APOBEC2, a selective inhibitor of TGFβ signaling, regulates left-right axis specification during early embryogenesis

The specification of left–right asymmetry is an evolutionarily conserved developmental process in vertebrates. The interplay between two TGFβ ligands, Derrière/GDF1 and Xnr1/Nodal, together with inhibitors such as Lefty and Coco/Cerl2, have been shown to provide the signals that lead to the establishment of laterality. However, molecular events leading to and following these signals remain mostly unknown. We find that APOBEC2, a member of the cytidine deaminase family of DNA/RNA editing enzymes, is induced by TGFβ signaling, and that its activity is necessary to specify the left–right axis in Xenopus and zebrafish embryos. Surprisingly, we find that APOBEC2 selectively inhibits Derrière, but not Xnr1, signaling. The inhibitory effect is conserved, as APOBEC2 blocks TGFβ signaling, and promotes muscle differentiation, in a mammalian myoblastic cell line. This demonstrates for the first time that a putative RNA/DNA editing enzyme regulates TGFβ signaling and plays a major role in development.     

Decorin-TGFβ axis in hepatic fibrosis and cirrhosis

Hepatic fibrosis and cirrhosis are worldwide health care problems, especially in regions with a high rate of hepatitis infection. As these diseases affect a major part of the human population, the search for antifibrotic therapies has a high priority in medical research. Transforming growth factor β1 (TGF-β1) is one of the most powerful profibrotic cytokines. Thus, blocking TGF-β1 activity by natural inhibitors represents a valid and logical strategy to combat hepatic fibrosis. One of the natural inhibitors of TGF-β1 is decorin, a small leucine-rich proteoglycan that binds with high affinity to this cytokine and prevents its interaction with pro-fibrotic receptors. Recent evidence has shown that decorin has a protective role in liver fibrogenesis insofar as its genetic ablation in mice leads to enhanced matrix deposition, impaired matrix degradation, and "activation" of hepatic stellate cells, the main producers of fibrotic tissue. Moreover, TGF-β1 exerts a stronger effect when functional decorin is absent. These data provide robust genetic evidence for a direct role of endogenous decorin in preventing and retarding hepatic fibrosis. Thus, boosting the endogenous production of decorin or systemic delivery of recombinant decorin could represent an additional therapeutic modality against hepatic fibrosis.     

What are the roles of retinoids,other morphogens,and Hox genes in setting up the vertebrate body axis?

This article is concerned with the roles of retinoids and other known anterior–posterior morphogens in setting up the embryonic vertebrate anterior–posterior axis. The discussion is restricted to the very earliest events in setting up the anterior–posterior axis (from blastula to tailbud stages in Xenopus embryos). In these earliest developmental stages, morphogen concentration gradients are not relevant for setting up this axis. It emerges that at these stages, the core patterning mechanism is timing: BMP‐anti BMP mediated time space translation that regulates Hox temporal and spatial collinearities and Hox‐Hox auto‐ and cross‐ regulation. The known anterior–posterior morphogens and signaling pathways––retinoids, FGF's, Cdx, Wnts, Gdf11 and others––interact with this core mechanism at and after space–time defined “decision points,” leading to the separation of distinct axial domains. There are also other roles for signaling pathways. Besides the Hox regulated hindbrain/trunk part of the axis, there is a rostral part (including the anterior part of the head and the extreme anterior domain [EAD]) that appears to be regulated by additional mechanisms. Key aspects of anterior–posterior axial patterning, including: the nature of different phases in early patterning and in the whole process; the specificities of Hox action and of intercellular signaling; and the mechanisms of Hox temporal and spatial collinearities, are discussed in relation to the facts and hypotheses proposed above.     

Neural correlates of parent–child HPA axis coregulation

Parents and children have been found to show coordination or coregulation of the hypothalamic–pituitary–adrenal (HPA) axis. This coordination may be reflected in adolescents' neural activation to parent stimuli, particularly in regions of the brain associated with social information processing.This study reports on 22 adolescents (13 males, mean age 17 years), recruited from a longitudinal study to participate in a functional MRI (fMRI) scanning protocol. Approximately 1.5 years before the scan, these same adolescents participated in a family conflict discussion in the lab with both parents, and all three family members provided samples of salivary cortisol five times, before and after the discussion. Multilevel models found positive cross-sectional and time-lagged associations between parents' and youth cortisol. Empirical Bayes (EB) coefficients, extracted from these models to reflect the strength of the relationship between parent and adolescent cortisol, were tested in conjunction with adolescents' neural activation to video clips of their parents taken from the conflict discussion. For both mothers and fathers, youth who showed stronger cortisol coregulation with each parent (both in cross-sectional and time-lagged analyses) showed more activation to that same parent in posteromedial regions (precuneus, posterior cingulate, and retrosplenial cortex) that have been linked with social cognition, e.g. mentalizing about others' emotions. Youths' adrenocortical coregulation with their parents may be reflected in their neural processing of stimuli featuring those same parents.     

Gut microbiota–bile acid–skeletal muscle axis

The gut microbiota represents a ‘metabolic organ’ that can regulate human metabolism. Intact gut microbiota contributes to host homeostasis, whereas compositional perturbations, termed dysbiosis, are associated with a wide range of diseases. Recent evidence demonstrates that dysbiosis, and the accompanying loss of microbiota-derived metabolites, results in a substantial alteration of skeletal muscle metabolism. As an example, bile acids, produced in the liver and further metabolized by intestinal microbiota, are of considerable interest since they regulate several host metabolic pathways by activating nuclear receptors, including the farnesoid X receptor (FXR). Indeed, alteration of gut microbiota may lead to skeletal muscle atrophy via a bile acid–FXR pathway. This Review aims to suggest a new pathway that connects different mechanisms, involving the gut–muscle axis, that are often seen as unrelated, and, starting from preclinical studies, we hypothesize new strategies aimed at optimizing skeletal muscle functionality.     

Gut–organ axis: a microbial outreach and networking

Human gut microbiota (GM) includes a complex and dynamic population of microorganisms that are crucial for well-being and survival of the organism. It has been reported as diverse and relatively stable with shared core microbiota, including Bacteroidetes and Firmicutes as the major dominants. They are the key regulators of body homeostasis, involving both intestinal and extra-intestinal effects by influencing many physiological functions such as metabolism, maintenance of barrier homeostasis, inflammation and hematopoiesis. Any alteration in GM community structures not only trigger gut disorders but also influence other organs and cause associated diseases. In recent past, the GM has been defined as a ‘vital organ’ with its involvement with other organs; thus, establishing a link or a bi- or multidirectional communication axis between the organs via neural, endocrine, immune, humoral and metabolic pathways. Alterations in GM have been linked to several diseases known to humans; although the exact interaction mechanism between the gut and the organs is yet to be defined. In this review, the bidirectional relationship between the gut and the vital human organs was envisaged and discussed under several headings. Furthermore, several disease symptoms were also revisited to redefine the communication network between the gut microbes and the associated organs.     

SIRT1/PGC-1: a neuroprotective axis?

Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.     

Somatostatin-14 influences pituitary–ovarian axis in peripubertal rats

The effects of multiple somatostatin (SRIH-14) administration on the pituitary-ovarian axis were examined in peripubertal rats. Female Wistar rats received subcutaneously, two daily doses of 20 mug SRIH-14 per 100 g body weight (b.w.) for five consecutive days (from the 33rd to the 37th day of life). Follicle-stimulating (FSH), luteinizing (LH) and somatotropic (GH) cells were examined by the peroxidase-anti-peroxidase immunocytochemical method. Changes in cell volumes, volume densities and number per unit area (mm(2)) of FSH-, LH- and GH-immunoreactive cells were evaluated by stereology and morphometry. Serum FSH and LH levels were determined by RIA. Ovaries were analyzed by simple point counting of follicles. The volumes and volume densities of FSH-, LH- and GH-immunoreactive cells were significantly decreased while their numbers per mm(2) remained unchanged. SRIH-14 induced a significant decrease in serum FSH and LH levels. In the ovary, SRIH-14 induced an increase in the number of primordial follicles, followed by a reduction in the number of small healthy growing follicles and absence of preovulatory follicles. The number of atretic follicles was unchanged. We concluded that treatment with SRIH-14 during the peripubertal period markedly inhibited pituitary FSH, LH and GH cells. In the ovary, SRIH-14 acted by inhibiting folliculogenesis without affecting atretic processes.     

Blocking OLFM4/HIF-1α axis alleviates hypoxia-induced invasion,epithelial–mesenchymal transition,and chemotherapy resistance in non-small-cell lung cancer

Hypoxia is a common biological hallmark of solid cancers, which has been proposed to be associated with oncogenesis and chemotherapy resistance. The purpose of the present study was to investigate the role and underlying mechanisms of olfactomedin 4 (OLFM4) in the hypoxia-induced invasion, epithelial–mesenchymal transition (EMT), and chemotherapy resistance of non-small-cell lung cancer (NSCLC). We observed dramatically upregulated expression of OLFM4 in several NSCLC cell lines, and this effect was more pronounced in A549 and H1299 cells. In addition, our data revealed that OLFM4 expression was remarkably increased in both A549 and H1299 cells under hypoxic microenvironment, accompanied by enhanced levels of hypoxia-inducible factor (HIF)-1α protein. The HIF-1α level was elevated in response to hypoxia, resulting in the regulation of OLFM4. Interestingly, OLFM4 was a positive regulator of hypoxia-driven HIF-1α production. Moreover, depletion of OLFM4 modulated multiple EMT-associated proteins, as evidenced by the enhanced E-cadherin levels along with the diminished expression of N-cadherin and vimentin in response to hypoxia, and thus blocked invasion ability of A549 and H1299 cells following exposure to hypoxia. Furthermore, ablation of OLFM4 accelerated the sensitivity of A549 cells to cisplatin under hypoxic conditions, implying that OLFM4 serves as a key regulator in chemotherapeutic resistance under hypoxia. In conclusion, OLFM4/HIF-1α axis might be a potential therapeutic strategy for NSCLC.     

Cattle on pastures do align along the North–South axis, but the alignment depends on herd density

Alignment is a spontaneous behavioral preference of particular body orientation that may be seen in various vertebrate or invertebrate taxa. Animals often optimize their positions according to diverse directional environmental factors such as wind, stream, slope, sun radiation, etc. Magnetic alignment represents the simplest directional response to the geomagnetic field and a growing body of evidence of animals aligning their body positions according to geomagnetic lines whether at rest or during feedings is accumulating. Recently, with the aid of Google Earth application, evidence of prevailing North–South (N–S) body orientation of cattle on pastures was published (Begall et al. PNAS 105:13451–13455, 2008; Burda et al. PNAS 106:5708–5713, 2009). Nonetheless, a subsequent study from a different laboratory did not confirm this phenomenon (Hert et al. J Comp Physiol A 197:677–682, 2011). The aim of our study was to enlarge the pool of independently gained data on this remarkable animal behavior. By satellite snapshots analysis and using blinded protocol we scored positions of 2,235 individuals in 74 herds. Our results are in line with the original findings of prevailing N–S orientation of grazing cattle. In addition, we found that mutual distances between individual animals within herds (herd density) affect their N–S preference—a new phenomenon giving some insight into biological significance of alignment.     

Molecular regulation of hypothalamus–pituitary–gonads axis in males

The hypothalamic–pituitary–gonadal axis (HPG) plays vital roles in reproduction and steroid hormone production in both sexes. The focus of this review is upon gene structures, receptor structures and the signaling pathways of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The hormones' functions in reproduction as well as consequences resulting from mutations are also summarized. Specific characteristics of hormones such as the pulsatile secretions of GnRH are also covered. The different regulators of the HPG axis are introduced including kisspeptin, activin, inhibin, follistatin, androgens and estrogen. This review includes not only their basic information, but also their unique function in the HPG axis. Here we view the HPG axis as a whole, so relations between ligands and receptors are well described crossing different levels of the HPG axis. Hormone interactions and transformations are also considered. The major information of this article is depicted in three figures summarizing the current discoveries on the HPG axis. This article systematically introduces the basic knowledge of the HPG axis and provides information of the current advances relating to reproductive hormones.     

Auxin and embryo axis formation: the ends in sight?

The major axis of polarity of the plant embryo serves as a reference for the formation of meristems and, thus, for all subsequent development. Mechanisms underlying the establishment of the embryo axis itself have remained elusive. This is now changing with recent reports documenting a role for auxin in embryo axis formation. Auxin accumulates dynamically at specific positions that correlate with developmental decisions in early embryogenesis, and this ties developmental decisions to both transport regulators and components of the response machinery. A major challenge for the future is to determine how auxin-dependent processes interact with other as yet unknown factors to mediate differential gene expression patterns in early embryogenesis.     

The minimal model of the hypothalamic–pituitary–adrenal axis

This paper concerns ODE modeling of the hypothalamic–pituitary– adrenal axis (HPA axis) using an analytical and numerical approach, combined with biological knowledge regarding physiological mechanisms and parameters. The three hormones, CRH, ACTH, and cortisol, which interact in the HPA axis are modeled as a system of three coupled, nonlinear differential equations. Experimental data shows the circadian as well as the ultradian rhythm. This paper focuses on the ultradian rhythm. The ultradian rhythm can mathematically be explained by oscillating solutions. Oscillating solutions to an ODE emerges from an unstable fixed point with complex eigenvalues with a positive real parts and a non-zero imaginary parts. The first part of the paper describes the general considerations to be obeyed for a mathematical model of the HPA axis. In this paper we only include the most widely accepted mechanisms that influence the dynamics of the HPA axis, i.e. a negative feedback from cortisol on CRH and ACTH. Therefore we term our model the minimal model. The minimal model, encompasses a wide class of different realizations, obeying only a few physiologically reasonable demands. The results include the existence of a trapping region guaranteeing that concentrations do not become negative or tend to infinity. Furthermore, this treatment guarantees the existence of a unique fixed point. A change in local stability of the fixed point, from stable to unstable, implies a Hopf bifurcation; thereby, oscillating solutions may emerge from the model. Sufficient criteria for local stability of the fixed point, and an easily applicable sufficient criteria guaranteeing global stability of the fixed point, is formulated. If the latter is fulfilled, ultradian rhythm is an impossible outcome of the minimal model and all realizations thereof. The second part of the paper concerns a specific realization of the minimal model in which feedback functions are built explicitly using receptor dynamics. Using physiologically reasonable parameter values, along with the results of the general case, it is demonstrated that un-physiological values of the parameters are needed in order to achieve local instability of the fixed point. Small changes in physiologically relevant parameters cause the system to be globally stable using the analytical criteria. All simulations show a globally stable fixed point, ruling out periodic solutions even when an investigation of the ‘worst case parameters’ is performed.     

Detrimental effects of chronic hypothalamic—pituitary—adrenal axis activation

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated.     

Is HPA axis reactivity in childhood gender-specific? A systematic review

Background

In adults, hypothalamus–pituitary–adrenal (HPA) axis activity shows sexual dimorphism, and this is thought to be a mechanism underlying sex-specific disease incidence. Evidence is scarce on whether these sex differences are also present in childhood. In a meta-analysis, we recently found that basal (non-stimulated) cortisol in saliva and free cortisol in 24-h urine follow sex-specific patterns. We explored whether these findings could be extended with sex differences in HPA axis reactivity.

Methods

From inception to January 2016, PubMed and EMBASE.com were searched for studies that assessed HPA axis reactivity in healthy girls and boys aged ≤18 years. Articles were systematically assessed and reported in the categories: (1) diurnal rhythm, (2) cortisol awakening response (CAR), (3) protocolled social stress tests similar or equal to the Trier Social Stress Test for children (TSST-C), (4) pharmacological (ACTH and CRH) stress tests, and (5) miscellaneous stress tests.

Results

Two independent assessors selected 109 out of 6158 records for full-text screening, of which 81 studies (with a total of 14,591 subjects) were included. Studies showed that girls had a tendency towards a more variable diurnal rhythm (12 out of 29 studies), a higher CAR (8 out of 18 studies), and a stronger cortisol response to social stress tests (9 out of 21 studies). We found no evidence for sex differences in cortisol response after a pharmacological challenge or to miscellaneous stress tests.

Discussion

Sex differences in HPA axis reactivity appear to be present in childhood, although evidence is not unequivocal. For a better evaluation of sex differences in HPA axis reactivity, standardization of protocols and reports of stress tests is warranted.

     

Nutriepigenetic regulation by folate–homocysteine–methionine axis: a review

Although normally folic acid is given during pregnancy, presumably to prevent neural tube defects, the mechanisms of this protection are unknown. More importantly it is unclear whether folic acid has other function during development. It is known that folic acid re-methylates homocysteine (Hcy) to methionine by methylene tetrahydrofolate reductase-dependent pathways. Folic acid also generates high-energy phosphates, behaves as an antioxidant and improves nitric oxide (NO) production by endothelial NO synthase. Interestingly, during epigenetic modification, methylation of DNA/RNA generate homocysteine unequivocally. The enhanced overexpression of methyl transferase lead to increased yield of Hcy. The accumulation of Hcy causes vascular dysfunction, reduces perfusion in the muscles thereby causing musculopathy. Another interesting fact is that children with severe hyperhomocysteinaemia (HHcy) have skeletal deformities, and do not live past teenage. HHcy is also associated with the progeria syndrome. Epilepsy is primarily caused by inhibition of gamma-amino-butyric-acid (GABA) receptor, an inhibitory neurotransmitter in the neuronal synapse. Folate deficiency leads to HHcy which then competes with GABA for binding on the GABA receptors. With so many genetic and clinical manifestations associated with folate deficiency, we propose that folate deficiency induces epigenetic alterations in the genes and thereby results in disease.