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Nowadays, many consumers prefer foods with a high content of nutraceuticals that contribute to the prevention or healing of chronic diseases. Therefore, in recent years, more and more researchers have studied the bioefficiency, safety, and toxicity of nutraceutical-enriched foods. The key stage of nutraceutical bioefficiency is oral bioavailability, which involves the following processes: the release of nutraceuticals from food matrices or nanocarriers in gastrointestinal fluids, the solubilization of nutraceuticals and their interaction with other components of gastrointestinal fluids, the absorption of nutraceuticals by the epithelial layer, and the chemical and biochemical transformations into epithelial cells. These processes are endogenous factors that greatly influence the bioavailability of nutraceuticals. In addition to endogenous factors, the bioavailability of nutraceuticals is also affected by exogenous factors, such as: physicochemical properties of nutraceuticals, food matrix, food processing and storage, and so forth. Both the endogenous and exogenous factors are comprehensively analyzed in this review. Thus, the physicochemical and enzymatic processes involved in food digestion are described, highlighting the role of each stage of gastrointestinal tract (mouth, stomach, and intestine) in nutraceuticals bioaccessibility. The structure and functions of the mucus and epithelial layers, the mechanisms involved in the active and passive transport of nutraceuticals through the cell membrane, and phase I and phase II metabolism reactions are also discussed. Finally, this review focuses on several types of bioactive-loaded nanocarriers such as lipid-based, surfactant-based, and biopolymeric nanocarriers that improve the bioavailability of nutraceuticals.

The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.

In most mammalian species, adult neurogenesis appears to occur only in the olfactory bulb and hippocampal dentate gyrus, where neural stem/progenitor cells exist to create new neurons. The discovery of multi-potential neural stem/progenitor cells (NPCs) in the adult brain has precipitated a novel therapeutic strategy for harnessing these endogenous cells to aid in recovery from neurodegenerative disorders. During neurodegeneration, a plethora of endogenous factors, including cytokines, chemokines, neurotransmitters, blood-derived factors, and reactive oxygen species, are released by the activation of resident microglia, astrocytes, and infiltrating peripheral macrophages. It is interesting that these endogenous factors affect the proliferation, migration, differentiation, and survival of newly generated cells involved in the incorporation of newly generated neurons into the brain's circuitry. The unique profile of these endogenous factors can vary the degree of neuroregeneration after neurodegeneration. We show that adult neurogenesis-activating signals are regulated by endogenous factors produced during neurodegeneration.

The resolution of inflammation (or inflammation-resolution) is an active and highly coordinated process. Inflammation-resolution is governed by several endogenous factors, and specialized pro-resolving mediators (SPMs) are one such class of molecules that have robust biological function. Non-resolving inflammation is associated with a variety of human diseases, including atherosclerosis. Moreover, non-resolving inflammation is a hallmark of ageing, an inevitable process associated with increased risk for cardiovascular disease. Uncovering mechanisms as to why inflammation-resolution is impaired in ageing and in disease and identifying useful biomarkers for non-resolving inflammation are unmet needs. Recent work has pointed to a critical role for balanced ratios of SPMs and pro-inflammatory lipids (i.e. leucotrienes and/or specific prostaglandins) as a key determinant of timely inflammation resolution. This review will focus on the accumulating findings that support the role of non-resolving inflammation and imbalanced pro-resolving and pro-inflammatory mediators in atherosclerosis. We aim to provide insight as to why these imbalances occur, the importance of ageing in disease progression, and how haematopoietic function impacts inflammation-resolution and atherosclerosis. We highlight open questions regarding therapeutic strategies and mechanisms of disease to provide a framework for future studies that aim to tackle this important human disease.

Programmed cell death (PCD) is a fundamental genetically controlled process in most organisms. PCD is responsible for the selective elimination of damaged or unwanted cells and organs to maintain cellular homeostasis during the organ’s development under normal conditions as well as during defense or adaptation to stressful conditions. PCD pathways have been extensively studied in animals. In plants, studies focusing on understanding the pathways of PCD have advanced significantly. However, the knowledge about the molecular basis of PCD is still very limited. Some PCD pathways that have been discovered in animals are not present in plants or found with a similar form. PCD in plants is developmentally controlled (by endogenous factors) to function in organ development and differentiations as well as environmentally induced (by exogenous stimuli) to help the plant in surviving under stress conditions. Here, we present a review of the role of PCD in plant development and explore different examples of stress-induced PCD as well as highlight the main differences between the plant and animal PCD.

REV-ERB is a member of the nuclear receptor superfamily of transcription factors involved in the regulation of many physiological processes, from circadian rhythm, to immune function and metabolism. Accordingly, REV-ERB has been considered as a promising, but difficult drug target for the treatment of numerous diseases. Here, we concisely review current understanding of the function of REV-ERB, modulation by endogenous factors and synthetic ligands, and the involvement of REV-ERB in select human diseases. Particular focus is placed on the medicinal chemistry of synthetic REV-ERB ligands, which demonstrates the need for higher quality ligands to aid in robust validation of this exciting target.

Seasonal breeding in buffalo is influenced by exogenous (photoperiod, climate, nutrition, management) and endogenous (hormones, genotype) factors. Buffalo are negatively photoperiodic and show a natural increase in fertility during decreasing day length. The hormone melatonin is produced by the pineal gland and has a fundamental role in photoperiodic time measurement within the brain. This drives annual cycles of gonadotropin secretion and gonadal function in buffaloes. Some melatonin is released into the systemic circulation and, together with peripherally produced melatonin, acts at somatic tissues. In the ovaries and testes of buffalo, melatonin acts as an antioxidant and scavenges oxygen free radicals to reduce both oxidative stress and apoptosis. This has beneficial effects on gametogenesis and steroidogenesis. Female buffalo treated with melatonin show an improved response to estrus synchronization protocols in out-of-season breeding. Melatonin acts through melatonin receptors MT1 and MT2 and the gene for MT1 (MTNR1A) is polymorphic in buffaloes. Single nucleotide polymorphisms (SNPs) in gene MTNR1A have been associated with fertility in female buffalo. The knowledge and tools are available to lift the reproductive performance of buffalo. This is highly important as the global demand for nutritious buffalo food products has undergone a sharp rise, and continues to grow. Buffalo can make an important contribution to affordable, nutritious animal protein. This will help address global nutritional security.

As heterogeneous immune cells, macrophages mount effective responses to various internal and external changes during disease progression. Macrophage polarization, rather than macrophage heterogenization, is often used to describe the functional differences between macrophages. While macrophage polarization partially contributes to heterogeneity, it does not completely explain the concept of macrophage heterogeneity. At the same time, there are abundant and sophisticated endogenous and exogenous substances that can affect macrophage heterogeneity. While the research on endogenous factors has been systematically reviewed, the findings on exogenous factors have not been well summarized. Hence, we reviewed the characteristics and inducing factors of heterogeneous macrophages to reveal their functional plasticity as well as their targeting manoeuvreability. In the process of constructing and analysing a network organized by disease‐related cells and molecules, paying more attention to heterogeneous macrophages as mediators of this network may help to explore a novel entry point for early prevention of and intervention in disease.

The testes are one of the most delicate organs in the male body and highly susceptible to the exogenous influences capable of inducing cell damage. Cancer therapies are well known to negatively affect the male reproductive tract with a severe impairment of spermatogenesis and infertility. The present work aimed to systematically review the available information about the different endogenous factors (hormonal and nonhormonal) that may have protective or advantageous properties on the recovery of male reproductive function after gonadal injury. Furthermore, the perspective that these endogenous molecules could act as cryoprotectants to improve the quality of cryopreserved semen samples was also discussed. The knowledge reviewed herein allowed to identify promising factors able to mitigate the male fertility problems arising either from oncological treatments or other gonadal damage, and opened new possibilities to ameliorate the recovery of spermatogenesis or to preserve fertility.

In this review, we highlight critical unresolved questions in the etiology and mechanisms causing preterm brain injury. Involvement of neurons, glia, endogenous factors and exogenous exposures is considered. The structural and functional correlates of interrupted development and injury in the premature brain are under active investigation, with the hope that the cellular and molecular mechanisms underlying developmental abnormalities in the human preterm brain can be understood, prevented or repaired.

Frontiers in immunology 10, 182 (2019). doi:10.3389/fimmu.2019.00182, Published by Frontiers Media, Lausanne

In temperate ecosystems, seasonality influences animal behaviour. Food availability, weather, photoperiod and endogenous factors relevant to the biological cycle of individuals have been shown as major drivers of temporal changes in activity rhythms and group size/structure of herbivorous species. We evaluated how diurnal female foraging activity and grouping patterns of a mountain herbivore, the Apennine chamois Rupicapra pyrenaica ornata, varied during a decreasing gradient of pasture availability along the summer-autumn progression (July–October), a crucial period for the life cycle of mountain ungulates. Females increased diurnal foraging activity, possibly because of constrains elicited by variation in environmental factors. Size of mixed groups did not vary, in contrast with the hypothesis that groups should be smaller when pasture availability is lower. Proportion of females in groups increased, possibly suggesting that they concentrated on patchily distributed nutritious forbs. Occurrence of yearlings in groups decreased, which may have depended on dispersal of chamois in this age class. Presence of kids in groups did not show variation through summer-autumn, suggesting a close mother-juvenile relationship even at the end of weaning and/or, possibly, low summer mortality. Both endogenous and environmental factors contribute to shape variation in foraging activity and grouping behaviour in mountain-dwelling herbivores.

Author(s): McQueen, Allison E; Koliwad, Suneil K; Wang, Jen-Chywan | Abstract: Purpose of reviewThe current review provides an update on secreted factors and mechanisms that promote a thermogenic program in beige adipocytes, and their potential roles as therapeutic targets to fight obesity.Recent findingsWe outline recent studies revealing unrecognized mechanisms controlling beige adipocyte physiology, and summarize in particular those that underlie beige thermogenesis independently of classical uncoupling. We also update strategies aimed at fostering beige adipogenesis and white-to beige adipocyte conversion. Finally, we summarize newly identified endogenous secreted factors that promote the thermogenic activation of beige adipocytes and discuss their therapeutic potential.SummaryThe identification of novel endogenous factors that promote beiging and regulate beige adipocyte-specific physiological pathways opens up new avenues for therapeutic engineering targeting obesity and related metabolic disorders.

The importance of microenvironment on dendritic cell (DC) function and development has been strongly established during the last two decades. Although DCs with general tolerogenic characteristics have been isolated and defined as a particular sub-population, it is predominantly their unequivocal biological plasticity, which allows for unparalleled responsiveness to environmental ques and shaping of their tolerogenic characteristics when interacting with tolerance-inducing biomolecules. Dendritic cells carry receptors for a great number of endogenous factors, which, after ligation, can importantly influence the development of their activation state. For this there is ample evidence merely by observation of DC characteristics isolated from various anatomical niches, e.g., the greater immunosuppressive potential of DCs isolated from intestine compared to conventional blood DCs. Endogenous biomolecules present in these environments most likely play a major role as a determinant of their phenotype and function. In this review, we will concisely summarize in what way various, tolerance-inducing endogenous factors influence DC biology, the development of their particular tolerogenic state and their subsequent actions in context of immune response inhibition and induction of regulatory T cells.

Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS). Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural damage process is complex, involving a vast array of tissue structure, transcriptional/translational, electrochemical, metabolic, and functional events within the intact neighbors surrounding injured neural tissues. During aging, multiple changes involving physical, chemical, and biochemical processes occur from the molecular to the morphological levels in neural tissues. Among many recommended therapeutic candidates, melatonin also plays a role in protecting the nervous system from anti-inflammation and efficiently safeguards neuronal cells via antioxidants and other endogenous/exogenous beneficial factors. Therefore, given the wide range of mechanisms responsible for neuronal damage, multi-action drugs or therapies for the treatment of neural injury that make use of two or more agents and target several pathways may have greater efficacy in promoting functional recovery than a single therapy alone.

In newborn mammals, most of the germ cell population rests in a pool of quiescent small follicles in the ovaries. Regularly throughout adulthood, a small percentage of these oocytes and follicles grows to a certain stage of development and then either degenerates or matures and ovulates. This entire process is under both exogenous and endogenous control. Recent work, including my laboratory’s, has clarified that cytokines and glycosaminoglycans are involved as exogenous and endogenous factors in ovarian follicular development, atresia, and maturation in mammals. The present article describes our contribution regarding the cytokines and ovarian glycosaminoglycans that act as intraovarian regulators of follicular development and oogenesis, including oocyte maturation, in mammals.

Circadian rhythms have long been known to regulate numerous physiological processes that vary across the diurnal cycle. The circadian clock system also controls various parameters of the immune system and its biological defense functions, allowing an organism to anticipate daily changes in activity and feeding and the associated risk of infection. Inflammation is an immune response triggered in living organisms in response to external stimuli. The risk of sepsis, an excessive inflammatory response, has been shown to have a diurnal variation. On the other hand, inflammatory responses are emerging to be induced by endogenous factors. Recent studies have suggested that chronic inflammation causes chronic diseases including rheumatoid arthritis, allergies, and aging-related diseases and that proteins encoded by clock genes affect the development of such chronic inflammatory diseases or increase the severity of their symptoms. Therefore, detailed understanding of circadian rhythm effects on inflammatory responses is expected to lead to new strategies for prevention or treatment of inflammatory diseases.

Tissue damage in various diseases, hypoxic conditions, and some pathologies are associated with production of endogenous factors such as the soluble form of the surface receptor CD100, malonic dialdehyde, and arginase and their release into circulation. These factors modulate functional state of lymphocytes in the immune system: potentiate activation of B lymphocytes, activate synthesis and secretion of IL-25 and IL-17 cytokines, and suppress proliferative activity of T lymphocytes, thus modulating immunological reactivity of the organism. Reactions of innate and adaptive immunity develop against the background of changed immunological reactivity, which should be taken into account in the development of pathogenetically substantiated therapy.

Fibroblast growth factor 21 (FGF21) plays a role in regulating adaptation to various metabolic abnormalities. In addition, FGF21 is involved in controlling glucose and lipid homeostasis. The regulation of FGF21 is a complex process and depends upon multiple metabolic factors and hormones. Humans and animals with obesity or type 2 diabetes have abnormal expression and changes of FGF21 in the circulation. Interventional studies in rodents and monkeys with obesity, insulin resistance or type 2 diabetes revealed a potential therapeutic relevance of FGF21 in correcting these abnormalities. This review summarizes the current knowledge about the regulation of FGF21 by distinct metabolic and endogenous factors, considering the most relevant studies. In this context, the results of interventional studies in humans and various animal models of diseases, such as diabetes and obesity, are discussed. In addition, potential mechanisms of the molecular regulation of FGF21 expression and secretion are reviewed.

The pathogenesis of hypertension remains elusive. Current treatments on hypertension have only achieved modest reductions. Facilitating theoretical research and looking for new therapeutic strategy are urgently needed. Besides food digestion and nutrients absorption, the gastrointestinal tract (GI) has been shown to influence the status of the central nervous system, immune system, metabolism, and cardiovascular homeostasis. Emerging findings demonstrate that endogenous factors derived from GI including gut hormones, autonomic nerve, and gut microbiota play important roles in the regulation of vascular function and/or blood pressure. Meanwhile, evidences from clinical practice and experimental study have found that intervention in GI through metabolic surgery, probiotics consumption, and dietary modification can efficiently ameliorate or even remit hypertension and related cardiometabolic diseases. Thus, we propose that GI might be an initiating organ of hypertension and a promising target for the management of hypertension. Further, illuminating this concept may aid to understand the pathogenesis and control of hypertension.

While many epidemiological studies have associated the consumption of polyphenols within fruits and vegetables with a decreased risk of developing several chronic diseases, intervention studies have generally not confirmed these beneficial effects. The reasons for this discrepancy are not fully understood but include potential differences in dosing, interaction with the food matrix, and differences in polyphenol bioavailability. In addition to endogenous factors such as microbiota and digestive enzymes, the food matrix can also considerably affect bioaccessibility, uptake, and further metabolism of polyphenols. While dietary fiber (such as hemicellulose), divalent minerals, and viscous and protein-rich meals are likely to cause detrimental effects on polyphenol bioaccessibility, digestible carbohydrates, dietary lipids (especially for hydrophobic polyphenols, e.g., curcumin), and additional antioxidants may enhance polyphenol availability. Following epithelial uptake, polyphenols such as flavonoids may reduce phase II metabolism and excretion, enhancing polyphenol bioavailability. Furthermore, polyphenols may act synergistically due to their influence on efflux transporters such as p-glycoprotein. In order to understand polyphenol bioactivity, increased knowledge of the factors affecting polyphenol bioavailability, including dietary factors, is paramount.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) has been widely described in many studies conducted thus far. The syndrome incorporates five immune-mediated conditions, all associated with previous exposure to various agents such as vaccines, silicone implants and several others. The emergence of ASIA syndrome is associated with individual genetic predisposition, for instance those carrying HLA-DRB1*01 or HLA-DRB4 and results from exposure to external or endogenous factors triggering autoimmunity. Such factors have been demonstrated as able to induce autoimmunity in both animal models and humans via a variety of proposed mechanisms. In recent years, physicians have become more aware of the existence of ASIA syndrome and the relationship between adjuvants exposure and autoimmunity and more cases are being reported. Accordingly, we have created a registry that includes at present more than 300 ASIA syndrome cases that have been reported by different physicians worldwide, describing various autoimmune conditions induced by diverse adjuvants. In this review, we have summarized the updated literature on ASIA syndrome and the knowledge accumulated since 2013 in order to elucidate the association between the exposure to various adjuvant agents and its possible clinical manifestations. Furthermore, we especially referred to the relationship between ASIA syndrome and systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS).

Species experience both internal feedbacks with endogenous factors such as trait evolution and external feedbacks with exogenous factors such as weather. These feedbacks can play an important role in determining whether populations persist or communities of species coexist. To provide a general mathematical framework for studying these effects, we develop a theorem for coexistence for ecological models accounting for internal and external feedbacks. Specifically, we use average Lyapunov functions and Morse decompositions to develop sufficient and necessary conditions for robust permanence, a form of coexistence robust to large perturbations of the population densities and small structural perturbations of the models. We illustrate how our results can be applied to verify permanence in non-autonomous models, structured population models, including those with frequency-dependent feedbacks, and models of eco-evolutionary dynamics. In these applications, we discuss how our results relate to previous results for models with particular types of feedbacks.

Inferring the factors responsible for declines in abundance is a prerequisite to preventing the extinction of wild populations. Many of the policies and programmes intended to prevent extinctions operate on the assumption that the factors driving the decline of a population can be determined. Exogenous factors that cause declines in abundance can be statistically confounded with endogenous factors such as density dependence. To demonstrate the potential for confounding, we used an experiment where replicated populations were driven to extinction by gradually manipulating habitat quality. In many of the replicated populations, habitat quality and density dependence were confounded, which obscured causal inference. Our results show that confounding is likely to occur when the exogenous factors that are driving the decline change gradually over time. Our study has direct implications for wild populations, because many factors that could drive a population to extinction change gradually through time.

The growing tumor employs various strategies to establish its growth, progression and spread in the host. Angiogenesis or formation of new blood vessels from existing ones and escape from immune surveillance are the two critical steps that ensure proper establishment and growth of the newly formed tumor. Thus understanding the novel pathways associated with tumor angiogenesis and immunity may lead to the development of newer therapeutic strategies using the regulators of these pathways to improve patient outcomes. These two pivotal steps in the process of tumorigenesis are governed by plethora of endogenous factors. The neuroendocrine molecules, which include the catecholamine neurotransmitters, dopamine, norepinephrine and epinephrine are of growing interest considering their varied and diverse regulatory roles both in the process of tumor angiogenesis and tumor immunity. This review focuses on the emerging roles of catecholamines in modulating tumor angiogenesis and immunity, and also discusses the probable molecular mechanisms of their actions. Understanding of this new group of endogenous regulators of tumor growth may lead to the development of newer therapeutic approaches for the treatment of cancer.

Brain injury during development can have severe, long-term consequences. Using an array of animal models, we have an understanding of the etiology of perinatal brain injury. However, we have only recently begun to address the consequences of endogenous factors such as genetic sex and developmental steroid hormone milieu. Our limited understanding has sometimes led researchers to make over-generalizing and potentially dangerous statements regarding treatment for brain injury. Therefore this review acts as a cautionary tale, speaking to our need to understand the effects of sex and steroid hormone environment on the response to brain trauma in the neonate.

Diseases cycle as a response to endogenous and exogenous factors. For infectious diseases caused by vector-transmitted pathogens, the exogenous factors are commonly equated to climatic forces and the endogenous factors to the recruitment of new susceptible individuals. Mathematical models that explicitly (parametrically) consider both types of factor are, however, very rare. An approach is presented to model the effects of endogenous and exogenous factors parametrically, using a time series for American cutaneous leishmaniasis (ACL) from Costa Rica. The seasonality of the disease is modelled using a seasonal autoregressive approach. The latter has the advantage of allowing the use of semi-mechanistic frameworks that consider infection clearance, while explicitly introducing the feedbacks produced by the transition between immune classes, as well as climatic forcing. It also uses a relatively small number of degrees of freedom (compared with the numbers involved in semi-parametric approaches), making it useful for relatively short time series and series with abrupt changes. Compared with non-mechanistic models built for prediction purposes, this way of modelling seems to increase the likelihood of the data being explained by a plausible mechanism. The approach used in this study of ACL could be useful in investigating the changes that occur in other diseases that show non-stationary seasonal dynamics, and can be easily adapted to model the dynamics of other infectious diseases that show trends or breakpoints. The present results support the view that humans affected by ACL are mostly incidental hosts, and indicate that, at the population level, there is a delay of about 5 months between human infection with the causative parasites and the onset of clinical symptoms. They encourage the development of surveillance systems, for monitoring the prevalence of infection in the sandflies that act as vectors, and the use of sentinel hosts, so that control measures can be rapidly applied or strengthened before a serious outbreak occurs. The development of more accurate mathematical models of ACL will depend largely on advances in the ecology of the disease and of all the hosts of the causative parasites.

The adrenal gland influences a multitude of processes during stress response, but also potently affects the immune system, glucose metabolism, electrolyte or water homeostasis, and cardiovascular functions. According to the present understanding, the adrenal cortex is tightly controlled by the hypothalamic–pituitary–adrenal axis. This axis involves hypothalamic CRH and pituitary ACTH which determine processes of adrenocortical growth and function. However, control of the adrenal gland comprises a plethora of additional endogenous or exogenous factors. Among those are diverse hormones, psychosocial parameters, physiological stress, secondary plant products, or even environmental pollutants. In the present review, we summarize the current view of endocrine growth control in the adrenal gland. We then discuss intracellular mechanisms of adrenal growth control and focus on extracellular signal regulated kinases 1/2 (ERK1/2), which have been demonstrated to be controlled by not only ACTH or angiotensin II, but also by a large number of additional effectors. On the basis of these multiple exogenous or endogenous factors which impact on the adrenal gland through ERK1/2 activity, we speculate on a mechanism by which ERK1/2 act as a central integrative growth regulatory elements in the adrenal gland.

Resolution of inflammation and induction of immune tolerance are essential to stabilize immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure the re-establishment of immune homeostasis and maintenance of tolerance. The identification of endogenous factors that regulate these processes is crucial for the development of new therapies for inflammatory/autoimmune conditions. Neuropeptides produced during an ongoing inflammatory response emerged as endogenous anti-inflammatory agents that participate in processes leading to the resolution of inflammation and maintenance of tolerance. Anti-inflammatory neuropeptides and hormones such as vasoactive intestinal peptide, urocortin, adrenomedullin, melanocyte stimulating hormone, ghrelin, and cortistatin have beneficial effects in a variety of experimental inflammatory and autoimmune models. Their therapeutic effect has been attributed to their capacity to downregulate innate immunity, to inhibit antigen-specific T(H)1-driven responses, and to generate regulatory T cells. Finally, some of these neuropeptides have been identified as mediators of innate defense acting as natural antimicrobial peptides. Here we present the research findings in the neuropeptide immunoregulatory field, and examine possible therapies based on anti-inflammatory neuropeptides and hormones as a new pharmacologic platform.

Cardiovascular disease is the leading cause of death in the United States and developing world. Experimental and clinical studies have demonstrated that a number of interventions including brief periods of ischemia or hypoxia and certain endogenous factors such as opioids, bradykinin, growth factors or pharmacological agents are capable of protecting the heart against post-ischemic contractile dysfunction, arrhythmias and myocardial infarction. This conventional cardioprotection occurs via an autocrine or paracrine action in which these protective factors are released from the heart to act upon itself. Over the last ten years, a growing body of evidence indicates that a brief ischemic insult on one organ releases endogenous factors that protect other organs against a prolonged ischemic insult. This phenomenon, termed remote preconditioning or preconditioning at a distance, implicates an endocrine action, and may involve humoral or neural-endocrine signaling. This review will summarize the endocrine factors identified and implicated in this inter-organ cytoprotection.

The induction of antigen-specific tolerance is essential to maintain immune homeostasis, control autoreactive T cells, prevent the onset of autoimmune diseases and achieve tolerance of transplants. Inflammation is a necessary process for eliminating pathogens, but can lead to serious deleterious effects in the host if left unchecked. Identifying the endogenous factors that control immune tolerance and inflammation is a key goal in the field of immunology. In the last decade, various neuropeptides that are produced by immune cells with potent anti-inflammatory actions were found to participate in the maintenance of tolerance in different immunological disorders.

Several animal species are considered to exhibit what is called negligible senescence, i.e. they do not show signs of functional decline or any increase of mortality with age, and do not have measurable reductions in reproductive capacity with age. Recent studies in Naked Mole Rat (NMR) and long- lived sea urchin showed that the level of gene expression changes with age is lower than in other organisms. These phenotypic observations correlate well with exceptional endurance of NMR tissues to various genotoxic stresses. Therefore, the lifelong transcriptional stability of an organism may be a key determinant of longevity. However, the exact relation between genetic network stability, stress-resistance and aging has not been defined. We analyze the stability of a simple genetic- network model of a living organism under the influence of external and endogenous factors. We demonstrate that under most common circumstances a gene network is inherently unstable and suffers from exponential accumulation of gene-regulation deviations leading to death. However, should the repair systems be sufficiently effective, the gene network can stabilize so that gene damage remains constrained along with mortality of the organism, which may then enjoy a remarkable degree of stability over very long times. We clarify the relation between stress-resistance and aging and suggest that stabilization of the genetic network may provide a mathematical explanation of the Gompertz equation describing the relationship between age and mortality in many species, and of the apparently negligible senescence observed in exceptionally long-lived animals. The model may support a range of applications, such as systematic searches for therapeutics to extend lifespan and healthspan., 8 pages, 2 figures

Kenneth A. Johnson bone, resulting in delayed or non-union is a vexing clinical problem in all species of animals. Recently, the focus of attention in orthopaedics has been on the treatment of fractures by bone grafts, mesenchymal stem cells, growth factors, biomaterials and improved mechanical environment, either alone or in some combination. These therapies have produced clearly demonstrable benefits in treating delayed and non-union. However there is still much to learn about the complex processes of fracture healing, and why it fails in some patients despite the management by ‘state of the art’ surgery employing, for example, minimally invasive osteosynthesis, locking implants, exogenous growth factor application, and 3D printed biomaterials and stem cells for the reconstruction of critical sized defects. Even so, in a proportion of fracture patients, endogenous factors predispose to impaired fracture healing. The pivotal role of immunity in fracture healing and bone regeneration was one such endogenous factor under discussion at the symposium. The immune system has direct involvement in guiding all stages of fracture healing starting with inflamImmune System and Bone Regeneration

Immunosuppressed patients retain transplants but become more susceptible to opportunistic infections, which is a major complication in organ transplantation. Life-long immunosuppression for such patients could be reduced by creating immune tolerance, although this might be associated with an increased risk for infections and malignancies. An alternative therapeutic concept could consist of boosting the innate immune response against infections while continuing to suppress the adaptive immune response to prevent graft rejection. We propose granulocyte-macrophage colony-stimulating factor (GM-CSF) as a novel candidate to achieve this goal, based on recent studies in which beneficial effects were demonstrated in immunosuppressed mice with skin allografts and in dexamethasone-suppressed blood from healthy volunteers and blood from liver transplant recipients undergoing immunosuppressive therapy. Such data suggest that GM-CSF or other endogenous factors with similar properties should be examined in clinical trials.

Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.

The development of asthmatic inflammation involves a complex array of cytokines that promote the recruitment and activation of a number of different immune cells. While factors involved in initiating and establishing inflammation are well characterized, the process by which this pro-inflammatory cascade is regulated is less well understood. The identification and characterization of immunomodulatory cytokines in asthma has been a difficult proposition. Many of the putative regulatory factors have pleiotropic bioactivities and have been characterized as pro-inflammatory in association with certain pathologic conditions. This chapter addresses the potential role of several endogenous factors which appear to attenuate asthmatic inflammation. Understanding the integration of these factors into the regulation of the inflammatory process will likely result in novel therapeutic approaches.

The risk for cardiovascular incidents is highest in the early morning, which seems partially due to endogenous factors. Endogenous circadian rhythms in mammalian physiology and behavior are regulated by the suprachiasmatic nucleus (SCN). Recently, anatomical evidence has been provided that SCN functioning is disturbed in patients with essential hypertension. Here we review neural and neuroendocrine mechanisms by which the SCN regulates the cardiovascular system. First, we discuss evidence for an endogenous circadian rhythm in cardiac activity, both in humans and rats, which is abolished after SCN lesioning in rats. The immediate impact of retinal light exposure at night on SCN-output to the cardiovascular system, which signals 'day' in both diurnal (human) and nocturnal (rat) mammals with opposite effects on physiology, is discussed. Furthermore, we discuss the impact of melatonin treatment on the SCN and its potential medical relevance in patients with essential hypertension. Finally, we argue that regional differentiation of the SCN and autonomous nervous system is required to explain the multitude of circadian rhythms. Insights into the mechanisms by which the SCN affects the cardiovascular system may provide new strategies for the treatment of disease conditions known to coincide with circadian rhythm disturbances, as is presented for essential hypertension.

Contains fulltext : 62152.pdf (Publisher’s version ) (Closed access) Examples from experimental epilepsy in animals are used to illustrate the view that a crucial role of the transfer of mechanisms from compensatory into pathogenic (e.g. lethal ones in the course of a disease), is played by the power of pathologic stimuli. In the genesis of epilepsy it is suggested that a critical increase of endogenous factors may underlie the conversion of the absence form of epilepsy into a generalized self-supporting form. The ability to precipitate endogenous self-augmenting mechanisms of diseases may have increased in the course of evolution. The lethal result of a serious pathogenic process leads to the suggestion that organisms cope with the disease by dying. This prevents spreading of the putative infectious disease within the population. The mechanisms of disease aggravation could pay a role in the survival of the species and in further evolutionary progress. This may explain why certain species may have survived in evolution and supports the theory of synthetic evolution.

Beta cell death is a hallmark of diabetes. It is not known whether specific cellular stresses associated with type 1 or type 2 diabetes require specific factors to protect pancreatic beta cells. No systematic comparison of endogenous soluble factors in the context of multiple pro-apoptotic conditions has been published.Primary mouse islet cells were cultured in conditions mimicking five type 1 or type 2 diabetes-related stresses: basal 5 mmol/l glucose, cytokine cocktail (25 ng/ml TNF-α, 10 ng/ml IL-1β, 10 ng/ml IFN-γ), 1 μmol/l thapsigargin, 1.5 mmol/l palmitate and 20 mmol/l glucose (all in the absence of serum). We surveyed the effects of a library of 206 endogenous factors (selected based on islet expression of their receptors) on islet cell survival through multi-parameter, live-cell imaging.Our survey pointed to survival factors exhibiting generalised protective effects across conditions meant to model different types of diabetes and stages of the diseases. For example, our survey and follow-up experiments suggested that OLFM1 is a novel protective factor for mouse and human beta cells across multiple conditions. Most strikingly, we also found specific protective survival factors for each model stress condition. For example, semaphorin4A (SEMA4A) was toxic to islet cells in the serum-free baseline and serum-free 20 mmol/l glucose conditions, but protective in the context of lipotoxicity. Rank product testing supported the consistency of our observations.Collectively, our survey reveals previously unidentified islet cell survival factors and suggest their potential utility in individualised medicine.

Mucosal tissues and especially the intestine are constantly exposed to abundant non-self materials yet simultaneously establish immune homeostasis to prevent excessive inflammatory responses. The maintenance of intestinal homeostasis is achieved by a harmonized immune network mediated by endogenous factors (e.g., cytokines and chemokines) and exogenous factors (e.g., commensal bacteria and dietary matter). Specifically, vitamins from such exogenous sources function immunologically in the control of homeostatic immune responses; thus, their deficient or excessive intake is associated with the development of inflammatory diseases. The focus of this review is the immunologic functions of vitamins B3, B9, A, and D in the regulation and development of inflammation.

The host immune system is regulated not only by endogenous factors, such as cytokines and chemokines, but also by exogenous factors, such as commensal bacteria and dietary materials. Vitamins are vital nutrients that are mainly derived from the diet and commensal bacteria. Accumulating evidence has revealed specific functions of vitamins in the control of host immunity. In agreement with their vital roles in the appropriate maintenance of immunity, excessive or insufficient intake of vitamins leads to the development of immune diseases or susceptibility to infection. In this review, we focus on the diverse but specific immunologic functions of vitamins in regulating host immune responses and their association with immune and infectious diseases.

Hippocampus-related topographic amnesia is the most common symptom of memory disorders in Alzheimer's disease (AD) patients. Recent studies have revealed that experience-mediated DNA methylation, which is regulated by enzymes with DNA methyltransferase (DNMT) activity, is required for the formation of recent memory as well as the maintenance of remote memory. Notably, overexpression of DNMT3a in the hippocampus can reverse spatial memory deficits in aged mice. However, a decline in global DNA methylation was found in the autopsied hippocampi of patients with AD. Exactly, what endogenous factors that affect DNA methylation still remain to be elucidated. Here, we report a marked increase in endogenous formaldehyde levels is associated with a decline in global DNA methylation in the autopsied hippocampus from AD patients. In vitro and in vivo results show that formaldehyde in excess of normal physiological levels reduced global DNA methylation by interfering DNMTs. Interestingly, intrahippocampal injection of excess formaldehyde before spatial learning in healthy adult rats can mimic the learning difficulty of early stage of AD. Moreover, injection of excess formaldehyde after spatial learning can mimic the loss of remote spatial memory observed in late stage of AD. These findings suggest that aging-associated formaldehyde contributes to topographic amnesia in AD patients.

The investigation is concerned with slow oscillations of the intracellular calcium concentration, fast oscillations of the membrane potential, and their interactions during bursting generation. The question associated with functioning of the bursting mode is considered: how is the condition of simultaneous existence of the slow and fast membrane potential oscillations (necessary for the bursting mode) realized under exo- and endogenous actions that result in changes in the neuron membrane parameters? To answer the question the regions of existence of fast, slow and bursting oscillations have been constructed on different parameter planes. The study has revealed that in spite of the fact the regions of the existence of the slow and fast oscillations are sensitive to parameter variations, the condition of the bursting mode existence remains due to invariance of the spatial vicinity of these regions. Furthermore, it has been demonstrated that there exists the possibility to enhance the maximal conductances of the calcium-dependent currents simultaneously such that even strong variations of their values do not induce changes of the oscillations mode (i.e. it remains bursting).

The vasculature suffers damage as a result of diabetes, often leading to conditions such as kidney failure. In bench to bedside, Christian Rask-Madsen and George King examine endogenous factors that protect against damage of the vasculature, such as vascular-endothelial growth factor (VEGF). Recent studies report that VEGF is expressed by kidneys and fends off renal failure; such findings have implications for the development of treatments that harness endogenous factors and sound a note of caution for the therapeutic use of VEGF inhibitors. People with end-stage renal disease often die of cardiovascular complications and clinical studies have shown that one popular class of drugs, statins, does not work in this population. In bedside to bench, S. Ananth Karumanchi and Ravi Thadhani show how this clinical finding is spurring research into the biological mechanisms behind cardiovascular death in people with kidney disease.

Carcinogenesis may be effected not only through exposure to exogenous stimuli but also by genetic and epigenetic influences derived from endogenous factors. In the latter case, the mechanisms are still largely obscure because of the limited availability of appropriate in vivo experimental models. However, continuous feeding of a diet deficient in choline and methionine is well known to cause hepatocellular carcinomas (HCC) in rats in the absence of any known exogenous carcinogens and can serve as a good research model. A semi-synthetic, choline-deficient, L-amino acid-defined (CDAA) diet, containing practically no choline and low methionine, induces HCC with a background of fatty liver and hepatocyte death, subsequent regeneration and fibrosis resulting in cirrhosis. Using the CDAA diet, we have revealed the participation of oxidative injury to DNA and other subcellular components and of alteration in intrahepatic signal transduction pathways in the mechanisms underlying this rat liver carcinogenesis model. In the present paper, the current understanding of endogenous rat liver carcinogenesis, due to dietary choline deficiency, is reviewed.

A number of theories have proposed the involvement of different brain structures and neurotransmitters in order to explain the regulation of the sleep wake cycle. However, there is no clear consensus as to the mechanisms through which the brain structures and their various neurotransmitters interact to produce theses phases. Perhaps the problem is related to the fact sleep is a very fragile state, easily modified or influenced by a variety of substances or experimental manipulations. In this paper, we describe the evidence of two different groups of factors that induce important changes on the sleep wake cycle. The endogenous factors: neurotransmitters; hormone; peptides; and some substances of lipidic nature and exogenous factors: stress, food intake, learning, sleep deprivation, sensorial stimulation, exercise and temperature on the regulation the sleep-wake cycle. Likewise, we propose a hypothesis which attempts to reconcile the fact that endogenous and exogenous factors have similar effects.

In their active hypophosphorylated state, members of the retinoblastoma family of pocket proteins negatively regulate cell cycle progression at least in part by repressing expression of E2F-dependent genes. Mitogen-dependent activation of G1 and G1/S Cyclin Dependent Kinases (CDKs) results in coordinated hyperphosphorylation and inactivation of these proteins, which no longer bind and repress E2Fs. S and G2/M CDKs maintain pocket protein hyperphosphorylated through the end of mitosis. The inactivating action of inducible CDKs is opposed by the Ser/Thr protein phosphatases PP2A and PP1. Various trimeric PP2A holoenzymes have been implicated in dephosphorylation of pocket proteins in response to specific cellular signals and stresses or as part of an equilibrium with CDKs throughout the cell cycle. PP1 has specifically been implicated in dephosphorylation of pRB in late mitosis and early G1. This review is particularly focused on the emerging role of PP2A as a major hub for integration of growth suppressor signals that require rapid inactivation of pocket proteins. Of note, activation of particular PP2A holoenzymes triggers differential activation of pocket proteins in the presence of active CDKs.

Genomic instability is a commonly observed feature of tumors. Most investigations addressing the mechanism of tumor progression have focused on the genetic factors that may play a role. Growing evidence now suggests that, in addition to these endogenous factors, the exogenous environment within solid tumors may by itself be mutagenic and constitute a significant source of genetic instability. The tumor microenvironment is characterized by regions of fluctuating hypoxia, low pH, and nutrient deprivation. Each of these microenvironmental factors has been shown to cause severe disturbance in cell metabolism and physiology. Both in vivo and in vitro data demonstrate that exposure of tumor cells to adverse conditions can directly cause mutations, contributing to genetic instability. In this review, we will reexamine the current body of evidence on the role of the tumor microenvironment in inducing mutagenesis and consequent tumor progression.

The gastric barrier could be considered an active tissue involved in many synthetic and metabolic functions, as the immunological defense, by activating mucosal immune system. Barrier integrity results from a balance between protective and aggressive endogenous factors and from their interaction with exogenous factors (steroidal or nonsteroidal anti-inflammatory drugs, dietary nitrates, nitrites and/or NaCl, stress, Helicobacter pylori infection, food allergens and contaminants, metals, chemicals, radiation, smoking and alcohol intake). Nutrients represent the most important exogenous factors affecting gastric barrier because of the impact on people's everyday life. We report evidence from the literature about nutrients affecting gastric barrier and we investigate the possible effect that nutrients can play to determining or maintaining a gastric barrier dysfunction.

The discovery of heterogeneous populations of retinal precursors with sequentially modified fates may help solve the conundrum of conserved histogenesis in the absence of determination either by birthdate or lineage. Combined with a wealth of new data on the exogenous and endogenous factors that influence cellular fate in the retina, models of how complexity is generated are beginning to emerge.