Showing papers in "Advances in Experimental Medicine and Biology in 2021"

The Idiosyncratic Physiological Traits of the Naked Mole-Rat; a Resilient Animal Model of Aging, Longevity, and Healthspan.

Abstract: The subterranean-dwelling naked mole-rat (Heterocephalus glaber) is an extremophilic rodent, able to thrive in the harsh underground conditions of sub-Saharan Northeast Africa. This pelage-free mammal exhibits numerous unusual ecophysiological features including pronounced tolerance of thermolability, hypoxia, hypercapnia and noxious substances. As a mammal, the naked mole-rat provides a proof-of-concept that age-related changes in physiology are avoidable. At ages far beyond their expected lifespans given both their body size and/or the timing of early developmental milestones, naked mole-rats fail to exhibit meaningful changes in physiological health or demographic mortality. Lack of physiological deterioration with age is also evident in lean and fat mass, bone quality, and reproductive capacity. Rather, regardless of age, under basal conditions naked mole-rats appear to “idle on low” with their “shields up” as is manifested by low body temperature, metabolic rate, cardiac output and kidney concentrating ability, enabling better protection of organs and cellular function. When needed, they can nevertheless ramp up these functions, increasing cardiac output and metabolism 2–5 fold. Here we review many unusual aspects of their physiology and examine how these attributes facilitate both tolerance of the diverse suite of hostile conditions encountered in their natural milieu as well as contribute to their extraordinary longevity and resistance to common, age-related chronic diseases.

Neuropharmacological Effects of the Main Phytocannabinoids: A Narrative Review.

Abstract: Cannabis can synthetize more than 400 compounds, including terpenes, flavonoids, and more than 100 phytocannabinoids. The main phytocannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabis-based products are used as medicines in several countries. In this text, we present an overview of the main neurochemical mechanisms of action of the phytocannabinoids, especially THC and CBD. We also reviewed the indications and adverse effects of the main cannabis-based medicinal products. THC acts as a partial agonist at cannabinoid 1/2 receptors (CB1/2). It is responsible for the characteristic effects of cannabis, such as euphoria, relaxation, and changes in perceptions. THC can also produce dysphoria, anxiety, and psychotic symptoms. THC is used therapeutically in nausea and vomiting due to chemotherapy, as an appetite stimulant, and in chronic pain. CBD acts as a noncompetitive negative allosteric modulator of the CB1 receptor, as an inverse agonist of the CB2 receptor, and as an inhibitor of the reuptake of the endocannabinoid anandamide. Moreover, CBD also activates 5-HT1A serotonergic receptors and vanilloid receptors. Its use in treatment-resistant epilepsy syndromes is approved in some countries. CBD does not produce the typical effects associated with THC and has anxiolytic and antipsychotic effects. Some of the most common adverse effects of CBD are diarrhea, somnolence, nausea, and transaminase elevations (with concomitant use of antiepileptics). The mechanisms of action involved in both the therapeutic and adverse effects of the phytocannabinoids are not fully understood, involving not only the endocannabinoid system. This "promiscuous" pharmacology could be responsible for their wide therapeutic spectrum.

Amino Acid Nutrition and Metabolism in Chickens.

Abstract: Both poultry meat and eggs provide high-quality animal protein [containing sufficient amounts and proper ratios of amino acids (AAs)] for human consumption and, therefore, play an important role in the growth, development, and health of all individuals. Because there are growing concerns about the suboptimal efficiencies of poultry production and its impact on environmental sustainability, much attention has been paid to the formulation of low-protein diets and precision nutrition through the addition of low-cost crystalline AAs or alternative sources of animal-protein feedstuffs. This necessitates a better understanding of AA nutrition and metabolism in chickens. Although historic nutrition research has focused on nutritionally essential amino acids (EAAs) that are not synthesized or are inadequately synthesized in the body, increasing evidence shows that the traditionally classified nutritionally nonessential amino acids (NEAAs), such as glutamine and glutamate, have physiological and regulatory roles other than protein synthesis in chicken growth and egg production. In addition, like other avian species, chickens do not synthesize adequately glycine or proline (the most abundant AAs in the body but present in plant-source feedstuffs at low content) relative to their nutritional and physiological needs. Therefore, these two AAs must be sufficient in poultry diets. Animal proteins (including ruminant meat & bone meal and hydrolyzed feather meal) are abundant sources of both glycine and proline in chicken nutrition. Clearly, chickens (including broilers and laying hens) have dietary requirements for all proteinogenic AAs to achieve their maximum productivity and maintain optimum health particularly under adverse conditions such as heat stress and disease. This is a paradigm shift in poultry nutrition from the 70-year-old "ideal protein" concept that concerned only about EAAs to the focus of functional AAs that include both EAAs and NEAAs.

Amino Acids in Swine Nutrition and Production

Abstract: Amino acids are the building blocks of proteins in animals, including swine. With the development of new analytical methods and biochemical research, there is a growing interest in fundamental and applied studies to reexamine the roles and usage of amino acids (AAs) in swine production. In animal nutrition, AAs have been traditionally classified as nutritionally essential (EAAs) or nutritionally nonessential (NEAAs). AAs that are not synthesized de novo must be provided in diets. However, NEAAs synthesized by cells of animals are more abundant than EAAs in the body, but are not synthesized de novo in sufficient amounts for the maximal productivity or optimal health (including resistance to infectious diseases) of swine. This underscores the conceptual limitations of NEAAs in swine protein nutrition. Notably, the National Research Council (NRC 2012) has recognized both arginine and glutamine as conditionally essential AAs for pigs to improve their growth, development, reproduction, and lactation. Results of recent work have also provided compelling evidence for the nutritional essentiality of glutamate, glycine, and proline for young pigs. The inclusion of so-called NEAAs in diets can help balance AAs in diets, reduce the dietary levels of EAAs, and protect the small intestine from oxidative stress, while enhancing the growth performance, feed efficiency, and health of pigs. Thus, both EAAs and NEAAs are needed in diets to meet the requirements of pigs. This notion represents a new paradigm shift in our understanding of swine protein nutrition and is transforming pork production worldwide.

Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology.

Abstract: Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology - all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+AT-rBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture.

Composition of Amino Acids in Foodstuffs for Humans and Animals.

Abstract: Amino acids (AAs) are the building blocks of proteins that have both structural and metabolic functions in humans and other animals. In mammals, birds, fish, and crustaceans, proteinogenic AAs are alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. All animals can synthesize de novo alanine, asparagine, aspartate, glutamate, glutamine, glycine, proline, and serine, whereas most mammals (including humans and pigs) can synthesize de novo arginine. Results of extensive research over the past three decades have shown that humans and other animals have dietary requirements for AAs that are synthesizable de novo in animal cells. Recent advances in analytical methods have allowed us to determine all proteinogenic AAs in foods consumed by humans, livestock, poultry, fish, and crustaceans. Both plant- and animal-sourced foods contain high amounts of glutamate, glutamine, aspartate, asparagine, and branched-chain AAs. Cysteine, glycine, lysine, methionine, proline, threonine, and tryptophan generally occur in low amounts in plant products but are enriched in animal products. In addition, taurine and creatine (essential for the integrity and function of tissues) are absent from plants but are abundant in meat and present in all animal-sourced foods. A combination of plant- and animal products is desirable for the healthy diets of humans and omnivorous animals. Furthermore, animal-sourced feedstuffs can be included in the diets of farm and companion animals to cost-effectively improve their growth performance, feed efficiency, and productivity, while helping to sustain the global animal agriculture (including aquaculture).

Nutrition and Functions of Amino Acids in Aquatic Crustaceans.

Abstract: Crustaceans (e.g., shrimp and crabs) are a good source of protein-rich foods for human consumption. They are the second largest aquaculture species worldwide. Understanding the digestion of dietary protein, as well as the absorption, metabolism and functions of amino acids (AAs) and small peptides is essential to produce cost-effective and sustainable aquafeeds. Hepatopancreas (the midgut gland) is the main site for the digestion of dietary protein as well as the absorption of small peptides and AAs into the hemolymph. Besides serving as the building blocks of protein, AAs (particularly aspartate, glutamate, glutamine and alanine) are the primary metabolic fuels for the gut and extra-hepatopancreas tissues (e.g., kidneys and skeletal muscle) of crustaceans. In addition, AAs are precursors for the syntheses of glucose, lipids, H2S, and low-molecular-weight molecules (e.g., nitric oxide, glutathione, polyamines, histamine, and hormones) with enormous biological importance, such as physical barrier, immunological and antioxidant defenses. Therefore, both nutritionally essential and nonessential AAs are needed in diets to improve the growth, development, molt rate, survival, and reproduction of crustaceans. There are technical difficulties and challenges in the use of crystalline AAs for research and practical production due to the loss of free AAs during feed processing, the leaching of in-feed free AAs to the surrounding water environment, and asynchronous absorption with peptide-bounded AAs. At present, much knowledge about AA metabolism and functions in crustaceans is based on studies of mammals and fish species. Basic research in this area is necessary to lay a solid foundation for improving the balances and bioavailability of AAs in the diets for optimum growth, health and wellbeing of crustaceans, while preventing and treating their metabolic diseases. This review highlights recent advances in AA nutrition and metabolism in aquatic crustacean species at their different life stages. The new knowledge is expected to guide the development of the next generation of their improved diets.

Nutrition and Functions of Amino Acids in Fish.

Abstract: Aquaculture is increasingly important for providing humans with high-quality animal protein to improve growth, development and health. Farm-raised fish and shellfish now exceed captured fisheries for foods. More than 70% of the production cost is dependent on the supply of compound feeds. A public debate or concern over aquaculture is its environmental sustainability as many fish species have high requirements for dietary protein and fishmeal. Protein or amino acids (AAs), which are the major component of tissue growth, are generally the most expensive nutrients in animal production and, therefore, are crucial for aquatic feed development. There is compelling evidence that an adequate supply of both traditionally classified nutritionally essential amino acids (EAAs) and non-essential amino acids (NEAAs) in diets improve the growth, development and production performance of aquatic animals (e.g., larval metamorphosis). The processes for the utilization of dietary AAs or protein utilization by animals include digestion, absorption and metabolism. The digestibility and bioavailability of AAs should be carefully evaluated because feed production processes and AA degradation in the gut affect the amounts of dietary AAs that enter the blood circulation. Absorbed AAs are utilized for the syntheses of protein, peptides, AAs, and other metabolites (including nucleotides); biological oxidation and ATP production; gluconeogenesis and lipogenesis; and the regulation of acid-base balance, anti-oxidative reactions, and immune responses. Fish producers usually focus on the content or digestibility of dietary crude protein without considering the supply of AAs in the diet. In experiments involving dietary supplementation with AAs, inappropriate AAs (e.g., glycine and glutamate) are often used as the isonitrogenous control. At present, limited knowledge is available about either the cell- and tissue-specific metabolism of AAs or the effects of feed processing methods on the digestion and utilization of AAs in different fish species. These issues should be addressed to develop environment-friendly aquafeeds and reduce feed costs to sustain the global aquaculture.

Amino Acid Nutrition and Reproductive Performance in Ruminants.

Abstract: Amino acids (AAs) are essential for the survival, growth and development of ruminant conceptuses. Most of the dietary AAs (including L-arginine, L-lysine, L-methionine and L-glutamine) are extensively catabolized by the ruminal microbes of ruminants to synthesize AAs and microbial proteins (the major source of AAs utilized by cells in ruminant species) in the presence of sufficient carbohydrates (mainly cellulose and hemicellulose), nitrogen, and sulfur. Results of recent studies indicate that the ruminal microbes of adult steers and sheep do not degrade extracellular L-citrulline and have a limited ability to metabolize extracellular L-glutamate due to little or no uptake by the cells. Although traditional research in ruminant protein nutrition has focused on AAs (e.g., lysine and methionine for lactating cows) that are not synthesized by eukaryotic cells, there is growing interest in the nutritional and physiological roles of AAs (e.g., L-arginine, L-citrulline, L-glutamine and L-glutamate) in gestating ruminants (e.g., cattle, sheep and goats) and lactating dairy cows. Results of recent studies show that intravenous administration of L-arginine to underfed, overweight or prolific ewes enhances fetal growth, the development of brown fat in fetuses, and the survival of neonatal lambs. Likewise, dietary supplementation with either rumen-protected L-arginine or unprotected L-citrulline to gestating sheep or beef cattle improved embryonic survival. Because dietary L-citrulline and L-glutamate are not degraded by ruminal microbes, addition of these two amino acids may be a new useful, cost-effective method for improving the reproductive efficiency of ruminants.

Glucose Metabolism in Cancer: The Warburg Effect and Beyond.

Abstract: Otto Warburg observed a peculiar phenomenon in 1924, unknowingly laying the foundation for the field of cancer metabolism. While his contemporaries hypothesized that tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, Warburg instead found them to rapidly consume glucose, converting it to lactate even in the presence of oxygen. The significance of this finding, later termed the Warburg effect, went unnoticed by the broader scientific community at that time. The field of cancer metabolism lay dormant for almost a century awaiting advances in molecular biology and genetics, which would later open the doors to new cancer therapies [2, 3].

Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans.

Abstract: As a functional amino acid (AA), L-arginine (Arg) serves not only as a building block of protein but also as an essential substrate for the synthesis of nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine in mammals (including humans). NO (a major vasodilator) increases blood flow to tissues. Arg and its metabolites play important roles in metabolism and physiology. Arg is required to maintain the urea cycle in the active state to detoxify ammonia. This AA also activates cellular mechanistic target of rapamycin (MTOR) and focal adhesion kinase cell signaling pathways in mammals, thereby stimulating protein synthesis, inhibiting autophagy and proteolysis, enhancing cell migration and wound healing, promoting spermatogenesis and sperm quality, improving conceptus survival and growth, and augmenting the production of milk proteins. Although Arg is formed de novo from glutamine/glutamate and proline in humans, these synthetic pathways do not provide sufficient Arg in infants or adults. Thus, humans and other animals do have dietary needs of Arg for optimal growth, development, lactation, and fertility. Much evidence shows that oral administration of Arg within the physiological range can confer health benefits to both men and women by increasing NO synthesis and thus blood flow in tissues (e.g., skeletal muscle and the corpora cavernosa of the penis). NO is a vasodilator, a neurotransmitter, a regulator of nutrient metabolism, and a killer of bacteria, fungi, parasites, and viruses [including coronaviruses, such as SARS-CoV and SARS-CoV-2 (the virus causing COVID-19). Thus, Arg supplementation can enhance immunity, anti-infectious, and anti-oxidative responses, fertility, wound healing, ammonia detoxification, nutrient digestion and absorption, lean tissue mass, and brown adipose tissue development; ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension); and treat individuals with erectile dysfunction, sickle cell disease, muscular dystrophy, and pre-eclampsia.

One-Carbon Metabolism and Development of the Conceptus During Pregnancy: Lessons from Studies with Sheep and Pigs

Abstract: The pregnancy recognition signal from the conceptus (embryo/fetus and associated membranes) to the mother is interferon tau (IFNT) in ruminants and estradiol, possibly in concert with interferons gamma and delta in pigs. Those pregnancy recognition signals silence expression of interferon stimulated genes (ISG) in uterine luminal (LE) and superficial glandular (sGE) epithelia while inducing expression of genes for transport of nutrients, including glucose and amino acids, into the uterine lumen to support growth and development of the conceptus. In sheep and pigs, glucose not utilized immediately by the conceptus is converted to fructose. Glucose, fructose, serine and glycine in uterine histotroph can contribute to one carbon (1C) metabolism that provides one-carbon groups for the synthesis of purines and thymidylate, as well as S-adenosylmethionine for epigenetic methylation reactions. Serine and glycine are transported into the mitochondria of cells and metabolized to formate that is transported into the cytoplasm for the synthesis of purines, thymidine and S-adenosylmethionine. The unique aspects of one-carbon metabolism are discussed in the context of the hypoxic uterine environment, aerobic glycolysis, and similarities in metabolism between cancer cells and cells of the rapidly developing fetal-placental tissues during pregnancy. Further, the evolution of anatomical and functional aspects of the placentae of sheep and pigs versus primates is discussed in the context of mechanisms to efficiently obtain, store and utilize nutrients required for rapid fetal growth in the last one-half of gestation.

Progressive Supranuclear Palsy and Corticobasal Degeneration.

Abstract: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative tauopathies with neuronal and glial lesions composed of tau that is composed predominantly of isomers with four repeats in the microtubule-binding domain (4R tau). The brain regions vulnerable to pathology in PSP and CBD overlap, but there are differences, particularly with respect to distribution of neuronal loss, the relative abundance of neuronal and glial lesions, the morphologic features of glial lesions, and the frequency of comorbid pathology. Both PSP and CBD have a wide spectrum of clinical manifestations, including disorders of movement and cognition. Recognition of phenotypic diversity in PSP and CBD may improve antemortem diagnostic accuracy, which tends to be very good for the most common presentation of PSP (Richardson syndrome), but poor for the most characteristic presentation of CBD (corticobasal syndrome: CBS). Development of molecular and imaging biomarkers may improve antemortem diagnostic accuracy. Currently, multidisciplinary symptomatic and supportive treatment with pharmacological and non-pharmacological strategies remains the standard of care. In the future, experimental therapeutic trials will be important to slow disease progression.

Cell-Specific Expression of Enzymes for Serine Biosynthesis and Glutaminolysis in Farm Animals.

Abstract: During the peri-implantation period, conceptuses [embryo and placental membranes, particularly the trophectoderm (Tr)] of farm animals (e.g., sheep and pigs) rapidly elongate from spherical to tubular to filamentous forms. In concert with Tr outgrowth during conceptus elongation, the Tr of sheep and pig conceptuses attaches to the endometrial luminal epithelium (LE) to initiate placentation. In sheep, binucleate cells (BNCs) begin to differentiate from the mononuclear trophectoderm cells and migrate to the endometrial LE to form syncytial plaques. These events require Tr cells to expend significant amounts of energy to undergo timely and extensive proliferation, migration and fusion. It is likely essential that conceptuses optimally utilize multiple biosynthetic pathways to convert molecules such as glucose, fructose, and glutamine (components of histotroph transport by sheep and pig endometria into the uterine lumen), into ATP, amino acids, ribose, hexosamines and nucleotides required to support early conceptus development and survival. Elongating and proliferating conceptus Tr cells potentially act, in a manner similar to cancer cells, to direct carbon generated from glucose and fructose away from the TCA cycle for utilization in branching pathways of glycolysis, including the pentose phosphate pathway, one-carbon metabolism, and hexosamine biosynthesis. The result is a limited availability of pyruvate for maintaining the TCA cycle within mitochondria, and Tr cells replenish TCA cycle metabolites via a process known as anaplerosis, primarily through glutaminolysis to convert glutamine into TCA cycle intermediates. Here we describe the cell-specific expression of enzymes required for serine biosynthesis, one-carbon metabolism and glutaminolysis at the uterine-placental interface of sheep and pigs, and propose that these biosynthetic pathways are essential to support early placental development including Tr elongation, cell migration, cell fusion and implantation by ovine and porcine conceptuses.

Notch Pathway: A Journey from Notching Phenotypes to Cancer Immunotherapy.

Abstract: Notch is a key evolutionary conserved pathway, which has fascinated and engaged the work of investigators in an uncountable number of biological fields, from development of metazoans to immunotherapy for cancer. The study of Notch has greatly contributed to the understanding of cancer biology and a substantial effort has been spent in designing Notch-targeting therapies. Due to its broad involvement in cancer, targeting Notch would allow to virtually modulate any aspect of the disease. However, this means that Notch-based therapies must be highly specific to avoid off-target effects. This review will present the newest mechanistic and therapeutic advances in the Notch field and discuss the promises and challenges of this constantly evolving field.

Redox Role of ROS and Inflammation in Pulmonary Diseases.

Abstract: Reactive oxygen species (ROS), either derived from exogenous sources or overproduced endogenously, can disrupt the body's antioxidant defenses leading to compromised redox homeostasis. The lungs are highly susceptible to ROS-mediated damage. Oxidative stress (OS) caused by this redox imbalance leads to the pathogenesis of multiple pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). OS causes damage to important cellular components in terms of lipid peroxidation, protein oxidation, and DNA histone modification. Inflammation further enhances ROS production inducing changes in transcriptional factors which mediate cellular stress response pathways. This deviation from normal cell function contributes to the detrimental pathological characteristics often seen in pulmonary diseases. Although antioxidant therapies are feasible approaches in alleviating OS-related lung impairment, a comprehensive understanding of the updated role of ROS in pulmonary inflammation is vital for the development of optimal treatments. In this chapter, we review the major pulmonary diseases-including COPD, asthma, ARDS, COVID-19, and lung cancer-as well as their association with ROS.

The Relevance of Notch Signaling in Cancer Progression

Abstract: The Notch signaling pathway controls normal embryonic development and tissue homeostasis of many cell types. It regulates cell proliferation, fate, differentiation, and cell death by short-range signaling between nearby cells that come in contact. The Notch pathway has also been critically involved in the pathobiology of a variety of malignancies, regulating cancer initiation and development, as well as early stages of cancer progression, by adjusting conserved cellular programs. Fibroblasts, an essential for tumor growth component of stroma, have also been affected by Notch regulation. Sequencing Notch gene mutations have been identified in a number of human tumors, revealing information on the progression of specific cancer types, such as ovarian cancer and melanoma, immune-associated tumors such as myeloid neoplasms, but especially in lymphocytic leukemia. Activation of the Notch can be either oncogenic or it may contain growth-suppressive functions, acting as a tumor suppressor in other hematopoietic cells, hepatocytes, skin, and pancreatic epithelium.

Amino Acids in Dog Nutrition and Health

Abstract: The dog has assumed a prominent role in human society. Associated with that status, diet choices for companion dogs have begun to reflect the personal preferences of the owners, with greater emphasis on specialty diets such as organic, vegan/vegetarian, and omission or inclusion of specific ingredients. Despite consumer preferences and many marketing strategies employed, the diets must ensure nutritional adequacy for the dog; if not, health becomes compromised, sometimes severely. The most frequent consideration of consumers and dog food manufacturers is protein source and concentration with a growing emphasis on amino acid composition and bioavailability. Amino acids in general play diverse and critical roles in the dog, with specific amino acids being essential. This review covers what is known regarding amino acids in dog nutrition.

Neuropeptidergic and Neuroendocrine Systems Underlying Eusociality and the Concomitant Social Regulation of Reproduction in Naked Mole-Rats: A Comparative Approach.

Abstract: The African mole-rat family (Bathyergidae) includes the first mammalian species identified as eusocial: naked mole-rats. Comparative studies of eusocial and solitary mole-rat species have identified differences in neuropeptidergic systems that may underlie the phenomenon of eusociality. These differences are found in the oxytocin, vasopressin and corticotrophin-releasing factor (CRF) systems within the nucleus accumbens, amygdala, bed nucleus of the stria terminalis and lateral septal nucleus. As a corollary of their eusociality, most naked mole-rats remain pre-pubertal throughout life because of the presence of the colony’s only reproductive female, the queen. To elucidate the neuroendocrine mechanisms that mediate this social regulation of reproduction, research on the hypothalamo-pituitary-gonadal axis in naked mole-rats has identified differences between the many individuals that are reproductively suppressed and the few that are reproductively mature: the queen and her male consorts. These differences involve gonadal steroids, gonadotrophin-releasing hormone-1 (GnRH-1), kisspeptin, gonadotrophin-inhibitory hormone/RFamide-related peptide-3 (GnIH/RFRP-3) and prolactin. The comparative findings in eusocial and solitary mole-rat species are assessed with reference to a broad range of studies on other mammals.

Transcription Factor RBPJ as a Molecular Switch in Regulating the Notch Response.

Abstract: The Notch signal transduction cascade requires cell-to-cell contact and results in the proteolytic processing of the Notch receptor and subsequent assembly of a transcriptional coactivator complex containing the Notch intracellular domain (NICD) and transcription factor RBPJ. In the absence of a Notch signal, RBPJ remains at Notch target genes and dampens transcriptional output. Like in other signaling pathways, RBPJ is able to switch from activation to repression by associating with corepressor complexes containing several chromatin-modifying enzymes. Here, we focus on the recent advances concerning RBPJ-corepressor functions, especially in regard to chromatin regulation. We put this into the context of one of the best-studied model systems for Notch, blood cell development. Alterations in the RBPJ-corepressor functions can contribute to the development of leukemia, especially in the case of acute myeloid leukemia (AML). The versatile role of transcription factor RBPJ in regulating pivotal target genes like c-MYC and HES1 may contribute to the better understanding of the development of leukemia.

Wnt Signaling in the Tumor Microenvironment.

Abstract: Dysregulated Wnt signaling plays a central role in initiation, progression, and metastasis in many types of human cancers. Cancer development and resistance to conventional cancer therapies are highly associated with the tumor microenvironment (TME), which is composed of numerous stable non-cancer cells, including immune cells, extracellular matrix (ECM), fibroblasts, endothelial cells (ECs), and stromal cells. Recently, increasing evidence suggests that the relationship between Wnt signaling and the TME promotes the proliferation and maintenance of tumor cells, including leukemia. Here, we review the Wnt pathway, the role of Wnt signaling in different components of the TME, and therapeutic strategies for targeting Wnt signaling.

Social Behavior in Naked Mole-Rats: Individual Differences in Phenotype and Proximate Mechanisms of Mammalian Eusociality.

Abstract: Naked mole-rats (Heterocephalus glaber) are small rodents native to east Africa, living in subterranean colonies of up to 300 individuals. Within each colony, reproduction is restricted to a single breeding female and 1-3 breeding males; all other colony members are reproductively suppressed and socially subordinate unless removed from the suppressive cues of the colony. Due to their striking reproductive skew, naked mole-rats are often considered eusocial mammals. Consistent with this idea, there are behavioral specializations and at least some evidence for morphological distinctions within and between the breeding and non-breeding members of the colony. Importantly, naked mole-rats show plasticity in their behavioral phenotype whereby changes in the social environment influence expression of both type and amount of social behavior. Thus, naked mole-rats provide the opportunity to examine the proximate mechanisms controlling individual differences in social behavior, shedding light on how mammals live in complex social groups.

Cannabis and Depression.

Abstract: There is a growing body of evidence pointing to the co-occurrence of cannabis use and depression. There is also some evidence that the use of cannabis may lead to the onset of depression; however, strong evidence points to the inverse association; i.e. that depression may lead to the onset or increase in cannabis use frequency. Observational and epidemiological studies have not indicated a positive long-term effect of cannabis use on the course and outcome of depression. The association between cannabis use and depression may be stronger among men during adolescence and emerging adulthood and stronger in women during midlife. There is an indication for potential genetic correlation contributing to the comorbidity of cannabis dependence and major depression, namely that serotonin (5-HT) may mediate such association and there is also evidence for specific risk alleles for cannabis addiction. There is preclinical evidence that alteration in the endocannabinoid system could potentially benefit patients suffering from depression. However, the issue of using cannabis as an anti-depressant is at an early stage of examination and there is little evidence to support it. Finally, there has been little support to the notion that selective serotonin reuptake inhibitors (SSRIs) may be effective in decreasing depressive symptoms or rates of substance use in adolescents treated for depression and a co-occurring substance use disorder. In conclusion, despite methodological limitations, research in the past decades has broadened our knowledge on the association between cannabis use and depression from epidemiological, neurological, genetic, and pharmacological perspectives.

Overview of Histone Modification.

Abstract: Epigenetics is the epi-information beyond the DNA sequence that can be inherited from parents to offspring. From years of studies, people have found that histone modifications, DNA methylation, and RNA-based mechanism are the main means of epigenetic control. In this chapter, we will focus on the general introductions of epigenetics, which is important in the regulation of chromatin structure and gene expression. With the development and expansion of high-throughput sequencing, various mutations of epigenetic regulators have been identified and proven to be the drivers of tumorigenesis. Epigenetic alterations are used to diagnose individual patients more accurately and specifically. Several drugs, which are targeting epigenetic changes, have been developed to treat patients regarding the awareness of precision medicine. Emerging researches are connecting the epigenetics and cancers together in the molecular mechanism exploration and the development of druggable targets.

Cannabidiol Therapy for Refractory Epilepsy and Seizure Disorders.

Abstract: Cannabis-derived cannabinoids have neuroactive properties. Recently, there has been emerging interest in the use of cannabidiol (CBD)-enriched products for treatment of drug-resistant epilepsy. In 2018, the FDA approved the use of CBD-rich Epidiolex for two severe forms of epilepsy in children (Lennox-Gastaut and Dravet syndromes). Experimental research supports the use of CBD in many CNS disorders, though the mechanisms underlying its anticonvulsant and neuroprotective effects remain unclear. CBD has been shown to reduce inflammation, protect against neuronal loss, normalize neurogenesis, and act as an antioxidant. These actions appear to be due to the multimodal mechanism of action of CBD in the brain. This chapter briefly describes the current information on cannabis pharmacology with an emphasis on the clinical utility of CBD in the treatment of refractory epilepsies and other related seizure conditions. Clinical trials are ongoing for other forms of epilepsy and refractory seizures associated with infantile spasms, tuberous sclerosis, and Rett syndrome. Overall, adjunct CBD has been found to be generally safe and effective for treatment-resistant seizures in children with severe early-onset epilepsy. Whether an add-on CBD is efficacious for the long-term treatment of various epilepsy and seizure types in adults being tested in various clinical trials.

Amino Acid Nutrition for Optimum Growth, Development, Reproduction, and Health of Zoo Animals

Abstract: Proteins are large polymers of amino acids (AAs) linked via peptide bonds, and major components for the growth and development of tissues in zoo animals (including mammals, birds, and fish). The proteinogenic AAs are alanine, arginine, aspartate, asparagine, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Except for glycine, they are all present in the L-isoform. Some carnivores may also need taurine (a nonproteinogenic AA) in their diet. Adequate dietary intakes of AAs are necessary for the growth, development, reproduction, health and longevity of zoo animals. Extensive research has established dietary nutrient requirements for humans, domestic livestock and companion animals. However, this is not true for many exotic or endangered species found in zoos due to the obstacles that accompany working with these species. Information on diets and nutrient profiles of free-ranging animals is needed. Even with adequate dietary intake of crude protein, dietary AAs may still be unbalanced, which can lead to nutrition-related diseases and disorders commonly observed in captive zoo species, such as dilated cardiomyopathy, urolithiasis, gut dysbiosis, and hormonal imbalances. There are differences in AA metabolism among carnivores, herbivores and omnivores. It is imperative to consider these idiosyncrasies when formulating diets based on established nutritional requirements of domestic species. With optimal health, populations of zoo animals will have a vastly greater chance of thriving in captivity. For endangered species especially, maintaining stable captive populations is crucial for conservation. Thus, adequate provision of AAs in diets plays a crucial role in the management, sustainability and expansion of healthy zoo animals.

Amino Acids in the Nutrition, Metabolism, and Health of Domestic Cats.

Abstract: Domestic cats (carnivores) require high amounts of dietary amino acids (AAs) for normal growth, development, and reproduction. Amino acids had been traditionally categorised as nutritionally essential (EAAs) or nonessential (NEAAs), depending on whether they are synthesized de novo in the body. This review will focus on AA nutrition and metabolism in cats. Like other mammals, cats do not synthesize the carbon skeletons of twelve proteinogenic AAs: Arg, Cys, His, Ile, Leu, Lys, Met, Phe, Thr, Trp, Tyr, and Val. Like other feline carnivores but unlike many mammals, cats do not synthesize citrulline and have a very limited ability to produce taurine from Cys. Except for Leu and Lys that are strictly ketogenic AAs, most EAAs are both glucogenic and ketogenic AAs. All the EAAs (including taurine) must be provided in diets for cats. These animals are sensitive to dietary deficiencies of Arg and taurine, which rapidly result in life-threatening hyperammonemia and retinal damage, respectively. Although the National Research Council (NCR, Nutrient requirements of dogs and cats. National Academies Press, Washington, DC, 2006) does not recommend dietary requirements of cats for NEAAs, much attention should be directed to this critical issue of nutrition. Cats can synthesize de novo eight proteinogenic AAs: Ala, Asn, Asp, Gln, Glu, Gly, Pro, and Ser, as well as some nonproteinogenic AAs, such as γ-aminobutyrate, ornithine, and β-alanine with important physiological functions. Some of these AAs (e.g., Gln, Glu, Pro, and Gly) are crucial for intestinal integrity and health. Except for Gln, AAs in the arterial blood of cats may not be available to the mucosa of the small intestine. Plant-source foodstuffs lack taurine and generally contain inadequate Met and Cys and, therefore, should not be fed to cats in any age group. Besides meat, animal-source foodstuffs (including ruminant meat & bone meal, poultry by-product meal, porcine mucosal protein, and chicken visceral digest) are good sources of proteinogenic AAs and taurine for cats. Meeting dietary requirements for both EAAs and NEAAs in proper amounts and balances is crucial for improving the health, wellbeing, longevity, and reproduction of cats.

Oxidation of Energy Substrates in Tissues of Fish: Metabolic Significance and Implications for Gene Expression and Carcinogenesis.

Abstract: Fish are useful animal models for studying effects of nutrients and environmental factors on gene expression (including epigenetics), toxicology, and carcinogenesis. To optimize the response of the animals to substances of interest (including toxins and carcinogens), water pollution, or climate changes, it is imperative to understand their fundamental biochemical processes. One of these processes concerns energy metabolism for growth, development, and survival. We have recently shown that tissues of hybrid striped bass (HSB), zebrafish, and largemouth bass (LMB) use amino acids (AAs; such as glutamate, glutamine, aspartate, alanine, and leucine) as major energy sources. AAs contribute to about 80% of ATP production in the liver, proximal intestine, kidney, and skeletal muscle tissue of the fish. Thus, as for mammals (including humans), AAs are the primary metabolic fuels in the proximal intestine of fish. In contrast, glucose and fatty acids are only minor metabolic fuels in the fish. Fish tissues have high activities of glutamate dehydrogenase, glutamate–oxaloacetate transaminase, and glutamate-pyruvate transaminase, as well as high rates of glutamate uptake. In contrast, the activities of hexokinase, pyruvate dehydrogenase, and carnitine palmitoyltransferase 1 in all the tissues are relatively low. Furthermore, unlike mammals, the skeletal muscle (the largest tissue) of HSB and LMB has a limited uptake of long-chain fatty acids and barely oxidizes fatty acids. Our findings explain differences in the metabolic patterns of AAs, glucose, and lipids among various tissues in fish. These new findings have important implications for understanding metabolic significance of the tissue-specific oxidation of AAs (particularly glutamate and glutamine) in gene expression (including epigenetics), nutrition, and health, as well as carcinogenesis in fish, mammals (including humans), and other animals.

NOTCH and Esophageal Squamous Cell Carcinoma

Abstract: Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH pathway regulates the development of esophageal squamous epithelium, in particular, squamous differentiation. Exposure to extrinsic and intrinsic factors, such as gastroesophageal reflux, alcohol drinking, and inflammation, downregulates the NOTCH pathway and thus inhibits squamous differentiation of esophageal squamous epithelial cells. In ESCC, NOTCH plays a dual role as both a tumor suppressor pathway and an oncogenic pathway. In summary, further studies are warranted to develop NOTCH activators for the prevention of ESCC and NOTCH inhibitors for targeted therapy of a subset of ESCC with activated NOTCH pathway.

HGF/c-Met Signalling in the Tumor Microenvironment.

Abstract: Recently, it has become clearer that tumor plasticity increases the chance that cancer cells could acquire new mechanisms to escape immune surveillance, become resistant to conventional drugs, and spread to distant sites.Effectively, tumor plasticity drives adaptive response of cancer cells to hypoxia and nutrient deprivation leading to stimulation of neoangionesis or tumor escape. Therefore, tumor plasticity is believed to be a great contributor in recurrence and metastatic dissemination of cancer cells. Importantly, it could be an Achilles' heel of cancer if we could identify molecular mechanisms dictating this phenotype.The reactivation of stem-like signalling pathways is considered a great determinant of tumor plasticity; in addition, a key role has been also attributed to tumor microenvironment (TME). Indeed, it has been proved that cancer cells interact with different cells in the surrounding extracellular matrix (ECM). Interestingly, well-established communication represents a potential allied in maintenance of a plastic phenotype in cancer cells supporting tumor growth and spread. An important signalling pathway mediating cancer cell-TME crosstalk is represented by the HGF/c-Met signalling.Here, we review the role of the HGF/c-Met signalling in tumor-stroma crosstalk focusing on novel findings underlying its role in tumor plasticity, immune escape, and development of adaptive mechanisms.