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The production of thyroid hormones is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropinreleasing hormone (TRH) is synthesized in the hypothalamus and stimulates the release of thyroid-stimulating hormone (TSH) from the anterior pituitary. Secretion of TRH is stimulated by factors such as exercise, stress, malnutrition, low plasma glucose and sleep. TSH secretion, in turn, is regulated by negative feedback from thyroid hormones thyroxine (T4) and triiodothyronine (T3), acting on both the pituitary gland and possibly the hypothalamus. Increased levels of T3 and T4 decrease TSH secretion and vice versa. TSH binds to the TSH-receptor (TSH-R) on the thyroid cell membrane, a G protein-coupled receptor (GPCR) that activates the Gs-adenylyl cyclase-cyclic AMP pathway. Activation of this pathway increases cAMP formation, which in turn mediates the increased uptake and transport of iodide, iodination of thyroglobulin and synthesis of iodotyrosines. TSH binding to TSH-R also stimulates phospholipase C, leading to thyroid cell hypertrophy. Chronic stimulation by TSH can cause hypertrophy of the entire gland, resulting in a goiter, particularly in cases of iodine deficiency. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate the value of the thyrotropin-releasing hormone (TRH) test in the diagnosis of central hypothyroidism (CH) in patients with pituitary disease.MethodsSystematic evaluation of 359 TRH tests in patients with pituitary disease including measurements of thyroxine (T4), TBG-corrected T4 (T4corr), baseline TSH (TSH0) and relative or absolute TSH increase (TSHfold, TSHabsolute).ResultsPatients diagnosed with CH (n=39) show comparable TSH0 (p-value 0.824) but lower T4corr (p-value

Simple Summary: Pituitary pars intermedia dysfunction (PPID) is a common disease of the geriatric horse population. The most common clinical sign of PPID is hypertrichosis, or a long hair-coat with delayed shedding. Hypertrichosis is the most easily recognized clinical sign of PPID. However, the presence of hypertrichosis is often associated with severe end-stage disease. There is little research investigating sub-clinical or early PPID and the clinical signs associated with these stages of disease. The benefit of being able to recognize early PPID, is that we are able to begin treatment earlier on in disease process, potentially reducing the deleterious consequences of PPID and improving survival. Laboratory tests are available to more accurately diagnose PPID, and these tests include the basal ACTH and TRH-stimulated ACTH tests. Basal ACTH is easy to perform and is recommended in cases where clinical disease is suspected. The TRH-stimulation test improves diagnostic accuracy in early PPID cases. This study documents both test results and clinical signs associated with the transition from subclinical to clinical PPID, so that we are better able to recognize potential early PPID, as well as interpret results in these horses. Poor recognition of subtle clinical abnormalities and equivocal ACTH concentrations make early diagnosis of PPID difficult. Progressive clinical findings and corresponding ACTH concentrations in horses transitioning to PPID over time have not been documented. Seven horses with ACTH concentrations equivocal for PPID (utilizing locally derived, seasonally adjusted diagnostic-cut off values (DCOV)) and no clinical signs of PPID were selected. Sequential measurement of basal and thyrotropin-releasing hormone (TRH)-stimulated ACTH concentrations and recording of clinical findings occurred from October 2017 to November 2021 in a prospective case series. In two horses, marked hypertrichosis developed. Although 1/11 basal ACTH concentrations were below DCOV in 2018, subsequently all basal ACTH concentrations in these two horses without treatment were greater than DCOV. One horse was treated with pergolide which normalized basal ACTH concentrations. Four horses developed intermittent, mild hypertrichosis, and one horse never developed hypertrichosis. Basal ACTH concentrations in these five horses were greater than DCOV in 63/133 (47.4%) of testing points. TRH-stimulated ACTH concentrations in these five horses were greater than DCOV in 77/133 (57.9%) of testing points, sometimes markedly increased and greater than the assay upper limit of detection (LoD) of 1250pg/mL. TRH-stimulated ACTH concentrations were most frequently positive in late summer and early autumn, with 24/37 (64.9%) of TRH-stimulated ACTH concentrations greater than the DCOV in February and March. Horses transitioning to PPID can have subtle clinical signs and equivocal ACTH concentrations. However, TRH-stimulated ACTH concentrations can be markedly greater than DCOV, especially in late summer and early autumn (February and March) allowing for identification of subclinical and transitional cases. [ABSTRACT FROM AUTHOR]

Intrinsic membrane excitability (IME) sets up neuronal responsiveness to synaptic drive. Several neurotransmitters and neuromodulators, acting through G-protein-coupled receptors (GPCRs), fine-tune motoneuron (MN) IME by modulating background K+ channels TASK1. However, intracellular partners linking GPCRs to TASK1 modulation are not yet well-known. We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment of MN IME via TASK1. Electrophysiological recordings were performed in hypoglossal MNs (HMNs) obtained from adult and neonatal rats, neonatal knockout mice for TASK1 (task1 –/–) and TASK3 (task3 –/–, the another highly expressed TASK subunit in MNs), and primary cultures of embryonic spinal cord MNs (SMNs). Small-interfering RNA (siRNA) technology was also used to knockdown either ROCK1 or ROCK2. Furthermore, ROCK activity assays were performed to evaluate the ability of various physiological GPCR ligands to stimulate ROCK. Microiontophoretically applied H1152, a ROCK inhibitor, and siRNA-induced ROCK2 knockdown both depressed AMPAergic, inspiratory-related discharge activity of adult HMNs in vivo , which mainly express the ROCK2 isoform. In brainstem slices, intracellular constitutively active ROCK2 (aROCK2) led to H1152-sensitive HMN hyper-excitability. The aROCK2 inhibited pH-sensitive and TASK1-mediated currents in SMNs. Conclusively, aROCK2 increased IME in task3 –/–, but not in task1 –/– HMNs. MN IME was also augmented by the physiological neuromodulator lysophosphatidic acid (LPA) through a mechanism entailing Gαi/o-protein stimulation, ROCK2, but not ROCK1, activity and TASK1 inhibition. Finally, two neurotransmitters, TRH, and 5-HT, which are both known to increase MN IME by TASK1 inhibition, stimulated ROCK2, and depressed background resting currents via Gαq/ROCK2 signaling. These outcomes suggest that LPA and several neurotransmitters impact MN IME via Gαi/o/Gαq-protein-coupled receptors, downstream ROCK2 activation, and subsequent inhibition of TASK1 channels. [ABSTRACT FROM AUTHOR]

Intrinsic membrane excitability (IME) sets up neuronal responsiveness to synaptic drive. Several neurotransmitters and neuromodulators, acting through G-protein-coupled receptors (GPCRs), fine-tune motoneuron (MN) IME by modulating background K+ channels TASK1. However, intracellular partners linking GPCRs to TASK1 modulation are not yet well-known. We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment of MN IME via TASK1. Electrophysiological recordings were performed in hypoglossal MNs (HMNs) obtained from adult and neonatal rats, neonatal knockout mice for TASK1 (task1–/–) and TASK3 (task3–/–, the another highly expressed TASK subunit in MNs), and primary cultures of embryonic spinal cord MNs (SMNs). Small-interfering RNA (siRNA) technology was also used to knockdown either ROCK1 or ROCK2. Furthermore, ROCK activity assays were performed to evaluate the ability of various physiological GPCR ligands to stimulate ROCK. Microiontophoretically applied H1152, a ROCK inhibitor, and siRNA-induced ROCK2 knockdown both depressed AMPAergic, inspiratory-related discharge activity of adult HMNs in vivo, which mainly express the ROCK2 isoform. In brainstem slices, intracellular constitutively active ROCK2 (aROCK2) led to H1152-sensitive HMN hyper-excitability. The aROCK2 inhibited pH-sensitive and TASK1-mediated currents in SMNs. Conclusively, aROCK2 increased IME in task3–/–, but not in task1–/– HMNs. MN IME was also augmented by the physiological neuromodulator lysophosphatidic acid (LPA) through a mechanism entailing Gαi/o-protein stimulation, ROCK2, but not ROCK1, activity and TASK1 inhibition. Finally, two neurotransmitters, TRH, and 5-HT, which are both known to increase MN IME by TASK1 inhibition, stimulated ROCK2, and depressed background resting currents via Gαq/ROCK2 signaling. These outcomes suggest that LPA and several neurotransmitters impact MN IME via Gαi/o/Gαq-protein-coupled receptors, downstream ROCK2 activation, and subsequent inhibition of TASK1 channels.

Objective: To evaluate the value of the thyrotropin-releasing hormone (TRH) test in the diagnosis of central hypothyroidism (CH) in patients with pituitary disease., Methods: Systematic evaluation of 359 TRH tests in patients with pituitary disease including measurements of thyroxine (T4), TBG-corrected T4 (T4 corr ), baseline TSH (TSH 0 ) and relative or absolute TSH increase (TSH fold , TSH absolute )., Results: Patients diagnosed with CH (n=39) show comparable TSH 0 (p-value 0.824) but lower T4 corr (p-value <0.001) and lower TSH increase (p-value <0.001) compared to patients without CH. In 54% (42 of 78 cases) of patients with low T4 corr , the CH diagnosis was rejected based on a high TSH fold . In these cases, a spontaneous increase and mean normalization in T4 corr (from 62 to 73 nmol/L, p-value <0.001) was observed during the follow-up period (7.6 ± 5.0 years). Three of the 42 patients (7%) were started on replacement therapy due to spontaneous deterioration of thyroid function after 2.8 years. Patients diagnosed with CH reported significantly more symptoms of hypothyroidism (p-value 0.005), although, symptoms were reported in most patients with pituitary disease. The TRH test did not provide clinical relevant information in patients with normal T4 or patients awaiting pituitary surgery (78%, 281 of 359). There were only mild and reversible adverse effects related to the TRH test except for possibly one case (0.3%) experiencing a pituitary apoplexy., Conclusion: The TRH test could be reserved to patients with pituitary disease, low T4 levels without convincing signs of CH. Approximately 50% of patients with a slightly decreased T4 were considered to have normal pituitary thyroid function based on the TRH test results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Christensen, Smith, Rosendal, Gulisano, Ettrup, Vestergaard, Nielsen, Karmisholt and Dal.)

Diagnosis of equine pituitary pars intermedia dysfunction (PPID) remains a challenge as multiple factors (stress, exercise, and time of year) influence ACTH and cortisol concentrations. To assess endocrine status in a study designed to evaluate the effects of age and diet on glucose and insulin dynamics, we performed thyrotropin-releasing hormone (TRH) stimulation tests and overnight dexamethasone suppression tests in March, May, August, and October on 16 healthy Thoroughbred and Standardbred mares and geldings. Horses were grouped by age: adult (mean ± SD; 8.8 ± 2.9 yr; n = 8) and aged (20.6 ± 2.1 yr; n = 8). None of the horses showed clinical signs (hypertrichosis, regional adiposity, skeletal muscle atrophy, lethargy) of pituitary pars intermedia dysfunction. Horses were randomly assigned to groups of 4, blocked for age, and fed grass hay plus 4 isocaloric concentrate diets (control, starch-rich, fiber-rich, and sugar-rich) using a balanced Latin square design. Data were analyzed using a multivariable linear mixed regression model. Baseline ACTH was significantly higher in aged horses (mean ± standard error of the mean; 60.0 ± 10.7 pg/mL) adapted to the starch-rich diet compared to adult horses (15.7 ± 12.0 pg/mL) on the same diet ( P = 0.017). After controlling for age and diet, baseline ACTH concentrations were significantly increased in October (57.7 ± 7.1 pg/mL) compared to March (13.2 ± 7.1 pg/mL; P < 0.001), May (12.4 ± 7.1 pg/mL; P < 0.001), and August (24.2 ± 7.1 pg/mL; P < 0.001), whereas post-TRH ACTH was higher in August (376.6 ± 57.6 pg/mL) and October (370.9 ± 57.5 pg/mL) compared to March (101.9 ± 57.3 pg/mL; P < 0.001) and May (74.5 ± 57.1 pg/mL; P < 0.001). Aged horses had significantly higher post-dexamethasone cortisol on the starch-rich diet (0.6 ± 0.1 μg/dL) compared to the sugar-rich diet (0.2 ± 0.1 μg/dL; P = 0.021). Post-dexamethasone cortisol was significantly higher in October (0.6 ± 0.1 μg/dL) compared to March (0.3 ± 0.1 μg/dL; P = 0.005), May (0.2 ± 0.1 μg/dL; P < 0.001), and August (0.3 ± 0.1 μg/dL; P = 0.004). Breed did not influence ACTH or cortisol measurements. In conclusion, in addition to age and time of year, diet is a potential confounder as animals on a starch-rich diet may be incorrectly diagnosed with pituitary pars intermedia dysfunction. [ABSTRACT FROM AUTHOR]

So far, little is known about the control of hypothalamic-prolactin axis activity by dopamine (DA) and thyrotropin-releasing hormone (TRH) in depressed patients with suicidal behavior disorder (SBD). We evaluated prolactin (PRL) responses to apomorphine (APO; a DA direct receptor agonist) and 0800 h and 2300 h protirelin (TRH) tests in 50 medication-free euthyroid DSM-5 major depressed inpatients with SBD (either current [n = 22], or in early remission [n = 28]); and 18 healthy hospitalized controls (HCs). Baseline (BL) PRL levels were comparable across the three diagnostic groups. SBDs in early remission did not differ from HCs regarding PRL suppression to APO (PRL s), PRL stimulation to 0800 h and 2300 h TRH tests (∆PRL), and ∆∆PRL values (difference between 2300 h-∆PRL and 0800 h-∆PRL values). Current SBDs showed lower PRL s and ∆∆PRL values than HCs and SBDs in early remission. Further analyses revealed that current SBDs with a history of violent and high-lethality suicide attempts were more likely to exhibit co-occurrence of low ∆∆PRL and PRL S values. Our results suggest that regulation of the hypothalamic-PRL axis is impaired in some depressed patients with current SBD, particularly those who have made serious suicide attempts. Considering the limitations of our study, our findings support the hypothesis that decreased pituitary D2 receptor functionality (possibly adaptive to increased tuberoinfundibular DAergic neuronal activity) together with decreased hypothalamic TRH drive might be a biosignature for high-lethality violent suicide attempts. [Display omitted] • Hypothalamic dopamine and TRH function is altered in depressed patients with a history of serious suicide attempts. • Disinhibition of TIDA neurons associated with decreased TRH drive could be predictive of serious suicide attempts. • Unaltered dopamine and TRH function could reflect a protective biological process against serious suicide attempts. [ABSTRACT FROM AUTHOR]

Thyrotropin Releasing Hormone (TRH) is a tripeptide that induces the release of Thyroid Stimulating Hormone (TSH) in the blood. Besides its role in the thyroid system, TRH has been shown to regulate several neuronal systems in the brain however its role in hippocampus remains controversial. Using electrophysiological recordings in acute mouse brain slices, we show that TRH depresses glutamate responses at the CA3-CA1 synapse through an action on NMDA receptors, which, as a consequence, decreases the ability of the synapse to establish a long term potentiation (LTP). TRH also induces a late increase in AMPA/kainate responses. Together, these results suggest that TRH plays an important role in the modulation of hippocampal neuronal activities, and they contribute to a better understanding of the mechanisms by which TRH impacts synaptic function underlying emotional states, learning and memory processes. [ABSTRACT FROM AUTHOR]

Rovatirelin ([1-[-[(4 S ,5 S )-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)- l -alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity ( K i =702 nM) than taltirelin ( K i =3877 nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD. [ABSTRACT FROM AUTHOR]

We studied the basal and thyrotropin-releasing hormone (TRH) (50 nM) induced thyrotropin (TSH) release in isolated hemipituitaries of ovariectomized rats treated with near-physiological or high doses of 17-ß-estradiol benzoate (EB; sc, daily for 10 days) or with vehicle (untreated control rats, OVX). One group was sham-operated (normal control). The anterior pituitary glands were incubated in Krebs-Ringer bicarbonate medium, pH 7.4, at 37oC in an atmosphere of 95% O2/5% CO2. Medium and pituitary TSH was measured by specific RIA (NIDDK-RP-3). Ovariectomy induced a decrease (P

Highlights: [•] We critically review the WHO-UNEP 2012 report on endocrine disruptors. [•] WHO-UNEP report is not an update of the WHO-IPCS 2002 state-of-the-science review. [•] WHO-UNEP report should not guide evidence-based decisions on endocrine disruption. [•] A balanced and objective review of all available literature is needed. [•] An update must note controversies, data gaps, and provide supported conclusions. [Copyright &y& Elsevier]

Highlights: [•] Defining the circuits which employ CART as neurotransmitter. [•] Analysis of the diverse functions attributed to the neuropeptide CART. [•] Understand the role of CART in disparate neuronal circuitries. [•] CART in the brain of vertebrates and its evolutionary significance. [•] Identify the lacunae in current literature on CART and to seek future directions. [Copyright &y& Elsevier]

Abstract: Cutaneous wound healing is a dynamic, complex, and well-organized process that requires the orchestration of many different cell types and cellular processes. Transforming growth factor β1 is an important factor that plays a key role during wound healing. Amphibian skin has been proven to possess excellent wound healing ability, whilst no bioactive substrate related to it has ever been identified. Here, a potential wound healing-promoting peptide (AH90, ATAWDFGPHGLLPIRPIRIRPLCG) was identified from the frog skin of Odorrana grahami. It showed potential wound healing-promoting activity in a murine model with full thickness dermal wound. AH90 promoted release of transforming growth factor β1 through activation of nuclear factor-κB and c-Jun NH2-terminal kinase mitogen-activated protein kinases signaling pathways, while inhibitors of nuclear factor-κB and c-Jun NH2-terminal kinase inhibited the process. In addition, the effects of AH90 on Smads family proteins, key regulators in transforming growth factor β1 signaling pathways, could also be inhibited by transforming growth factor β1 antibody. Altogether, this indicated that AH90 promoted wound healing by inducing the release of transforming growth factor β1. This current study may facilitate the understanding of effective factors involved in the wound repair of amphibians and the underlying mechanisms as well. Considering its favorable traits as a small peptide that greatly promoting generation of endogenous wound healing agents (transforming growth factor β1) without mitogenic effects, AH90 might be an excellent template for the future development of novel wound-healing agents. [Copyright &y& Elsevier]

Abstract: Objective: GLUT4 protein, encoded by the Slc2a4 gene, plays a key role in muscle glucose uptake, and its expression decreases in muscles under insulin resistance. Slc2a4/GLUT4 decreases with fasting and rapidly increases with refeeding and the same occurs to plasma glucose, amino acids, insulin and T3. Thus, they might be potential regulators of the Slc2a4 gene, which makes them promising targets for strategies to improve GLUT4 expression. Herein, we investigate the role of metabolic–hormonal parameters triggered by refeeding upon the Slc2a4 expression. Materials/Methods: Plasma glucose/insulin/T3, and gastrocnemius Slc2a4 mRNA contents were measured in rats studied at the end of 48-h fasting, and subsequently at: i) 2–4h after spontaneous refeeding; ii) 2–4h after T3 injection, without refeeding; and iii) 0.5–2h after intravenous infusion of insulin, insulin+glucose and insulin+amino acids, without refeeding. Results: Refeeding increased plasma glucose/insulin/T3 and muscle Slc2a4 mRNA, reverting insulin resistance. Post-fasting infusions surprisingly induced a further Slc2a4 mRNA decrease (~20%, P <0.05 vs. fasting), but T3 injection induced a ~2-fold increase in Slc2a4 mRNA, 2–4h later (P <0.001). Moreover, T3 increased glycemia and insulinemia to the 2h-refed rats levels, suggesting that T3 elevation is a key factor to the mechanisms of metabolic balance during refeeding. Conclusions: Refeeding induces a rapid increase in muscle Slc2a4 expression, not associated with increased plasma glucose, insulin or amino acids, but highly correlated to increased plasma T3 concentration. This result points out T3 hormone as a powerful Slc2a4 enhancer, an effect that may be acutely explored in situations of insulin resistance. [Copyright &y& Elsevier]

Highlights: [•] RXRs can be active heterodimer partners in hypothalamic T3-dependent Trh repression. [•] RXRα and β subtypes display specific roles in this transcriptional regulation. [•] Gain or loss of function of RXRγ does not affect T3-dependent Trh repression. [Copyright &y& Elsevier]

Abstract: The present study was aimed at assessing the influence of noradrenergic innervation of the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the brain hypothalamus on cytochrome P450 expression in the liver. DSP-4, a neurotoxin specific to noradrenergic nerve terminals, was administrated locally into the PVN or ARC. One week after neurotoxin injection, the levels of neurotansmitters (noradrenaline/dopamine/serotonin) were measured in the middle part of the hypothalamus, hormone concentrations were estimated in blood plasma, and the activity and the protein levels of CYP isoforms were measured in the liver. A significant decrease in noradrenaline level in the hypothalamus was observed after DSP-4 injection into the PVN or ARC. The levels of dopamine or serotonin remained unchanged or slightly lowered. Simultaneously, significant changes in the plasma concentration of growth hormone were found; its elevation in PVN-lesioned rats and a drop in ARC-lesioned ones. There were no changes in the plasma concentration of the thyroid hormones or corticosterone. The activity and protein levels of isoforms CYP2C11, CYP3A and CYP2A rose in the liver of PVN-lesioned rats, but the activity and protein level of CYP2C11 fell in ARC-lesioned animals such a tendency being also observed in the case of CYP3A. Our study shows that noradrenergic innervation of the PVN and ARC of the hypothalamus exerts an opposite effect on the regulation of cytochrome P450 in the liver. These findings may be important for pharmacological experiments and pharmacotherapy with neuroactive drugs, since cytochrome P450 is responsible for the metabolism of steroids and the majority of drugs. [Copyright &y& Elsevier]

Highlights: [•] Several peptides are expressed in the PVN-RVLM neurons. [•] The large majority of PVN-RVLM neurons expressed OT and Dyn. [•] The PVN-RVLM neurons predominantly co-expressed multiple peptides. [•] Peptides were differentially distributed between subdivisions of PVN-RVLM neurons. [Copyright &y& Elsevier]

Highlights: [•] Hypo- and hyperthyroidism blunted serum LH surge and modified serum estradiol levels in the afternoon of the proestrus day. [•] Hypo- and hyperthyroidism modified NEI concentrations in discrete brain areas related to neuroendocrine control and reproduction in female rats. [•] In the PLH lower NEI concentrations were observed in the hypothyroid group during diestrus and proestrus day of the female cycle. [•] In the PeFLH NEI concentrations were lower in both treated groups in the afternoon of the proestrus day. [•] In the OVLT+AVPV NEI concentrations were higher in hypothyroidism in the afternoon of the proestrus. [ABSTRACT FROM AUTHOR]

Abstract: Inhalant misuse starts at an early age, and a large number of users are women in reproductive age. This study investigates whether exposure to toluene, a commonly misused solvent, alone or combined with restraint stress during pregnancy, produces adverse effects in pregnant mice and their offspring during lactation and adulthood. Pregnant animals were exposed to either 8000ppm toluene (30min/twice daily from gestational days 7–19), restraint stress (three times/day during the same gestation period) or both; control mice were only exposed to air. Our results show that toluene, stress and their combination reduced body weight gain in pregnant females without changing food consumption. In the offspring, all treatments resulted in low body weight at weaning, but with the toluene and stress combination this effect was seen from birth. Weight deficiency could not be attributed to poor maternal behavior during the first 3weeks of age, but to a reduction in pro-TRH mRNA expression in the hypothalamic paraventricular nucleus and serum prolactin levels in dams. After weaning, pups that were subjected to toluene and stress during gestation had lower body weight and ate less than control animals. In conclusion, the combined exposure to toluene and stress during pregnancy lead to more pronounced effects in dams and longer-lasting actions in pups than exposure to either toluene or stress. [Copyright &y& Elsevier]

Highlights: [•] Monocrotophos decreased plasma TT3 levels and TT3-to-TT4 ratios in male goldfish. [•] Decreases in plasma FT3 levels were correlated with hepatic transthyretin transcription. [•] Pituitary tshβ mRNA levels increased as a compensatory response to decreased T3. [•] Monocrotophos caused tissue-specific changes in deiodinase expression. [ABSTRACT FROM AUTHOR]

Abstract: Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin–angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin–proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to examine the effect of the brain noradrenergic system on the expression of cytochrome P450 in the liver. The experiment was carried out on male Wistar rats. Intracerebroventricular injection of the noradrenergic neurotoxin DSP-4 diminished noradrenaline level in the brain. Simultaneously, significant decreases in the serum concentration of the growth hormone, testosterone and the thyroid hormone thyroxine, as well as an increase in corticosterone level were observed. The concentrations of triiodothyronine and the cytokines interleukine 2 (IL-2) and 6 (IL-6) were not changed by DSP-4. The neurotoxin produced complex changes in the functioning of cytochrome P450. Significant decreases in the activity of liver CYP2C11 (measured as a rate of the 2α- and 16α-hydroxylation of testosterone) and CYP3A (measured as a rate of the 2β- and 6β-hydroxylation of testosterone) were found. In contrast, the activity of CYP1A (measured as a rate of caffeine metabolism) rose, while that of CYP2A (measured as a rate of the 7α-hydroxylation of testosterone), CYP2C6 (measured as a rate of the 7-hydroxylation of warfarin) and CYP2D (the 1′-hydroxylation of bufuralol) remained unchanged. The changes in the activity of CYP1A, CYP2C11 and CYP3A correlated positively with those in CYP protein levels and with the CYP mRNA levels of CYP1A1, CYP2C11 and CYP3A1/2 genes, respectively. The obtained results indicate an important role of the brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 expression, which may be of significance in pathological states involving this system, or during pharmacotherapy with drugs affecting noradrenergic transmission. [Copyright &y& Elsevier]

Highlights: [•] Food intake is reduced in type 2 diabetic Goto-Kakizaki (GK) rats. [•] Hormonal and neuronal responses to fasting and refeeding are disturbed in GK rats. [•] Brainstem TRH dysfunction results in vagal dysregulation of food intake. [Copyright &y& Elsevier]

Highlights: [•] Maternal nicotine exposure during lactation alters the expression of orexigenic and anorexigenic neuropeptides. [•] Nicotine during lactation leads to long-term leptin resistance and changes energy metabolism control. [•] Maternal nicotine exposure alters hypothalamic neuropeptides of the progeny in adulthood. [•] Maternal nicotine exposure increases NPY and melanocortin system activation (POMC and α-MSH) in adult offspring. [ABSTRACT FROM AUTHOR]

Abstract: Besides intervening in calcium homeostasis by means of calcitonin, C cells are also implicated in the synthesis of an increasing number of regulatory peptides that could exert a paracrine regulation on the neighbouring follicular cells. Among the latest peptides reported in C cells, there are several characteristic hypothalamic peptides, such as TRH, CART, and ghrelin, which are mainly involved in the regulation of the metabolism at hypothalamic-pituitary-thyroid axis. The main aim of the present work has been to study the synthesis of the referred hypothalamic peptides by normal and neoplastic C cells of different mammals as well as in C-cell lines of both rat (CA-77, 6-23) and human (TT) origins in order to elucidate whether this is a fact in this kind of vertebrates. With that objective, we have applied the immunoperoxidase technique to analyze the presence of TRH, CART, ghrelin, and somatostatin in thyroid tissues of different species, and immunofluorescence to study those same peptides in C-cell cultures. Furthermore, we have investigated their expression at mRNA level by RT-PCR analysis. Our results demonstrate immunocolocalization of CART, ghrelin, somatostatin and TRH with calcitonin in normal C cells of different mammals, as well as in rat and human neoplastic C cells. We also confirm the expression of those peptides in rat and human C-cell lines by RT-PCR. Consequently, we can conclude that the synthesis of those peptides by C cells is a general event characteristic of the thyroid gland in mammals. [Copyright &y& Elsevier]

Abstract: In this study the sialorphin (Gln-His-Asn-Pro-Arg) and its analog (Glp-His-Asn-Pro-Arg) were analyzed in terms of metal binding ability. Both peptides were synthesized using the solid-phase method. The application of number analytical methods: potentiometry, spectroscopy (UV–Vis, CD, NMR) and mass spectrometry allowed for a detailed characterization of the coordination abilities of presented peptides. The analysis of the obtained results has shown that both peptides are able to form a series of complexes. However due to the presence of free N-terminal amino group the sialorphin is more effective in metal ion binding. Nevertheless, in basic conditions both peptides involve the amide nitrogen belonging to the side chain of Asn3 moiety and form 4N complex with square planar structure. This unusual ability has been confirmed by the results obtained from the NMR studies. [Copyright &y& Elsevier]

Acutely ill patients typically present with low circulating T3 and increased reverse T3. When illness is severe and prolonged, also pulsatile TSH secretion and circulating T4 levels are low. This constellation of changes within the thyroid axis is referred to as the low T3 syndrome or non-thyroidal illness syndrome (NTI), and comprises both peripheral and central alterations in the thyroid axis. Acute alterations are dominated by changes in thyroid hormone binding, in thyroid hormone uptake by the cell and in the activity of the type-1 and type-3 deiodinase enzymes. Prolonged critical illness is associated with a neuroendocrine dysfunction characterized by suppressed hypothalamic thyrotropin-releasing hormone (TRH) expression, resulting in reduced stimulation of the thyrotropes whereby thyroidal hormone release is impaired. During prolonged critical illness, several tissue responses could be interpreted as compensatory to low thyroid hormone availability, such as increased expression of monocarboxylate transporters, upregulation of type 2 deiodinase activity and increased sensitivity at the receptor level. Whether the low T3 syndrome should be treated and which compound should be used remains to be further studied. [Copyright &y& Elsevier]

Abstract: Objective: To explore pathological mechanisms of central hyponatremia and its treatment. Methods: Synchronous assay was made for changes of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), endogenous digitalis-like substance (EDLS), antidiuretic hormone (ADH) in blood, and Na+ concentrations in blood and urine, and plasma- and urine-osmolality in 68 patients with acute craniocerebral injury (ACI). Results: Of the 68 patients with ACI, 27 were found to have hyponatremia, and such illness was mostly concentrated on severe cases. Conclusions: The central hyponatremia in patients with ACI may be related to the increase in the secretion of EDLS and ADH as the result of damaged functions of the hypothalamic-hypophysial system, and it seems that the decrease in blood ANP and BNP has no direct effect on Na+ concentrations in blood. Inappropriate secretion of antidiuretic hormone syndrome and cerebral salt-wasting syndrome are the two main reasons for hyponatremia in patients with craniocerebral injury. The pathological mechanism, diagnostic standards, as well as treatment methods for the two, however, are not just the same. Intravenous injection of extrinsic thyrotropin-releasing hormone might inhibit dilutional hyponatremia arising from the increase in ADH secretion by patients with ACI. [ABSTRACT FROM AUTHOR]

Abstract: The hypothalamus integrates metabolic and endocrine signals. As such it represents a potential target for a wide spectrum of endocrine disrupting chemicals (EDCs). We investigated hypothalamic effects of two environmentally abundant xenobiotics, the flame-retardant tetrabromo bisphenol A (TBBPA) and the anti-fouling agent tributyltin (TBT). These EDCs affect endocrine signalling through different nuclear receptors including the thyroid hormone receptor (TR) or its partner, the retinoid X receptor (RXR). Promoter sequences of two hypothalamic genes implicated in metabolic control and regulated by thyroid hormone, thyrotropin-releasing hormone (Trh) and type 4 melanocortin receptor (Mc4r), were studied in vivo using reporter assays. Chronic exposure of gestating dams or acute exposure of their newborns to TBBPA abrogated activation of both Trh and Mc4r transcription. Exposure of lactating dams to TBT amplified activation of Trh without affecting Mc4r transcription. Thus, perinatal exposure to EDCs affecting nuclear receptor signalling modulates hypothalamic set-points controlling metabolic responses. [Copyright &y& Elsevier]

Abstract: Thyroid hormone receptor (TR) and peroxisome proliferator-activated receptor γ (PPARγ) co-regulate numerous peripheral metabolic responses. To examine potential crosstalk between PPARγ and TRβ in the hypothalamus, thyrotropin-releasing hormone (Trh) regulation in the newborn mouse hypothalamus was followed. QPCR showed PPARγ to be expressed in the hypothalamus at this developmental stage. Intracerebral injection of PPARγ agonists modified transcription from a TRH-luc construct introduced into the hypothalamus and increased serum thyroxine levels. Furthermore, shRNA-based in vivo PPARγ knockdown amplified T3-independent transcription and PPARγ overexpression dose-dependently abrogated T3-dependent Trh repression. Overexpression of retinoid X receptor-α (RXRα), the common heterodimeric partner of PPARγ and TRβ, rescued PPARγ abrogation of T3-dependent repression. Thus, competition for RXR could represent one mechanism underlying this hypothalamic crosstalk between PPARγ and TRβ. These demonstrations of PPARγ effects on hypothalamic Trh transcription in vivo consolidate the role of the TRH neuron as a central integrator of energy homeostasis. [Copyright &y& Elsevier]

Thyrotropin-releasing hormone (TRH) was initially discovered as a neuropeptide synthesized in the hypothalamus. Receptors for this hormone include TRH-receptor-1 (TRH-R1) and -2 (TRH-R2). Previous studies have shown that TRH-R1 and TRH-R2 are localized exclusively in adult Leydig cells (ALCs). We have investigated TRH-R1 and TRH-R2 expression in the testes of postnatal 8-, 14-, 21- 35-, 60-, and 90-day-old rats and in ethane dimethane sulfonate (EDS)-treated adult rats by using Western blotting, immunohistochemistry, and immunofluorescence. The effects of TRH on testosterone secretion of primary cultured ALCs from 90-day-old rats and DNA synthesis in Leydig cells from 21-day-old rats have also been examined. Western blotting and immunohistochemistry demonstrated that TRH-R1 and TRH-R2 were expressed in fetal Leydig cells (in 8-day-old rats) and in all stages of adult-type Leydig cells during development. Immunofluorescence double-staining revealed that newly regenerated Leydig cells in post-EDS 21-day rats expressed TRH-R1 and TRH-R2 on their first reappearance. Incubation with various doses of TRH affected testosterone secretion of primary cultured ALCs. Low concentrations of TRH (0.001, 0.01, and 0.1 ng/ml) inhibited basal and human chorionic gonadotrophin (hCG)-stimulated testosterone secretion of isolated ALCs, whereas relatively high doses of TRH (1 and 10 ng/ml) increased hCG-stimulated testosterone secretion. As detected by a 5-bromo-2′-deoxyuridine incorporation test, the DNA synthesis of Leydig cells from 21-day-old rats was promoted by low TRH concentrations. Thus, we have clarified the effect of TRH on testicular function: TRH might regulate the development of Leydig cells before maturation and the secretion of testosterone after maturation. [ABSTRACT FROM AUTHOR]

Abstract: Hyperglycemia in thyrotropin-releasing hormone (TRH) null mice indicates that TRH is involved in the regulation of glucose homeostasis. Further, TRH levels in the pancreas peak during the stages of late embryonic and early neonatal β cell development. These observations are consistent in linking TRH to islet cell proliferation and differentiation. In this study, we examined the effect of TRH administration in damaged pancreatic rat (streptozotocin, STZ) to determine whether TRH could improve damaged pancreatic β cells function. We hypothesize that TRH is able to reverse STZ-induced hyperglycemia by increasing pancreatic islet insulin content, preventing apoptosis, and potentially induce islet regeneration. It was found that following intra-peritoneal (ip) injection, TRH (10μg/kg body weight (bwt)) reverses STZ (65mg/kg bwt)-induced hyperglycemia (TRH given 3 days after STZ injection). Increased circulating insulin levels and insulin content in extracted pancreas suggests that TRH reversed STZ-induced hyperglycemia through improving pancreatic islet β cell function. Further studies show a significantly lower level of apoptosis in islets treated with TRH as well as the presence of proliferation marker nestin and Brdu, suggesting that the TRH has the potential to prevent apoptosis and stimulate islet proliferation. [Copyright &y& Elsevier]

Abstract: Although crucial for TH homeostasis, the molecular mechanisms responsible of thyroid hormone receptors (TRs)-mediated regulation of the hypothalamic–pituitary–thyroid axis (HPT) axis remain unclear. We examined the role played by TR-isoforms in combination with RanBPM, a novel coactivator of TRs. In transient transfections studies with the human TRH and TSH-α subunit promoters, we found that the overexpression of RanBPM increases the transcriptional activity of all TR-isoforms by a magnitude of 1.7- to 3-fold. The addition of RanBPM, in the absence of THs, increased the ligand-independent activation (LIA) of TRα1 and TRβ1 on both promoters tested by 300% and 200%, respectively, whereas, the LIA of TRβ2 was not significantly modified. This data reinforces the concept of isoform-specific regulation of genes of the HPT axis and demonstrates that RanBPM may be an important factor to achieve adequate regulation of nTREs in the presence of low TH levels. [Copyright &y& Elsevier]

Abstract: Thyroid-stimulating hormone (TSH) stimulates the synthesis and release of thyroid hormones including triiodothyronine (T3) and thyroxine (T4). Semiquantitative analyses using northern blot and in situ hybridization suggested that TSH gene transcription is upregulated under conditions of hypothyroidism. However, no quantitative analysis of TSH gene expression using real-time polymerase chain reaction (PCR) has been reported. In this study, we quantitated the TSHβ messenger ribonucleic acid (mRNA) level as well as the TSHβ heterogeneous nuclear ribonucleic acid (hnRNA) level in the anterior pituitary of hypothyroid rats, by real-time PCR using the LightCycler® system. The hnRNA is the primary deoxyribonucleic acid (DNA) transcript, which reflects the transcription rate more reliably than the mRNA because of its short half-life. In the anterior pituitary of rats with methimazol-induced chronic hypothyroidism, both mRNA and hnRNA expression of TSHβ were upregulated fourfold relative to normal rats (n =4). Our method provides a rapid and accurate measure of gene transcription. In the present report, we described a technique for accurate measurement of TSHβ hnRNA level. [Copyright &y& Elsevier]

Abstract: Hypophysiotropic thyrotropin-releasing hormone (TRH): synthesizing neurons reside in the hypothalamic paraventricular nucleus (PVN) and are the central regulators of the hypothalamic-pituitary-thyroid (HPT) axis. TRH synthesis and release from these neurons are primarily under negative feedback regulation by thyroid hormone. Under certain conditions such as cold exposure and fasting, however, inputs from neurons in the brainstem and hypothalamic arcuate and dorsomedial nuclei alter the set point for negative feedback through regulation of CREB phosphorylation. Thus, during cold exposure, adrenergic neurons stimulate the HPT axis, while fasting-induced central hypothyroidism is mediated through an arcuato-paraventricular pathway. Feedback regulation of TRH neurons may also be modified by local tissue levels of thyroid hormone regulated by the activation of type 2 iodothyronine deiodinase (D2), the primary enzyme in the brain that catalyzes T4 to T3 conversion. During infection, endotoxin or endotoxin induced cytokines increase D2 activity in the mediobasal hypothalamus, which by inducing local hyperthyroidism, may play an important role in infection-induced inhibition of hypophysiotropic TRH neurons. [Copyright &y& Elsevier]

This article reviews current rodent screens and tests to detect thyroid toxicants. Many points of disruption for thyroid toxicants are outlined and include: (a) changes in serum hormone level; (b) thyroperoxidase inhibitors; (c) the perchlorate discharge test; (d) inhibitors of iodide uptake; (e) effects on iodothyronine deiodinases; (f) effects on thyroid hormone action; and (g) role of binding proteins (e.g., rodent transthyretin). The major thyroid endpoints currently utilized in existing in vivo assay protocols of the Organization for Economic Cooperation and Development (OECD), Japanese researchers, and U.S. Environmental Protection Agency (EPA) include thyroid gland weight, histopathology, circulating thyroid hormone measurements, and circulating thyroid-stimulating hormone (TSH). These endpoints can be added into the existing in vivo assays for reproduction, development, and neurodevelopment that are outlined in this chapter. Strategic endpoints for possible addition to existing protocols to detect effects on developmental and adult thyroid endpoints are discussed. Many of these endpoints for detecting thyroid system disruption require development and additional research before they can be considered in existing assays. Examples of these endpoints under development include computer-assisted morphometry of the brain and evaluation of treatment-related changes in gene expression, thyrotropin-releasing hormone (TRH) and TSH challenge tests, and tests to evaluate thyroid hormone (TH)-dependent developmental events, especially in the rodent brain (e.g., measures of cerebellar and cortical proliferation, differentiation, migration, apoptosis, planimetric measures and gene expression, and oligodendrocyte differentiation). Finally, TH-responsive genes and proteins as well as enzyme activities are being explored. Existing in vitro tests are also reviewed, for example, thyroid hormone (TH) metabolism, receptor binding, and receptor activation assays, and their restrictions are described. The in vivo assays are currently the most appropriate for understanding the potential effects of a thyroid toxicant on the thyroid system. The benefits and potential limitations of the current in vivo assays are listed, and a discussion of the rodent thyroid system in the context of human health is touched upon. Finally, the importance of understanding the relationship between timing of exposure, duration of dose, and time of acquisition of the endpoints in interpreting the results of the in vivo assays is emphasized. [ABSTRACT FROM AUTHOR]

Abstract: Cocaine- and amphetamine regulated transcript (CART) is a recently discovered anorexigenic peptide, widely expressed in the central nervous system. Included among presumed hypothalamic mediated functions of CART are inhibition of food intake, stimulation of energy expenditure and regulation of hypothalamic–pituitary axes. CART-immunoreactive (IR) axons densely innervate the majority of hypophysiotropic thyrotropin-releasing hormone-(TRH) containing neurons in the hypothalamic paraventricular nucleus (PVN) and establish asymmetric synaptic specializations with the TRH neurons. The CART-IR innervation of TRH neurons originates from at least two major sources: CART neurons in the arcuate nucleus that co-express the anorexigenic peptide, alpha-melanocyte-stimulating hormone (α-MSH), and adrenergic CART neurons in the medulla. Based on the origins of the CART innervation and potent stimulatory effects of CART on TRH gene expression of hypophysiotropic neurons, CART is suggested to be involved in the regulation of the hypothalamic–pituitary–thyroid (HPT) axis by different physiological stimuli. This regulatory control may contribute to the effects of fasting and cold exposure to reset the set point for feedback regulation of hypophysiotropic TRH gene expression and hence, affect circulating thyroid hormone levels. In addition, CART is present in the majority of hypophysiotropic TRH neurons and in TRH-containing axon terminals adjacent to the capillary vessels in the median eminence. While CART, alone, has no effect on the TSH and prolactin secretion from anterior pituitary cells, CART inhibits the stimulatory effect of TRH on prolactin secretion, but has no effect on TRH-induced increase of TSH release. Co-secretion of CART with TRH into the portal pituitary circulation, therefore, may have an important modulatory influence on the effect of TRH on pituitary hormone secretion. [Copyright &y& Elsevier]