Class Of Hormones Research Articles

Ethylene Measurements from Sweet Fruits Flowers Using Photoacoustic Spectroscopy.

Ethylene is a classical plant hormone and has appeared as a strong molecule managing many physiological and morphological reactions during the life of a plant. With laser-based photoacoustic spectroscopy, ethylene can be identified with high sensitivity, at a high rate and with very good selectivity. This research presents the dynamics of trace gases molecules for ethylene released by cherry flowers, apple flowers and strawberry flowers. The responses of distinctive organs to ethylene may fluctuate, depending on tissue sensitivity and the phase of plant development. From the determinations of this study, the ethylene molecules at the flowers in the nitrogen flow were established in lower concentrations when the value is correlated to the ethylene molecules at the flowers in synthetic air flow.

Targeting the Brain to Cure Type 2 Diabetes.

Present pharmacological treatments of type 2 diabetes aim mainly at increasing insulin secretion by pancreatic β-cells, at improving insulin action on liver, fat, or muscle, and, more recently, at favoring renal glucose elimination. Although efficacious, these treatments do not have the rapid and long-term efficacy of bariatric surgery on correcting diabetic hyperglycemia, suggesting that alternate therapeutic targets can still be identified. Neuronal circuits in the brain, in particular in the hypothalamus and brain stem, can exert strong control on glucose homeostasis. The activity of these circuits is controlled by a variety of cell types—neurons, glial cells, tanycytes—that are sensitive to interoceptive signals such as glucose and various hormones, including insulin, leptin, or ghrelin. When activated, these neuronal circuits can regulate, by controlling autonomic nervous system activity, the secretion of insulin and glucagon by pancreatic endocrine cells as well as glucose metabolic pathways in liver, fat, and muscle. Targeting these neuronal circuits could lead to innovative therapies for diabetes. In the report by Scarlett et al. (1) in this issue of Diabetes and in a previous publication (2), the Schwartz group demonstrated that a single intracerebroventricular (i.c.v.) injection of fibroblast growth factor 1 (FGF1) in diabetic mice and rats leads to a long-term (up to 18 weeks) correction of diabetic hyperglycemia. FGF1 belongs to the fibroblast growth factor (FGF) family, which contains 18 members (3). Most of the FGFs act as paracrine regulators because they bind to heparan sulfate proteoglycans present in the extracellular space, preventing their diffusion beyond the local environment where they are secreted. The exceptions to this rule are FGF15 (or the human ortholog FGF19) and FGF21, which lack the heparan sulfate proteoglycan binding site and, thus, act as classic endocrine hormones. FGF1 binds to all FGF receptors (FGFRs) (FGFR1 to FGFR4) and their splice variants; high-affinity binding …

Extracellular ATP Shapes a Defense-Related Transcriptome Both Independently and along with Other Defense Signaling Pathways.

ATP is not only an essential metabolite of cellular biochemistry but also acts as a signal in the extracellular milieu. In plants, extracellular ATP is monitored by the purinergic receptor P2K1. Recent studies have revealed that extracellular ATP acts as a damage-associated molecular pattern in plants, and its signaling through P2K1 is important for mounting an effective defense response against various pathogenic microorganisms. Biotrophic and necrotrophic pathogens attack plants using different strategies, to which plants respond accordingly with salicylate-based or jasmonate/ethylene-based defensive signaling, respectively. Interestingly, defense mediated by P2K1 is effective against pathogens of both lifestyles, raising the question of the level of interplay between extracellular ATP signaling and that of jasmonate, ethylene, and salicylate. To address this issue, we analyzed ATP-induced transcriptomes in wild-type Arabidopsis (Arabidopsis thaliana) seedlings and mutant seedlings defective in essential components in the signaling pathways of jasmonate, ethylene, and salicylate (classic defense hormones) as well as a mutant and an overexpression line of the P2K1 receptor. We found that P2K1 function is crucial for faithful ATP-induced transcriptional changes and that a subset of genes is more responsive in the P2K1 overexpression line. We also found that more than half of the ATP-responsive genes required signaling by one or more of the pathways for the classical defense hormones, with the jasmonate-based signaling being more critical than others. By contrast, the other ATP-responsive genes were unaffected by deficiencies in signaling for any of the classical defense hormones. These ATP-responsive genes were highly enriched for defense-related Gene Ontology terms. We further tested the ATP-induced genes in knockout mutants of transcription factors, demonstrating that MYCs acting downstream of the jasmonate receptor complex and calmodulin-binding transcription activators are nuclear transducers of P2K1-mediated extracellular ATP signaling.

Pleiotropic influences of brassinosteroids on fruit crops: a review

Brassinosteroids (BRs) are a group of naturally occurring plant steroidal compounds having varied biological activities. This group was recently added in the category of classical hormones and considered as sixth novel plant growth hormone. BRs regulate numerous important pomological attributes such as initiation and cessation of flowering, plant canopy architecture, micropropagation, cell division and elongation, vegetative growth, flowering, fruit set, fruit ripening, quality and yield. Besides, BRs can improve resistance/tolerance to biotic and abiotic stresses. These are also known to enhance postharvest fruit quality. Owing to multiple and diverse physiological roles in plant growth and development, BRs have been collectively referred to as ‘pleotropic phytohormones’. In the present review, we have attempted to highlight the conceptual research and development of BRs with their wide range of physiological functions and economic significance in relation to modern fruit production.

Premises for Cholecystokinin and Gastrin Peptides in Diabetes Therapy.

Gastrin and cholecystokinin (CCK) are classical gastrointestinal peptide hormones. Their biogenesis, structures, and intestinal secretory patterns are well-known with the striking feature that their receptor-bound ‘active sites’ are highly homologous and that this structure is conserved for more than 500 million years during evolution. Consequently, gastrin and CCK are agonists for the same receptor (the CCK2 receptor). But in addition, tyrosyl O-sulphated CCK are also bound to the specific CCK1 receptor. The receptors are widely expressed in the body, including pancreatic islet-cell membranes. Moreover, CCK and gastrin peptides are at various developmental stages and diseases expressed in pancreatic islets; also in human islets. Accordingly, bioactive gastrin and CCK peptides stimulate islet-cell growth as well as insulin and glucagon secretion. In view of their insulinotropic effects, gastrin and CCK peptides have come into focus as drug targets, either alone or in combination with other insulinotropic gut hormones or growth factors. So far, modified CCK and gastrin peptides are being examined as potential drugs for therapy of type 1 as well as type 2 diabetes mellitus.

Partial androgen insensitivity syndrome presenting as pubertal gynecomastia: clinical and hormonal findings and a novel mutation in the androgen receptor gene

SummaryPubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1–2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene.Learning points:Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization.The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS.Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.

Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease

The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, the vasculature, and the kidneys. This is why MR antagonists reduce morbidity and mortality of heart disease patients and are part of the mainstay pharmacotherapy of advanced human heart failure. A plethora of animal studies using cell type–specific targeting of the MR gene have established the importance of MR signaling and function in cardiac myocytes, vascular endothelial and smooth muscle cells, renal cells, and macrophages. In terms of its signaling properties, the MR is distinct from nuclear receptors in that it has, in reality, two physiological hormonal agonists: not only aldosterone but also cortisol. In fact, in several tissues, including in the myocardium, cortisol is the primary hormone activating the MR. There is a considerable amount of evidence indicating that the effects of the MR in each tissue expressing it depend on tissue- and ligand-specific engagement of molecular co-regulators that either activate or suppress its transcriptional activity. Identification of these co-regulators for every ligand that interacts with the MR in the heart (and in other tissues) is of utmost importance therapeutically, since it can not only help elucidate fully the pathophysiological ramifications of the cardiac MR’s actions, but also help design and develop novel better MR antagonist drugs for heart disease therapy. Among the various proteins the MR interacts with are molecules involved in cardiac G protein-coupled receptor (GPCR) signaling. This results in a significant amount of crosstalk between GPCRs and the MR, which can affect the latter’s activity dramatically in the heart and in other cardiovascular tissues. This review summarizes the current experimental evidence for this GPCR-MR crosstalk in the heart and discusses its pathophysiological implications for cardiac adverse remodeling as well as for heart disease therapy. Novel findings revealing non-conventional roles of GPCR signaling molecules, specifically of GPCR-kinase (GRK)-5, in cardiac MR regulation are also highlighted.

Modulations of Neuroendocrine Stress Responses During Confinement in Antarctica and the Role of Hypobaric Hypoxia.

The Antarctic continent is an environment of extreme conditions. Only few research stations exist that are occupied throughout the year. The German station Neumayer III and the French-Italian Concordia station are such research platforms and human outposts. The seasonal shifts of complete daylight (summer) to complete darkness (winter) as well as massive changes in outside temperatures (down to -80°C at Concordia) during winter result in complete confinement of the crews from the outside world. In addition, the crew at Concordia is subjected to hypobaric hypoxia of ∼650 hPa as the station is situated at high altitude (3,233 m). We studied three expedition crews at Neumayer III (sea level) (n = 16) and two at Concordia (high altitude) (n = 15) to determine the effects of hypobaric hypoxia on hormonal/metabolic stress parameters [endocannabinoids (ECs), catecholamines, and glucocorticoids] and evaluated the psychological stress over a period of 11 months including winter confinement. In the Neumayer III (sea level) crew, EC and n-acylethanolamide (NAE) concentrations increased significantly already at the beginning of the deployment (p < 0.001) whereas catecholamines and cortisol remained unaffected. Over the year, ECs and NAEs stayed elevated and fluctuated before slowly decreasing till the end of the deployment. The classical stress hormones showed small increases in the last third of deployment. By contrast, at Concordia (high altitude), norepinephrine concentrations increased significantly at the beginning (p < 0.001) which was paralleled by low EC levels. Prior to the second half of deployment, norepinephrine declined constantly to end on a low plateau level, whereas then the EC concentrations increased significantly in this second period during the overwintering (p < 0.001). Psychometric data showed no significant changes in the crews at either station. These findings demonstrate that exposition of healthy humans to the physically challenging extreme environment of Antarctica (i) has a distinct modulating effect on stress responses. Additionally, (ii) acute high altitude/hypobaric hypoxia at the beginning seem to trigger catecholamine release that downregulates the EC response. These results (iii) are not associated with psychological stress.

Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites.

Thyroxine (T4) and 3,5,3'-triiodothyronine (T3) are secreted by the thyroid gland, while T3 is also generated from the peripheral metabolism of T4 by iodothyronine deiodinases types I and II. Several conditions like stress, diseases, and physical exercise can promote changes in local TH metabolism, leading to different target tissue effects that depend on the presence of tissue-specific enzymatic activities. The newly discovered physiological and pharmacological actions of T4 and T3 metabolites, such as 3,5-diiodothyronine (3,5-T2), and 3-iodothyronamine (T1AM) are of great interest. A classical thyroid hormone effect is the ability of T3 to increase oxygen consumption in almost all cell types studied. Approximately 30 years ago, a seminal report has shown that 3,5-T2 increased oxygen consumption more rapidly than T3 in hepatocytes. Other studies demonstrated that exogenous 3,5-T2 administration was able to increase whole body energy expenditure in rodents and humans. In fact, 3,5-T2 treatment prevents diabetic nephropathy, hepatic steatosis induced by high fat diet, insulin resistance, and weight gain during aging in Wistar male rats. The regulation of mitochondria is likely one of the most important actions of T3 and its metabolite 3,5-T2, which was able to restore the thermogenic program of brown adipose tissue (BAT) in hypothyroid rats, just as T3 does, while T1AM administration induced rapid hypothermia. T3 increases heart rate and cardiac contractility, which are hallmark effects of hyperthyroidism involved in cardiac arrhythmia. These deleterious cardiac effects were not observed with the use of 3,5-T2 pharmacological doses, and in contrast T1AM was shown to promote a negative inotropic and chronotropic action at micromolar concentrations in isolated hearts. Furthermore, T1AM has a cardioprotective effect in a model of ischemic/reperfusion injury in isolated hearts, such as occurs with T3 administration. Despite the encouraging possible therapeutic use of TH metabolites, further studies are needed to better understand their peripheral effects, when compared to T3 itself, in order to establish their risk and benefit. On this basis, the main peripheral effects of thyroid hormones and their metabolites in tissues, such as heart, liver, skeletal muscle, and BAT are discussed herein.

Cytokinin activity of N6-benzyladenine derivatives assayed by interaction with the receptors in planta, in vitro, and in silico

Biological effects of hormones in both plants and animals are based on high-affinity interaction with cognate receptors resulting in their activation. The signal of cytokinins, classical plant hormones, is perceived in Arabidopsis by three homologous membrane receptors: AHK2, AHK3, and CRE1/AHK4. To study the cytokinin–receptor interaction, we used 25 derivatives of potent cytokinin N6-benzyladenine (BA) with substituents in the purine heterocycle and/or in the side chain. The study was focused primarily on individual cytokinin receptors from Arabidopsis. The main in planta assay system was based on Arabidopsis double mutants retaining only one isoform of cytokinin receptors and harboring cytokinin-sensitive reporter gene. Classical cytokinin biotest with Amaranthus seedlings was used as an additional biotest. In parallel, the binding of ligands to individual cytokinin receptors was assessed in the in vitro test system. Quantitative comparison of results of different assays confirmed the partial similarity of ligand-binding properties of receptor isoforms. Substituents at positions 8 and 9 of adenine moiety, elongated linker up to 4 methylene units, and replacement of N6 by sulfur or oxygen have resulted in the suppression of cytokinin activity of the derivative toward all receptors. Introduction of a halogen into position 2 of adenine moiety, on the contrary, often increased the ligand activity, especially toward AHK3. Features both common and distinctive of cytokinin receptors in Arabidopsis and Amaranthus were revealed, highlighting species specificity of the cytokinin perception apparatus. Correlations between the extent to which a compound binds to a receptor in vitro and its ability to activate the same receptor in planta were evaluated for each AHK protein. Interaction patterns between individual receptors and ligands were rationalized by structure analysis and molecular docking in sensory modules of AHK receptors. The best correlation between docking scores and specific binding was observed for AHK3. In addition, receptor-specific ligands have been discovered with unique properties to predominantly activate or block distinct cytokinin receptors. These ligands are promising for practical application and as molecular tools in the study of the cytokinin perception by plant cells.

The SET protein promotes androgen production in testicular Leydig cells.

SummaryApproximately 40% of middle‐aged men exhibit symptoms of late‐onset hypogonadism (LOH). However, the mechanism of androgen deficiency is still currently unclear. As shown in our previous studies, the SET protein is expressed in testicular Leydig cells and ovarian granule cells. This study was designed to investigate the effect of the SET protein on androgen production in Leydig cells. The AdCMV/SET and AdH1siRNA/SET adenoviruses were individually transduced into a cultured mouse Leydig cell line (mLTC‐1) with or without human chorionic gonadotropin (HCG) stimulation in vitro. The primary mouse Leydig cells were used to confirm the main data from mLTC‐1 cells. The SET protein was expressed in the cytoplasm and nucleus of mLTC‐1 cells. Testosterone production was significantly increased in mLTC‐1 cells overexpressing the SET protein compared with the control group (p < 0.05), whereas testosterone production was significantly decreased in the SET knockdown mLTC‐1 cells (p < 0.05). Consistent with the testosterone levels, the expression levels of the steroidogenic acute regulatory (StAR) and cytochrome P450c17α‐hydroxylase (CYP17a1) mRNAs and proteins synchronously changed according to the expression level of the SET protein. Interestingly, the expression of the SET protein was significantly increased in the mLTC‐1 cells stimulated with 0.04 and 0.1 U/mL hCG. In the mLTC‐1 cells transfected with AdH1siRNA/SET and concurrently stimulated with 0.1 U/mL hCG, both testosterone production and StAR expression were significantly lower than in the cells without SET knockdown (p < 0.05). In conclusion, the SET protein participates in regulating testosterone production by increasing the expression of StAR and CYP17a1, and it may be a downstream factor of the classic luteinizing hormone (LH)/luteinizing hormone receptor (LHR) signaling pathway. This study improves our understanding of the intracellular mechanism of testicular steroidogenesis and the pathophysiological mechanism of LOH in the aging male.

SIAMESE-RELATED1 Is Regulated Posttranslationally and Participates in Repression of Leaf Growth under Moderate Drought.

The plant cell cycle is tightly regulated by factors that integrate endogenous cues and environmental signals to adapt plant growth to changing conditions. Under drought, cell division in young leaves is blocked by an active mechanism, reducing the evaporative surface and conserving energy resources. The molecular function of cyclin-dependent kinase-inhibitory proteins (CKIs) in regulating the cell cycle has already been well studied, but little is known about their involvement in cell cycle regulation under adverse growth conditions. In this study, we show that the transcript of the CKI gene SIAMESE-RELATED1 (SMR1) is quickly induced under moderate drought in young Arabidopsis (Arabidopsis thaliana) leaves. Functional characterization further revealed that SMR1 inhibits cell division and affects meristem activity, thereby restricting the growth of leaves and roots. Moreover, we demonstrate that SMR1 is a short-lived protein that is degraded by the 26S proteasome after being ubiquitinated by a Cullin-RING E3 ubiquitin ligase. Consequently, overexpression of a more stable variant of the SMR1 protein leads to a much stronger phenotype than overexpression of the native SMR1. Under moderate drought, both the SMR1 transcript and SMR1 protein accumulate. Despite this induction, smr1 mutants do not show overall tolerance to drought stress but do show less growth inhibition of young leaves under drought. Surprisingly, the growth-repressive hormone ethylene promotes SMR1 induction, but the classical drought hormone abscisic acid does not.

A review of the role of estrogen in dermal aging and facial attractiveness in women.

Estrogens are known to have protective and favorable influences on skin health; conversely, androgens oppose the actions of estrogens. Estrogen's chemical messages are transmitted via the classical nuclear hormone estrogen receptors (ER) alpha and beta and the rapid-acting G-coupled membrane estrogen receptor. Androgens [both testosterone and 5α-dihydrotestosterone (5α-DHT)] bind the same androgen receptor. Estrogen levels peak in the mid- to late 20s in women and then decline by 50% by 50years of age and dramatically decrease further after menopause. The loss of estrogens with aging contributes to diminished dermal health, whereas estrogen hormone therapy [eg, oral conjugated equine estrogens (CEE)] restores skin health. Several reports suggest positive correlations between the levels of circulating estrogens and: (1) perceived age, (2) attractiveness, (3) enhanced skin health, and (4) facial coloration in women. Based upon a psychological dermato-endocrine perspective, the positive correspondence of high estrogens levels with perceived age and facial attractiveness in women especially with aging demonstrates the importance of hormonal influences on observed dermal health and youthful appearance.

Mechanisms of resistance in the rice cultivar Manikpukha to the rice stem nematode Ditylenchus angustus.

The incompatible interaction between the rice cultivar Manikpukha and the rice stem nematode Ditylenchus angustus has been reported recently. This research focuses on the underlying mechanisms of resistance in Manikpukha. Invasion, post-infection development and reproduction of D.angustus were compared in compatible and incompatible interactions to identify the stage inwhich resistance occurs. The results indicate that resistance in Manikpukha is associated with reduced development and reproduction, implying that resistance acts post-invasion. We studied the possible involvement of three classical defence hormones, salicylic acid (SA), jasmonic acid (JA) and ethylene (ET), in response to infection in a compatible interaction using biosynthesis/signalling-deficient transgenic rice lines. All three hormones appear to have an influence on the basal defence of Nipponbare against the stem nematode. Although hormone application increases basal defences, expression studies and hormone analyses after nematode infection in Manikpukha did not show a clear involvement of the hormone defense pathways for SA, ET and JA. However, it seems that OsPAL1 plays a pivotal role in resistance, indicating that the phenylpropanoid pathway and its products might be key players in the incompatible interaction. Lignin measurement showed that, although basal levels are similar, Manikpukha had a significantly higher lignin content on nematode infection, whereas it was decreased in the susceptible cultivar. The results presented here show that SA, ET and JA are involved in basal defences, but the resistance of Manikpukha against D.angustus probably relies on products of the phenylpropanoid pathway.

Structure and Function of Bone Marrow Adipocytes.

Adipocytes are heterogeneous cells strongly linked to energy storage and disposal. In parallel, adipocytes are endowed with an extensive portfolio of endocrine molecules, whose secretion varies depending on nutritional status. Marrow adipose tissue (MAT) has specific characteristics that are not shared by white (WAT) or brown (BAT) adipose tissue. First, marrow adipocytes and osteoblasts are terminally differentiated cells that originate from the same bone marrow mesenchymal stromal cell. Differently from WAT adipocytes, marrow adipocytes expand under conditions of energy restriction and seem to be not influenced by energy surplus, at least in humans. Over the last few years, several lines of evidence have suggested that bone cells and MAT are mutually connected regarding the modulation of both energy metabolism and bone remodeling. Adipokines (e.g., adiponectin, leptin, and chemerin), incretins (GLP1 and GIP), and several classical hormones (e.g., GH and insulin) are biochemical components involved in the modulation of bone remodeling, marrow adipogenesis, and energy metabolism. As expected, metabolic and nutritional diseases such as diabetes mellitus and anorexia nervosa (AN) greatly affect MAT quantity and quality as well as bone strength. Although the interest in MAT started recently, the rapid advances in current technology have expedited unprecedented growth of knowledge in this area. The present review intends to give to the reader an up-to-date perspective about MAT structure and physiology as well as its involvement in metabolic and nutritional diseases such as diabetes mellitus and ano-rexia. © 2018 American Physiological Society. Compr Physiol 8:315-349, 2018.

Low-dose metformin exposure causes changes in expression of endocrine disruption-associated genes

The presence of intersex fish in watersheds around the world is a warning of the presence of anthropogenic endocrine-disrupting compounds (EDCs) being deposited into the aquatic environment. The anti-diabetic drug metformin is among the most prevalent and ubiquitous of the myriad pharmaceuticals found in wastewater effluent and watersheds worldwide. In addition to its prescription for type-2 diabetes, metformin is indicated as a treatment in cancers and the endocrine disorder polycystic ovarian syndrome (PCOS). Our previous research found evidence of endocrine-disruption following Pimephales promelas (fathead minnow) exposure to metformin at an environmentally relevant concentration. However, the mechanism of action leading to these impacts is unknown. Although metformin does not structurally resemble classical EDCs, there’s an increasing recognition that endocrine disruption may occur by mechanisms other than classical endocrine receptor binding, and metformin’s off-label use for treating endocrine-related disorders such as PCOS indicates its potential interaction with the endocrine system. To further explore metformin’s mechanism of action as an EDC, we measured expression of numerous endocrine-related genes in male fathead minnows exposed to metformin at a low-dose similar to that found in wastewater effluent and the environment (40 μg L−1) for a full year (early development to adulthood) and discovered significant upregulation of the AR (3.6 ± 0.9-fold), 3β-HSD (3.9 ± 0.8-fold), 17β-HSD (17 ± 4-fold), CYP19A1 (40 ± 20-fold), and SULT2A1 (2.3 ± 0.4-fold) genes in exposed male gonad. We also found a significant correlation between expression of 3β-HSD, 17β-HSD, and CYP19A1 in testis of metformin-treated male fish and the degree of intersex occurring in their gonads. These results provide additional evidence of the endocrine disrupting impact of the drug metformin and insight into the potential mechanisms by which metformin may influence the endocrine system in aquatic organisms.

Enhanced bone regeneration using an insulin-loaded nano-hydroxyapatite/collagen/PLGA composite scaffold.

Insulin is widely considered as a classical hormone and drug in maintaining energy and glucose homeostasis. Recently, insulin has been increasingly recognized as an indispensable factor for osteogenesis and bone turnover, but its applications in bone regeneration have been restricted because of the short periods of activity and uncontrolled release. In this study, we incorporated insulin-loaded poly lactic-co-glycolic-acid (PLGA) nanospheres into nano-hydroxyapatite/collagen (nHAC) scaffolds and investigated the bioactivity of the composite scaffolds in vitro and in vivo. Bioactive insulin was successfully released from the nanospheres within the scaffold, and the release kinetics of insulin could be efficiently controlled by uniform-sized nanospheres. The physical characterizations of the composite scaffolds demonstrated that incorporation of nanospheres in nHAC scaffolds using this method did not significantly change the porosity, pore diameters, and compressive strengths of nHAC. In vitro, the insulin-loaded nHAC/PLGA composite scaffolds possessed favorable biological function for bone marrow mesenchymal stem cells adhesion and proliferation, as well as the differentiation into osteoblasts. In vivo, the optimized bone regenerative capability of this composite scaffold was confirmed in rabbit mandible critical size defects. These results demonstrated successful development of a functional insulin–PLGA–nHAC composite scaffold that enhances the bone regeneration capability of nHAC.

Role of Kisspeptin and Leptin in the Development of Immune Reactivity during Pregnancy

The effects of kisspeptin, an important regulator of reproductive function, and leptin, a classical metabolic hormone, on the formation of inducible regulatory T cells (iTreg) and T helper cells that produce interleukin 17 (Th17), as well as on the activity of indoleamine 2,3-dioxygenase (IDO) have been studied. Both hormones are actively produced by the placenta and involved in the formation of a new hormonal profile during pregnancy. It was found that kisspeptin at concentrations typical for trimesters I–III of pregnancy stimulates the formation of iTreg and simultaneously inhibit Th17 induction. Regardless of the used concentration, kisspeptin increases the secretion of interleukin-10 (IL-10) and reduces the production of IL-17A in CD4+ T lymphocytes in women. At the same time leptin at physiological concentrations typical for pregnancy has the opposite effect, inhibiting the formation of iTreg without affecting the production of IL-10 in cultures of CD4+T lymphocytes and simultaneous stimulating the induction of Th17 and production of IL-17A in CD4+T lymphocytes. At the concentration corresponding to trimesters II–III of pregnancy both hormones significantly enhance lipopolysaccharide-induced activity of IDO in monocytes.

Membrane delimited estrogen receptor activation protects heart against ischemic-reperfusion injury in mice with cardiac but not endothelial specific ablation of ERα

Steroid hormone receptors, such as estrogen receptors (ER) function as ligand-regulated transcription factors. However, recent data indicate that estrogen also elicits effects through binding to estrogen receptors (ER-α, ER-β and GPER) at the plasma membrane and initiating signaling. In this study, ovariectomized C57BL/6J mice were treated with estradiol (6 μg/day) or estrogen-dendrimer conjugate (EDC, a membrane delimited ER modulator) for two weeks. Ischemia-reperfusion injury was evaluated in Langendorff perfused hearts. Similar to estradiol-treated hearts, EDC treatment significantly decreased infarct size and improved post-ischemic functional recovery. EDC treatment also resulted in an increase in protein S-nitrosylation (SNO), consistent with previous studies showing a SNO role in cardioprotection. In further support of a role for SNO, inhibition of nitric oxide synthase but not soluble guanylyl cyclase blocked EDC-mediated protection. ICI182,780 (antagonist of classic ER but agonist of GPER) significantly blocked the EDC-mediated cardioprotection, suggesting EDC-induced protection is mediated by classic ER. Cardiac- or endothelial-specific (cs- or es-) ERα knockout (KO) mice were generated to test tissue-specific ERα involved in EDC protection. In cs-ERαKO mice, EDC treatment still significantly decreased infarct size and improved functional recovery similar to that found in wildtype, while protection was lost in es-ERαKO mice, suggesting an important role for endothelial ERα. In contrast to wildtype hearts, EDC treatment did not increase SNO in es-ERαKO mice. ERα but not ERβ was found significantly decreased in cs-ERαKO mice, while opposite results were found in es-ERαKO mice. Thus, loss of EDC-induced protection and SNO increase in es-ERαKO mice could also be due to significant down-regulation of cardiac ERβ/SNO signaling. In conclusion, these results demonstrated a role of activation of membrane delimited ER in cardioprotection, suggesting that EDC-like compounds could be used clinically to provide cardiovascular benefit without the classical steroid hormone side effects, such as stimulation of uterine and breast cancer.

Suppression of progesterone synthesis in human trophoblast cells by fine particulate matter primarily derived from industry

Epidemiological studies have exhibited a positive association between fine particulate matter (PM2.5) exposure and adverse pregnancy outcome (APO). However, source-related effect and the potential mechanism have not been thoroughly elucidated in toxicology. In this study, PM2.5 was collected during a severe winter haze episode in an energy-base city of China. We coupled this approach with the source appointment by applying the Lagrangian Integrated Trajectory and Concentration Weighted Trajectory model. We observed that the primary trajectory with high polluted air mass came from the northwest of the sampling site. Approximately 90% or more of PM2.5 was derived from the industry at this haze period. Next, the sampled PM2.5 was used to study the classical hormone synthesis pathway on trophoblast JEG-3 cells. PM2.5 induced the secretion of human chorionic gonadotrophin (HCG) and the proliferation of JEG-3 cells at a noncytotoxic concentration. However, the synthesis of progesterone was significantly suppressed, even if both hCG and cyclic adenosine monophosphate (cAMP) were increased, suggesting that PM2.5 may interfere the downstream of cAMP. As expected, the phosphorylated activity of protein kinase A (PKA) was attenuated. Subsequently, the downstream molecules of steroidogenesis, such as ferredoxin reductase (FDXR), CYP11A1 (encoded P450scc), and 3β-Hydroxysteroid dehydrogenase type 1 (3β-HSD1), were inhibited. Therefore, PM2.5, primarily derived from industry, may directly inhibit the phosphorylation status of PKA in JEG-3 which, in turn, inhibited the proteins expression in progesterone-synthesis to suppress progesterone levels. Considering the pivotal role of progesterone in pregnancy maintenance, the mechanism on hormone synthesis may provide a better understanding for PM2.5-caused APO. Industry-emanated PM2.5, though not specific, could threaten the placenta, which needs to be verified by further epidemiological studies.