Tph2 deficiency leads to alterations in social adjustment and socio-affective communication in neonatal rats: No rescue effect of communal nesting.

Deficiency of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme for serotonin (5-hydroxytryptamine, 5-HT) synthesis in the brain, was repeatedly reported to cause impairments in socio-affective communication and maternal affiliation across species, including mice, rats, and monkeys. We recently applied a rescue protocol in the Tph2 knockout rat model and demonstrated that communal nesting ameliorates maternal affiliation impairments. Interestingly, however, this rescue strategy did not lead to improvements in socio-affective communication and was associated with an aggravated growth retardation phenotype in Tph2-deficient offspring.

Guidance on minimum information requirements (MIR) from designing to reporting human biomonitoring (HBM).

Human biomonitoring (HBM) provides an integrated chemical exposures assessment considering all routes and sources of exposure. The accurate interpretation and comparability of biomarkers of exposure and effect depend on harmonized, quality-assured sampling, processing, and analysis. Currently, the lack of broadly accepted guidance on minimum information required for collecting and reporting HBM data, hinders comparability between studies.

Tryptophan hydroxylase 2 deficiency alters autism-related behavioural phenotypes in rats.

Serotonin is a crucial neurotransmitter implicated in various physiological processes. Dysregulation of the serotonergic system, particularly in early life, may be associated with neuropsychiatric disorders, including autism spectrum disorder. This study utilises a rat model lacking the central serotonin-synthesising enzyme tryptophan hydroxylase 2 (TPH2) to investigate the effects of brain serotonin depletion on core autism-related behaviours.

Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice.

Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer's disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and KPNA4 (also named importin alpha3) could be associated with the development of motor neuron diseases, a condition specifically affecting the neurons projecting from brain to spinal cord or from spinal cord to the muscles. Here we set out to analyze the neuronal function of mice deficient in KPNA3 (-KO) or KPNA4 (-KO).

Selectivity and Safety Characterization of a Xanthine-Imidazothiazole Lead Structure: a Novel Tryptophan Hydroxylase Inhibitor of Peripheral Serotonin Synthesis.

Serotonin (5-HT), a crucial neurotransmitter and peripheral mediator, regulates various physiological processes and is synthesized by tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme responsible for its production. 5-HT overproduction is implicated in multiple diseases, making TPH1 a promising therapeutic target. However, selectivity remains a challenge due to the structural similarity of TPH1 with other members of the aromatic amino acid hydroxylase (AAAH) family, including TPH2, phenylalanine hydroxylase (PAH), and tyrosine hydroxylase (TH).

Built Environment Change over Time Using Google Street View Assessments of Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Cities.

Google Street View's historical imagery is a promising data source for measuring neighborhood conditions over time. However, images are not available for all years. To assess bias that may arise due to a mismatch between the year imagery is available and the year of researcher interest, we assessed prevalence of change in 20 commonly assessed built environment features between the oldest and newest available high-quality images (median difference 10.

ACE2/Angiotensin-(1-7)/Mas and the brain.

It is well known that the renin-angiotensin system (RAS) plays a key role in regulating blood pressure and hydroelectrolyte balance. In addition to angiotensin (Ang) II, Ang-(1-7) has emerged as an important component of this system. Here we review evidence regarding the presence and actions of ACE2/Ang-(1-7)/Mas receptor pathway within the central nervous system, where the RAS possesses a crucial role in controlling cardiovascular, metabolic and stress-coping behavior functions.

16/8 intermittent fasting in mice protects from diet-induced obesity by increasing leptin sensitivity and postprandial thermogenesis.

Aims: To evaluate the molecular mechanisms involved in intermittent fasting 16/8 (16/8 IF), a widespread dietary practice adopted worldwide that consists of 16 h of fasting and 8 h of feeding.

Methods: Obese mice were fasted daily from 6 am to 10 pm. Food intake, body weight, and energy expenditure were measured.

Central Serotonin Deficiency Impairs Recovery of Sensorimotor Abilities After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) affects millions of people worldwide. One of the main challenges of rehabilitation strategies is re-training and enhancing the plasticity of the spinal circuitry that was preserved or rebuilt after the injury. The serotonergic system appears to be crucial in these processes, since recent studies have reported the capability of serotonergic (5-HT) axons for axonal sprouting and regeneration in response to central nervous system (CNS) trauma or neurodegeneration.

The anti-atherosclerotic effect of chronic AT1 receptor blocker treatment also depends on the ACE2/Ang(1-7)/Mas axis.

Blockade of AT-receptors by telmisartan (TEL) has anti-atherosclerotic efficacy. We investigated to what extent the ACE2/Ang1-7/Mas axis-dependent mechanism contributes to the TEL-induced protection of endothelial function. Atherosclerosis was induced in C57BL/6 N, Mas-knock out (ko), and Ace2-ko mice by AAV-PCSK9 (2 ×10 VG) injections plus Western diet (WD) feeding (12w).

Diminazene Aceturate (DIZE) Ameliorates Hypertension and Induces Anxiolytic- and Antidepressant-like Effects in TGR(mRen2)27.

Introduction: Diminazene aceturate (DIZE) was described as an angiotensin-converting enzyme 2 (ACE2) activator. ACE2/Angiotensin-(1-7)/Mas receptor axis presents protective actions on cardiovascular diseases and plays an important modulatory role in the neurobiology of mood and anxiety disorders.

Objectives: To evaluate the effects of chronic intracerebroventricular (ICV) treatment with DIZE on blood pressure, anxiety- and depression-like behaviors in hypertensive transgenic (mRen2)27 rats (TGR).

Bradykinin B1 receptor signaling triggers complement activation on endothelial cells.

Introduction: The complement and kallikrein-kinin systems (KKS) are both activated during vascular inflammation, and there are many known interactions between the two systems. This study investigated if KKS activation induced complement activation on endothelial cells, and if activation was dependent on bradykinin B1 receptor (B1R) signaling.

Methods: KKS was activated in normal human serum by kaolin or activated factor XII (FXIIa).

Acute Optogenetic Stimulation of Serotonin Neurons Reduces Cell Proliferation in the Dentate Gyrus of Mice.

The dentate gyrus of the hippocampus is targeted by axons from serotonin raphe neurons, where the neurotransmitter modulates adult neurogenesis and antidepressant action, and mediates the neurogenic effect of running. Whether running-induced cell proliferation is directly mediated by serotonin remains unknown. Here, we took advantage of Tph2-ChR2-YFP transgenic mice in which the light-sensitive protein channelrhodopsin-2 (ChR2) is specifically expressed in tryptophan hydroxylase 2 (TPH2)-expressing neurons.

Inhalation of the Novel Tryptophan Hydroxylase 1 Inhibitor TPT-004 Alleviates Pulmonary Arterial Hypertension.

Inhaled pharmacotherapies are promising treatment options for patients with pulmonary arterial hypertension (PAH), as they minimize extrapulmonary adverse effects. Recently, we developed a highly specific tryptophan hydroxylase 1 inhibitor (TPHi): TPT-004. We hypothesized that repetitive nose-only inhalation of TPT-004 alleviates PAH and pulmonary vascular remodeling in the Sugen 5416/hypoxia (SuHx) rat model.

Renal damage-induced hepcidin accumulation contributes to anemia in angiotensinogen-deficient mice.

Angiotensin II (Ang II) is the most active peptide hormone produced by the renin-angiotensin system (RAS). Genetic deletion of genes that ultimately restrict Ang II formation has been shown to result in marked anemia in mice. In this study, adult mice with a genetic deletion of the RAS precursor protein angiotensinogen (Agt-KO) were used.

Trace amine-associated receptor 1 agonist reduces aggression in brain serotonin-deficient tryptophan hydroxylase 2 knockout rats.

Introduction: Aggression and self-harm disproportionately occur in youths preoccupied with social status tracking. These pathological conditions are linked to a serotonin (5-HT) deficit in the brain. Ablation of 5-HT biosynthesis by tryptophan hydroxylase 2 knockout (TPH2-KO) increases aggression in rodents.

Dermal penetration of 2-phenoxyethanol in humans: in vivo metabolism and toxicokinetics.

2-Phenoxyethanol (PhE) is an amphiphilic organic compound frequently used as a broad-spectrum preservative in cosmetic products and other consumer goods. PhE is also used as a biocidal component in occupational settings. A previous volunteer study by our working group following oral exposure to PhE showed that PhE is almost completely taken up into the human body followed by an extensive metabolization and fast urinary elimination.

Hyperphenylalaninemia and serotonin deficiency in Dnajc12-deficient mice.

Serotonin exerts numerous neurological and physiological actions in the brain and in the periphery. It is generated by two different tryptophan hydroxylase enzymes, TPH1 and TPH2, in the periphery and in the brain, respectively, which are members of the aromatic amino acid hydroxylase (AAAH) family together with phenylalanine hydroxylase (PAH), degrading phenylalanine, and tyrosine hydroxylase (TH), generating dopamine. In this study, we show that the co-chaperone DNAJC12 is downregulated in serotonergic neurons in the brain of mice lacking TPH2 and thereby central serotonin.

Introducing the OECD guidance document on occupational biomonitoring: A harmonized methodology for deriving occupational biomonitoring levels (OBL).

Derivation of occupational biomonitoring levels (OBLs) is needed to effectively utilize biomonitoring for assessing exposures to chemical substances, and consequently, implement risk reduction measures to reduce health risks among workers. OBLs are the appropriate option for chemical substances that can be absorbed through the skin. This methodology for derivation of OBLs has been developed in collaboration with scientific and regulatory experts from more than 40 institutes in 15 countries within the Organization for Economic Cooperation and Development (OECD) framework.

Socio-affective communication in Tph2-deficient rat pups: communal nesting aggravates growth retardation despite ameliorating maternal affiliation deficits.

Background: A lack of serotonin (also known as 5-hydroxytryptamine, 5-HT) in the brain due to deficiency of the rate-limiting enzyme in 5-HT synthesis, tryptophan hydroxylase 2 (TPH2), was recently reported to result in impaired maternal affiliation across species, including mice, rats, and monkeys. In rodents, this was reflected in a lack of preference for maternal odors and reduced levels of isolation-induced ultrasonic vocalizations (USV), possibly contributing to a severe growth retardation phenotype.

Methods: Here, we tested whether growth retardation, maternal affiliation deficits, and/or impairments in socio-affective communication caused by Tph2 deficiency can be rescued through early social enrichment in rats.

Transgenic rat with ubiquitous expression of angiotensin-(1-7)-producing fusion protein: a new tool to study the role of protective arm of the renin-angiotensin system in the pathophysiology of cardio-renal diseases.

The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e.