repeated periods of weight loss and regain have been termed "weight cycling." It has been speculated that weight cycling may further increase the elevated disease risk common with weight gain, obesity, and physical inactivity. Alterations in adipose tissue with weight cycling may create a more hypoxic environment; hypoxic adipose tissue secretes leptin, a stimulus for macrophage activation and accumulation within adipose tissue. Hypoxic adipocytes and macrophages release pro-inflammatory cytokines into circulation. Elevated body weight and adiposity are linked to cardiovascular disease and type 2 diabetes via an inflammatory mechanism. Thus, it is reasonable to speculate that weight cycling causes a more profound change in chronic inflammation than sustained weight gain. The purpose of this review is to explore inflammatory consequences associated with weight cycling as they are related to sustained weight gain, obesity, physical inactivity as well as relative disease risk.

Physiological modeling for technical, clinical and research applications.

Abstract: Various and disparate technical disciplines have identified a growing need for tools to predict human thermal and thermoregulatory responses to environmental heating and cooling and other thermal challenges such as anesthesia and non-ionizing radiation. In this contribution, a dynamic simulation model is presented and used to predict human thermophysiological and perceptual responses for different applications and situations. The multi-segmental, multi-layered mathematical model predicts body temperatures, thermoregulatory responses, and components of the environmental heat exchange in cold, moderate, as well as hot stress conditions. The incorporated comfort model uses physiological states of the human body to predict thermal sensation responses to steady state and transient conditions. Different validation studies involving climate-chamber physiological and thermal comfort experiments, exposures to uncontrolled outdoor weather conditions, extreme climatic and radiation asymmetry scenarios revealed the model to predict physiological and perceptual responses typically within the standard deviation of the experimental observations. Applications of the model in biometeorology, clothing research, the car industry, clinical and safety applications are presented and discussed.

TRPC channels in smooth muscle cells.

Abstract: Transient receptor potential canonical (TRPC) proteins constitute a family of seven (TRPC1-7) nonselective cation channels within the wider TRP superfamily. TRPC1, TRPC3, TRPC4, TRPC5 and TRPC6 channels are expressed in vascular smooth muscle cells from human vessels of all calibers and in smooth muscle from organs such as the uterus and the gastrointestinal tract. TRPC channels have recently emerged as important players in the control of smooth muscle function. This review will focus on the retrospective analysis of studies proposing contributions of TRPC channels to native calcium entry pathways in smooth muscle and to physiological and pathophysiological responses with emphasis on the vascular system.

Osteomimicry: how tumor cells try to deceive the bone.

Abstract: Bone metastases are complications of multiple myeloma and solid tumors, including breast and prostate carcinomas. Several reports have demonstrated that the preference to metastasize to bone by tumor cells is not a casual but an addressed event, which relies on specific interactions among tumor cells, bone marrow microenvironment and bone cells. One of the features that gives tumor cells more chances to survive and proliferate into the bone tissue is osteomimicry, that is the ability to acquire a bone cell phenotype, especially osteoblast-like. As clearly demonstrated, prostate and breast cancer cells try to resemble osteoblasts by expressing bone matrix proteins, the specific marker alkaline phosphatase, and molecules regulating the osteoblast/osteoclast cross-talk. Based on this evidence it is crucial to dissect in more detail the molecular mechanisms underlying the osteomimetic properties of cancer cells and identify new therapeutic targets eventually leading to a better and prolonged life expectation for patients with bone.

Acetyl-CoA carboxylase-a as a novel target for cancer therapy.

Abstract: Acetyl-CoA carboxylases (ACC) are rate-limiting enzymes in de novo fatty acid synthesis, catalyzing ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Malonyl-CoA is a critical bi-functional molecule, i.e., a substrate of fatty acid synthase (FAS) for acyl chain elongation (fatty acid synthesis) and an inhibitor of carnitine palmitoyltransferase I (CPT-I) for fatty acid beta-oxidation. Two ACC isoforms have been identified in mammals, i.e. ACC-alpha (ACCA, also termed ACC1) and ACC-beta (ACCB, also designated ACC2). ACC has long been used as a target for the management of metabolic diseases, such as obesity and metabolic syndrome, and various inhibitors have been developed in clinical trials. Recently, ACCA up-regulation has been recognized in multiple human cancers, promoting lipogenesis to meet the need of cancer cells for rapid growth and proliferation. Therefore, ACCA might be effective as a potent target for cancer intervention, and the inhibitors developed for the treatment of metabolic diseases would be potential therapeutic agents for cancer therapy. This review summarizes our recent findings and updates the current understanding of the ACCA with focus on cancer research.

Mechanisms of protein aggregation in the retinal pigment epithelial cells

Abstract: The pathogenesis of age-related macular degeneration (AMD) essentially involves chronic oxidative stress, increased accumulation of lipofuscin in retinal pigment epithelial (RPE) cells and extracellular drusen formation, as well as the presence of chronic inflammation. The capacity to prevent the accumulation of cellular cytotoxic protein aggregates is decreased in senescent cells which may evoke lipofuscin accumulation into lysosomes in postmitotic RPE cells. This presence of lipofuscin decreases lysosomal enzyme activity and impairs autophagic clearance of damaged proteins which should be removed from cells. Proteasomes are another crucial proteolytic machine which degrade especially cellular proteins damaged by oxidative stress. This review examines the cross-talk between lysosomes, autophagy and proteasomes in RPE cell protein aggregation, their role as a possible therapeutic target and their involvement in the pathogenesis of AMD.

Changes in the immune system during menopause and aging.

Abstract: The fact that gender influences the immune system has long been recognised. The higher risk of women developing autoimmune diseases suggests that these are somehow mediated by sex steroids, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune-suppressors. The concept of immunosenescence reflects changes in both cellular and humoral immune responses. This may be related with the higher incidence of infectious and chronic diseases. Besides age, in postmenopausal women, changes of the immune system have been attributed to estrogen deprivation. There is an increase in pro-inflammatory serum markers, an increasing response of the body's cells to cytokines, a decrease in CD4 T and B lymphocytes and in the cytotoxic activity of NK cells. In fact IL-6 is a key factor in bone reabsorption by osteoclast activation and also seems to be associated with diseases that occur more in menopause such as diabetes, atherosclerosis and cardiovascular diseases. Recent studies indicate several changes in immune response, either with suspension of hormone therapy or with its replacement at menopause.