Adrenergic Signaling Pathways Research Articles

Exploring the potential pharmacological mechanism of aripiprazole against hyperprolactinemia based on network pharmacology and molecular docking

The current primary therapeutic approach for schizophrenia is antipsychotic medication, and antipsychotic-induced hyperprolactinemia occurs in 40–80% of patients with schizophrenia. Aripiprazole, an atypical antipsychotic belonging to the quinolinone derivative class, can reduce the likelihood of developing hyperprolactinemia, but the pharmacological mechanisms of this reduction are unknown. This study aimed to explore the molecular mechanism of action of aripiprazole in treating hyperprolactinemia based on network pharmacology and molecular docking techniques. This study identified a total of 151 potential targets for aripiprazole from the DrugBank, TCMSP, BATMAN-TCM, TargetNet, and SwissTargetPrediction databases. Additionally, 71 hyperprolactinemia targets were obtained from the PharmGKB, DrugBank, TTD, GeneCards, OMIM, and DisGENET databases. Utilizing Venny 2.1.0 software, an intersection of 27 genes was identified between aripiprazole and hyperprolactinemia. To construct a common target protein–protein interaction (PPI) network, the common targets obtained from both sources were input into the STRING database. The resulting PPI network was then imported into Cytoscape 3.7.2 software, which identified eight core targets associated with aripiprazole’s treatment of hyperprolactinemia. Subsequently, a PPI network was established for these targets. Enrichment analysis of the key targets was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes in the DAVID database. Additionally, molecular docking verification of the interaction between aripiprazole and the core targets was performed using AutoDock Vina software. Aripiprazole’s intervention in hyperprolactinemia primarily targets the following core proteins: Solute Carrier Family 6 Member 3 (SLC6A3), monoamine oxidase (MAO-B), Dopamine D2 receptor (DRD2), 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A), 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C), cytochrome P450 2D6 (CYP2D6), Dopamine D1 receptor (DRD1), Dopamine D4 receptor (DRD4). These targets are predominantly involved in biological processes such as the adenylate cyclase-activating adrenergic receptor signaling pathway, G-protein coupled receptor signaling pathway coupled to cyclic nucleotide second messenger, phospholipase C-activating G-protein coupled receptor signaling pathway, chemical synaptic transmission, and response to xenobiotic stimulus. Primary enrichment occurs in signaling pathways such as the neuroactive ligand-receptor interaction and serotonergic synapse pathways. Molecular docking results demonstrate a favorable affinity between aripiprazole and the core target proteins MAO-B, DRD2, SLC6A3, HTR2C, HTR2A, CYP2D6, DRD4, and DRD1. Network pharmacology predicted potential targets and signaling pathways for aripiprazole’s intervention in hyperprolactinemia, offering theoretical support and a reference basis for optimizing clinical strategies and drug development involving aripiprazole.

The Role of TPM3 in Protecting Cardiomyocyte from Hypoxia-Induced Injury via Cytoskeleton Stabilization.

Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl2) to simulate low-oxygen conditions. We found that CoCl2 treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein-protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies.

Patulin alters alpha-adrenergic receptor signalling and induces epigenetic modifications in the kidneys of C57BL/6 mice

Patulin (PAT) is a food-borne mycotoxin produced by Penicillium and Byssochlamys species. It is widely known for its mutagenic, carcinogenic, and genotoxic effects and has been associated with kidney injury; however, the mechanism of toxicity remains unclear. To address this gap, we conducted a study to explore the changes in α-adrenergic receptor signalling pathways and epigenetic modifications induced by PAT in the kidneys of C57BL/6 mice during acute (1 day) and prolonged (10 days) exposure. The mice (20–22 g) were orally administered PAT (2.5 mg/kg; at 1 and 10 days), and post-treatment, the kidneys were harvested, homogenised and extracted for RNA, DNA, and protein. The relative gene expression of the α-adrenergic receptors (ADRA1, ADRA2A, ADRA2B) and associated signalling pathways (MAPK, MAPK14, ERK, PI3K, and AKT) was assessed by qPCR. The protein expression of ERK1/2 and MAPK was determined by western blot. The impact of PAT on DNA methylation was evaluated by quantifying global DNA methylation; qPCR was used to determine gene expression levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) and demethylase (MBD2). PAT downregulated the expression of ADRA1, ADRA2A, ADRA2B, PI3K, and AKT and upregulated ERK1/2 and MAPK protein expression. Furthermore, PAT induced alterations in DNA methylation patterns by upregulating DNMT1 and MBD2 expressions and downregulating DNMT3A and DNMT3B expressions, resulting in global DNA hypomethylation. In conclusion, PAT disrupts α-1 and α-2 adrenergic receptor signalling pathways and induces epigenetic modifications, that can lead to kidney injury.

Adrenoreceptor phylogeny and novel functions of nitric oxide in ascidian immune cells

Nitric oxide (NO) is a simple molecule involved in many biological processes and functions in the cardiovascular, neural, and immune systems. In recent years, NO has also been recognized as a crucial messenger in communication between the nervous and immune systems. Together with NO, catecholamines are the main group of neurotransmitters involved in cross-talk between the nervous and immune systems. Catecholamines such as noradrenaline, can act on immune cells through adrenoreceptors (ARs) present on the cell surface, and NO can cross the cell membrane and interact with secondary messengers, modulating catecholamine production. Here, we analyzed the mutual modulation by noradrenaline and NO in Phallusia nigra immune cells for specific subtypes of ARs. We also investigated the involvement of protein kinases A and C as secondary messengers to these specific subtypes of ARs in the adrenergic signaling pathway that culminates in NO modulation, and the phylogenetic distribution of ARs in deuterostome genomes. This analysis provided evidence for single-copy orthologs of α1, α2 and β-AR in ascidian genomes, suggesting that NO and NA act on a less diverse set of ARs in urochordates. Pharmacological assays showed that high levels of NO can induce ascidian immune cells to produce catecholamines. We also observed that protein kinases A and C are the secondary messengers involved in downstream modulation of NO production through an ancestral β-AR. Taken together, these results provide new information on NO as a modulator of immune cells, and reveal the molecules involved in the signaling pathway of ARs. The results also indicate that ARs may participate in NO modulation. Finally, our results suggest that the common ancestor of urochordates possessed a less complex system of ARs required for immune action and diverse pharmacological responses, since the α-ARs are phylogenetically more related to D1-receptors than are the β-ARs.

Abstract 19018: Unraveling the Regulatory Landscape of NKX2-5 in Human Left Atrial Tissue: Implications for Atrial Fibrillation

Cardiac transcription factors are emerging as crucial modulators of atrial fibrillation (AF), with rare and common variation implicated in AF. Mutations in NKX2-5 and more recently, NFATC1 were reported in families with autosomal dominant young-onset AF. Here, we explore the landscape of NKX2-5 and NFATC1 in human left atrium, using Chromatin Immunoprecipitation Sequencing (ChIP-seq), DAVID functional annotation and HOMER motif analyses. Post-mortem human left atrial tissue samples (n=5) were obtained from the National Disease Research Interchange (NDRI) within a recovery interval of < 4 hours. Preserved microstructural integrity and normal staining patters for TNNT2 and vimentin were verified using confocal microscopy. ChIP-seq analysis revealed an average of 2.62k NKX2-5 binding peaks, with 118 genes bound in all samples. Functional analysis identified significant enrichment in gene ontology categories and pathways (Table 1), including adrenergic and PPAR signaling pathways known to participate in AF susceptibility. Using HOMER, we mapped 55 NFATC1 consensus binding sites to the NKX2-5 ChIP peaks. Two NFATC1 consensus sites localized to an NKX2-5 binding peak located upstream from MEF2A (Figure 1). Published HI-C data from human right atrium indicates the NFATC1 binding sites are adjacent to the promoter of MEF2A in 3D space, suggesting that NKX2-5 and NFATC1 co-regulate MEF2A. In murine atria, mef2A regulates genes involved in fibrosis and adhesion, processes that are crucial in the pathogenesis of atrial fibrillation. Our data, together with published literature, provide a framework for understanding transcriptional networks that may predispose to human AF.

Expression profiles and functional analysis of tRNA-derived small RNAs in epicardial adipose tissue of patients with heart failure

Background Heart failure is considered an epidemic disease in the modern world. Since it presents as a multifactorial, systemic disease, a comprehensive understanding of the underlying mechanism is essential. Epicardial adipose tissue (EAT) is increasingly recognized to be metabolically active and is able to secrete myriad bioactive molecules, including exosomes carrying tRNA-derived small RNAs (tsRNAs). Mounting evidence has suggested that these specific tsRNAs dynamically impact fundamental cellular processes, but no studies have focused on the influence of tsRNA in EAT on cardiac dysfunction. Methods To investigate the regulatory mechanism of tsRNAs of EAT associated with HF, we collected EAT from HF (n = 5) patients and controls (n = 5) and used a combination of RNA sequencing, quantitative reverse transcription-polymerase chain reaction (qRT–PCR) and bioinformatics to screen the expression profiles of tsRNAs in HF. Results We ultimately identified an expression profile of 343 tsRNAs in EAT. Of those, a total of 24 tsRNAs were significantly differentially expressed between HF and controls: 17 were upregulated and 7 were downregulated (fold change >1.5, p < 0.05). Four tsRNAs (tiRNA-Pro-TGG-001, tRF-Met-CAT-002, tRF-Tyr-GTA-010 and tRF-Tyr-GTA-011) were randomly selected and validated by qRT–PCR. Bioinformatics analyses revealed a dense interaction of target genes between tRF-Tyr-GTA-010 and tRF-Tyr-GTA-011. Based on functional analysis, these two tRFs might play a protective role by regulating sphingolipid and adrenergic signaling pathways by targeting genes mainly contributing to calcium ion transport. Conclusions Our study profiled tsRNA expression in EAT with HF and identified a comprehensive dimension of potential target genes and tsRNA-mRNA interactions.

Transcriptome-wide analysis of trigeminal ganglion and subnucleus caudalis in a mouse model of chronic constriction injury-induced trigeminal neuralgia.

Trigeminal neuropathic pain (TNP) induces mechanical allodynia and hyperalgesia, which are known to alter gene expression in injured dorsal root ganglia primary sensory neurons. Non-coding RNAs (ncRNAs) have been linked to TNP. However, the functional mechanism underlying TNP and the expression profile of ncRNAs in the trigeminal ganglion (TG) and trigeminal subnucleus caudalis (Sp5C) are still unknown. We used RNA sequencing and bioinformatics analysis to examine the TG and Sp5C transcriptomes after infraorbital nerve chronic constrictive injury (IoN-CCI). The robust changes in the gene expression of lncRNAs, circRNAs, and mRNAs were observed within the TG and Sp5C from mice that underwent IoN-CCI and the sham-operated mice (day 7). In total, 111,003 lncRNAs were found in TG and 107,157 in Sp5C; 369 lncRNAs were differentially expressed in TG, and 279 lncRNAs were differentially expressed in Sp5C. In addition, 13,216 circRNAs in TG and 21,658 circRNAs in Sp5C were identified, with 1,155 circRNAs and 2,097 circRNAs differentially expressed in TG and Sp5C, respectively. Furthermore, 5,205 DE mRNAs in TG and 3,934 DE mRNAs in Sp5C were differentially expressed between IoN-CCI and sham groups. The study revealed a high correlation of pain-related differentially expressed genes in the TG and Sp5C to anxiety, depression, inflammation, neuroinflammation, and apoptosis. Gene Ontology analysis revealed that binding-related molecular functions and membrane-related cell components were significantly enriched. Kyoto Encyclopedia of Genes and Genomes analysis shows the most significant enrichments in neurogenesis, nervous system development, neuron differentiation, adrenergic signaling, cAMP signaling, MAPK signaling, and PI3K-Akt signaling pathways. Furthermore, protein-protein interaction analysis showed that hub genes were implicated in neuropeptide signaling pathways. Functional analysis of DE ncRNA-targeting genes was mostly enriched with nociception-related signaling pathways underpinning TNP. Our findings suggest that ncRNAs are involved in TNP development and open new avenues for research and treatment.

Genetics of Functional Seizures; A Scoping Systematic Review.

Evidence on the genetics of functional seizures is scarce, and the purpose of the current scoping systematic review is to examine the existing evidence and propose how to advance the field. Web of science and MEDLINE were searched, from their initiation until May 2023. The following key words were used: functional neurological disorder(s), psychogenic neurological disorder(s), functional movement disorder(s), psychogenic movement disorder(s), functional seizures(s), psychogenic seizure(s), nonepileptic seizure(s), dissociative seizure(s), or psychogenic nonepileptic seizure(s), AND, gene, genetic(s), polymorphism, genome, epigenetics, copy number variant, copy number variation(s), whole exome sequencing, or next-generation sequencing. We identified three original studies. In one study, the authors observed that six (5.9%) patients with functional seizures carried pathogenic/likely pathogenic variants. In another study, the authors observed that, in functional seizures, there was a significant correlation with genes that are over-represented in adrenergic, serotonergic, oxytocin, opioid, and GABA receptor signaling pathways. In the third study, the authors observed that patients with functional seizures, as well as patients with depression, had significantly different genotypes in FKBP5 single nucleotide polymorphisms compared with controls. Future genetic investigations of patients with functional seizures would increase our understanding of the pathophysiological and neurobiological problems underlying this common neuropsychological stress-associated condition.

The high ventricular function in the shortfin mako shark (Isurus oxyrinchus)

The shortfin mako sharks ( Isurus oxyrinchus) belongs to the family Lamnidae, which is a group of high performance regional endothermic elasmobranch fishes that has metabolic rates (47.4±8 ml/kg/min) higher than ectothermic elasmobranchs, and also rivals that of mammals. As in all elasmobranchs, the mako sharks do not possess direct cardiac sympathetic innervation to elevate cardiac performance, but it still retains an ancient design of a capacious semi-rigid pericardium (5.4±0.6 ml/kg) likely to accommodate its large atrial diastolic volume. This study test the hypothesis that the increase in cardiac output in the mako is influenced by a strong positive lusitrophic effect that serves to increase stroke volume, which in turn invokes the Frank-Starling’s effects. The objectives is to show differences in the physiology and biochemical properties between mako (Is) and an ectothermic blue shark ( Prioance glauca, Pg), both are oceanic species and share similar life history. Echocardiography showed a higher early to late filling velocity ratio (p=0.036) in the Is (0.92±0.16, [n=15]) than in Pg (0.45±0.04, [9]). The early time velocity integral is also greater in Is (8.8±2.4 cm, [15]) vs Pg (6.8±0.8 cm [9]) indicating a stronger conduit filling imparted by the energy from previous systole in Is. However, basal cAMP (Is: 31±12 [7] vs Pg: 31±1 [3] fmol/min/μg) and stimulated cAMP with isoproterenol+GTPγS (Is: 65±21 [7] vs Pg: 59±7 [3] fmol/min/μg) activity are similar in both groups. This suggests that the differences in ventricular contractility are not through the classic adrenergic signaling pathway involving adenylyl cyclases, but likely through the mechanical stretching of the myofibrils from diastole. Caveolin distribution of the ventricular tissues following sucrose density gradient shows a higher degree of Caveolin-1/3 in the buoyant fraction and little in the in the heavy fraction in both shark species indicating an absence of t-tubules. However, Is shows a remarkably high amount of buoyant Cav-1/3 fraction compared to Pg. We posit that the high fraction abundance of Cav-1/3 provides a gateway for corticotropin-releasing factor, such as urotensin I or possibly an ancestral precursor of urocortin, which has been shown to elevate heart function in mammals. The study is supported by NSF IBN93-16621. No disclosure. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis.

We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet®, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF.

An Ethanol Extract of Perilla frutescens Leaves Suppresses Adrenergic Agonist-Induced Metastatic Ability of Cancer Cells by Inhibiting Src-Mediated EMT.

Previous studies have indicated that the adrenergic receptor signaling pathway plays a fundamental role in chronic stress-induced cancer metastasis. In this study, we investigated whether an ethanol extract of Perilla frutescens leaves (EPF) traditionally used to treat stress-related symptoms by moving Qi could regulate the adrenergic agonist-induced metastatic ability of cancer cells. Our results show that adrenergic agonists including norepinephrine (NE), epinephrine (E), and isoproterenol (ISO) increased migration and invasion of MDA-MB-231 human breast cancer cells and Hep3B human hepatocellular carcinoma cells. However, such increases were completely abrogated by EPF treatment. E/NE induced downregulation of E-cadherin and upregulation of N-cadherin, Snail, and Slug. Such effects were clearly reversed by pretreatment with EPF, suggesting that the antimetastatic activity of EPF could be related to epithelial-mesenchymal transition (EMT) regulation. EPF suppressed E/NE-stimulated Src phosphorylation. Inhibition of Src kinase activity with dasatinib completely suppressed the E/NE-induced EMT process. Transfecting MDA-MB-231 cells with constitutively activated Src (SrcY527F) diminished the antimigration effect of EPF. Taken together, our results demonstrate that EPF can suppress the adrenergic agonist-promoted metastatic ability of cancer cells by inhibiting Src-mediated EMT. This study provides basic evidence supporting the probable use of EPF to prevent metastasis in cancer patients, especially those under chronic stress.

Abstract 3007: Psychosocial stressors and breast cancer gene expression in the Black Women's Health Study

Abstract Introduction: Chronic sympathetic nervous system (SNS) activation following exposure to psychosocial stressors may influence cancer risk through dysregulation of immune function or adrenergic signaling pathways. Prior research out of the Black Women’s Health Study (BWHS) reported associations between psychosocial stressors and breast cancer risk. We hypothesized that women with greater exposure to psychosocial stressors before their breast cancer diagnosis have higher tumor gene expression of immune-related and adrenergic signaling pathways. Methods: The BWHS is a large, prospective cohort study that has collected health and lifestyle information biennially since 1995. We included data from 417 BWHS breast cancer cases with RNA sequencing data and information on early-life trauma and neighborhood disadvantage. We used the R package DESeq2 to conduct age-adjusted differential gene expression analyses by levels of each stress exposure and described the top differentially expressed pathways using the Molecular Signature Database REACTOME subset of canonical pathways. Targeted analyses of immune-related pathways used CIBERSORT to quantify the proportions of infiltrating immune cells and the R package GSVA for single-sample gene set enrichment analysis (ssGSEA) of genes comprising a T cell exhaustion signature. We also used ssGSEA to evaluate a set of genes involved in adrenergic signaling. Given the variability in gene expression for ER+ versus ER- breast cancers, all analyses were run separately for ER+ (n=299) and ER- (n=118) tumors. Results: Pathways related to nervous system development and the metabolism of RNA were differentially expressed by levels of stress exposures among ER+ and ER- cases, while pathways related to immune function and adrenergic signaling were differentially expressed only among ER- cases, and only when evaluating differential gene expression by levels of neighborhood disadvantage. Targeted analyses of tumor immune infiltration showed significantly higher B cell fractions among ER+ cases without exposure to early trauma compared to those with early trauma. The relative fractions of other immune cells did not differ by stress exposure for ER+ or ER- tumors. Findings from ssGSEA gene set analyses indicated similar expression of genes involved in T cell exhaustion and adrenergic signaling pathways by stress exposure levels for both ER+ and ER- breast cancers. Conclusions: Our findings provide evidence of differential gene expression by levels of stress exposure; however, the differential expression may be driven by multiple pathways and not just the hypothesized immune-related and adrenergic signaling pathways. Additional studies are needed to describe mechanisms by which psychosocial stressors may influence breast cancer risk, both overall and by gene expression profile. Citation Format: Mollie E. Barnard, Xutao Wang, Jessica L. Petrick, W. Evan Johnson, Julie R. Palmer. Psychosocial stressors and breast cancer gene expression in the Black Women's Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3007.

Upregulations of α1 adrenergic receptors and noradrenaline synthases in the medial prefrontal cortex are associated with emotional and cognitive dysregulation induced by post-weaning social isolation in male rats

Early-life social isolation induces emotional and cognitive dysregulation, such as increased aggression and anxiety, and decreases neuron excitability in the medial prefrontal cortex (mPFC). The noradrenergic system in the mPFC regulates emotion and cognitive function via α1 or α2A adrenergic receptors, depending on noradrenaline levels. However, social isolation-induced changes in the mPFC noradrenergic system have not been reported. Here, male Wistar rats received post-weaning social isolation for nine consecutive weeks and were administered behavioral tests (novel object recognition, elevated plus maze, aggression, and forced swimming, sequentially). Protein expression levels in the mPFC noradrenergic system (α1 and α2A adrenergic receptors, tyrosine hydroxylase, and dopamine-β-hydroxylase used as indices of noradrenaline synthesis and release) were examined through western blotting. Social isolation caused cognitive dysfunction, anxiety-like behavior, and aggression, but not behavioral despair. Socially-isolated rats exhibited increased protein levels of the α1 adrenergic receptor, tyrosine hydroxylase, and dopamine-β-hydroxylase in the mPFC; there was no significant difference between the groups in the α2A adrenergic receptor expression levels. Preferential activation of the α1 adrenergic receptor caused by high noradrenaline concentration in the mPFC may be involved in social isolation-induced emotional and cognitive regulation impairments. Targeting the α1 adrenergic receptor signaling pathway is a potential therapeutic strategy for psychiatric disorders with symptomatic features such as emotional and cognitive dysregulation.

α-Adrenergic blockade prevented environmental temperature reduction-induced transient portal pressure surge in cirrhotic and portal hypertensive rats.

Exposure to low temperatures has been associated with increased gastroesophageal variceal bleeding in patients with cirrhosis and portal hypertension; however, the mechanism remains unclear. Therefore, the aim of the present study was to evaluate the impact of environmental temperature reduction on portal hypertension and the role of adrenergic signaling pathways in this phenomenon. Male Sprague-Dawley rats underwent common bile duct ligation or partial portal vein ligation to induce liver cirrhosis and/or portal hypertension. The impacts of acute or chronic changes in environmental temperature were surveyed. The results showed that acute cooling from 25 to 15°C and 5°C increased the portal pressure by 10.6% and 15.5% in cirrhotic rats, and by 22.2% and 36.1% in portal hypertensive rats, respectively. The transient portal pressure surge started shortly after cooling, reached a peak within 5 min and returned to baseline after 10 min. Systemic vascular resistance, mean arterial pressure and splanchnic blood flow increased significantly at the same time. Plasma epinephrine and norepinephrine concentrations, phospholipase C, protein kinase C activity and myosin phosphorylation of peripheral arteries increased significantly in response to cooling. Phentolamine (an α-blocker) but not propranolol (a non-selective β-blocker) dose-dependently inhibited the transient portal pressure surge and aforementioned molecular changes. In conclusion, environmental temperature reduction induced peripheral vasoconstriction via α-adrenergic pathways, and redistribution of blood flow to the splanchnic system led to a surge in transient portal pressure. Treatment with α-adrenergic receptor antagonists may exert additional benefits in controlling portal hypertension, especially on exposure to low temperatures.

Potato protease inhibitor II prevents obesity by inducing browning of white adipose tissue in mice via β3 adrenergic receptor signaling pathway.

There are currently few effective and safe pharmacologic means for inducing beige adipogenesis in humans. This study highlights the role of potato protease inhibitor II (PPI II) in regulating the browning of adipose tissue. The in vitro results showed that PPI II increased the expression of the uncoupling protein 1 (UCP1) protein and gene and beige-specific genes, including Cd137, Cited1, Tbx1, and Tmem26 in vitro. PPI II treatment for three months in diet-induced obesity mice increased the levels of the UCP1 protein in white adipose tissue, causing elevated energy expenditure, thus preventing obesity and improving glucose tolerance. Mechanistic studies further revealed that PPI II regulated the abundance and activity of β3 adrenergic receptor (β3 -AR) in white adipocytes. Chemical-inhibition experiments revealed the crucial role of β3 -AR-dependent protein kinase A (PKA)-p38 kinase (p38)/extracellular signal-related kinase1/2 (ERK1/2) signaling in PPI II-mediated browning program of white adipose tissues. In summary, our findings highlight the role of PPI II in beige adipocyte differentiation and thermogenesis and provide new insights into its use in preventing obesity.

Genetics of Base Coat Colour Variations and Coat Colour-Patterns of the South African Nguni Cattle Investigated Using High-Density SNP Genotypes.

Nguni cattle are a Sanga type breed with mixed B. taurus and B. indicus ancestry and proven resistance to ticks, diseases and other harsh conditions of the African geographical landscape. The multi-coloured Nguni coats have found a niche market in the leather industry leading to breeding objectives towards the promotion of such diversity. However, there is limited studies on the genomic architecture underlying the coat colour and patterns hampering any potential breeding and improvement of such trait. This study investigated the genetics of base coat colour, colour-sidedness and the white forehead stripe in Nguni cattle using coat colour phenotyped Nguni cattle and Illumina Bovine HD (770K) genotypes. Base coat colour phenotypes were categorised into eumelanin (n = 45) and pheomelanin (n = 19). Animals were categorised into either colour-sided (n = 46) or non-colour-sided (n = 94) and similarly into presence (n = 15) or absence (n = 67) of white forehead stripe. Genome-wide association tests were conducted using 622,103 quality controlled SNPs and the Efficient Mixed Model Association eXpedited method (EMMAX) implemented in Golden Helix SNP Variation Suite. The genome-wide association studies for base coat colour (eumelanin vs. pheomelanin) resulted into four indicative SNPs on BTA18 and a well-known gene, MC1R, was observed within 1 MB from the indicative SNPs (p < 0.00001) and found to play a role in the melanogenesis (core pathway for melanin production) and the MAPK signalling pathway. GWAS for colour-sidedness resulted in four indicative SNPs, none of which were in close proximity to the KIT candidate gene known for colour-sidedness. GWAS for the white forehead stripe resulted in 17 indicative SNPs on BTA6. Four genes MAPK10, EFNA5, PPP2R3C and PAK1 were found to be associated with the white forehead stripe and were part of the MAPK, adrenergic and Wnt signalling pathways that are synergistically associated with the synthesis of melanin. Overall, our results prove prior knowledge of the role of MC1R in base coat colours in cattle and suggested a different genetic mechanism for forehead stripe phenotypes in Nguni cattle.

Network construction revealed that gestational diabetes mellitus may lead to congenital heart disease via potential lncRNAs-miRNAs regulating PPARγ

Backgroundcongenital heart disease (CHD) is the most common birth defect. Gestational diabetes mellitus (GDM) induces a pro-inflammatory environment in the uterus which makes it difficult for the placenta, fetus, and embryo to develop properly. Despite the progress in underlying physiological knowledge, the knowledge of molecular mechanisms of potential connection of metabolic conditions to CHD is limited. This study aimed to mine potential regulatory missing links between GDM and CHD. MethodsWe constructed a network based on 914 differentially expressed mRNAs obtained from public GEO datasets analysis of cardiac differentiation and their regulatory miRNAs, predicted via complementarity algorithms and lncRNAs acquired from disease-associated databases. Furthermore, we compared the revealed gene set with reported RNA-seq results regarding Heart failure and Diabetes. Also, protein-protein interactions, particularly with PPARγ, were obtained from String database and visualized in Cytoscape v3.6.1. We finally mined the literature according to the applications of the revealed data. ResultsThe final resulted ncRNAs network consisted of 55 mRNAs, 13 miRNAs, and 7 lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed two conserved miRNAs in this network comprising miR-27a-3p and miR-130b-3p, primarily enriched in insulin resistance, AGE-RAGE signaling, and adrenergic signaling pathways. In addition, the screened key lncRNAs Jpx, Meg3, Xist, H19, and Mir17hg were potential regulators of diabetes-associated genes involved in Glycolysis/Gluconeogenesis and insulin signaling pathways. Retrospective literature mining showed the potential of AGE-RAGE manipulation in the nutrigenomics area according to PPARγ application. Besides, RNA-seq reports confirmed that some of our identified genes and mechanisms were involved in Heart failure and Diabetes biomarkers. ConclusionOur findings are some of the first to show a potential axis through which GDM could lead to CHD via metabolism-associated noncoding networks. PPARγ may mediate the effects of this noncoding network on cardiac differentiation and shed light on the road of nutrigenomics consultations for GDM patients.

Impact of intermittent hypoxia on ischemic cardiomyopathy progression: Role of insulin and adrenergic cross-talk

Patients with obstructive sleep apnea (OSA) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of OSA, promotes sympathetic hyperactivity, hyperinsulinemia and insulin resistance, and has been identified as a major contributor to post-MI cardiac remodeling and contractile dysfunction. We hypothesize that IH-induced sympathetic activation and insulin resistance lead to desensitization of cardiac adrenergic and insulin signaling pathways, which contribute to the progression of ischemic cardiomyopathy. MI is induced in C57bl6 mice by permanent ligation of the left coronary artery. Mice were then randomized to IH (21–5% FiO 2 , 60 s cycle, 8 h/day) or normoxia for up to 6 weeks. Longitudinal follow-up of mice includes evaluation of systemic insulin sensitivity (dynamic insulin tolerance test), cardiac sympathetic activity, spectral analysis of heart rate variability (HRV) and determination of cardiac function/remodeling (echocardiography). Following the completion of IH protocol, cardiac interstitial fibrosis and hypertrophy are evaluated by RT-qPCR and histology (Sirius Red and WGA staining, respectively). Assessment of adrenergic and insulin signaling pathways and there cross-talk are performed by Western blot (WB). IH worsens MI-induced cardiac contractile dysfunction in mice, resulting in a significant decrease in ejection fraction (19.4 ± 2.1% vs. 33.3 ± 3.9% in IH vs. N respectively, P < 0.05). MI causes significant cardiac remodeling in both N and IH groups, characterized by upregulation of several markers of cardiac fibrosis (Col1a1, Col3a1) and hypertrophy (Acta1, MyH7), which tend to be higher in IH compared to N. In our MI model, IH does not induce significant systemic insulin resistance and tends to increase LF power with no significant modification of LF/HF ratio compared to N mice. Histological experiments will be performed to confirm IH-induced aggravation of post-MI cardiac remodeling and ongoing WB will determine whether IH specifically affects cardiac insulin and adrenergic signaling. These findings demonstrate that IH is responsible for aggravation of contractile function in our ischemic cardiomyopathy mice model. Ongoing experiments will determine whether alteration of adrenergic and insulin signalling are involved as contributing mechanisms.

Stress in Metastatic Breast Cancer: To the Bone and Beyond.

Simple SummaryBreast cancer is the most common cancer affecting women of all ages worldwide. In spite of the encouraging advances made in early diagnosis, 10% of breast cancer patients are still affected with metastatic breast cancer at the time of diagnosis. The available therapeutic options are predominantly palliative, and thus this unfavourable prognosis is associated with a low survival rate. Intriguingly, stress has been shown to promote the growth of breast tumours and the incidence of metastasis. Herein, we describe the contribution of the sympathetic hyperactivation induced by stress to the progression of breast cancer and its dissemination to distant organs, specifically to the bone, but also to the lung, liver and brain. The putative sympathetic adrenergic signalling mechanisms responsible for this modulation are also summarised. The knowledge gathered highlights the therapeutic potential of targeting sympathetic signalling to tackle cancer progression and metastasis.Breast cancer (BRCA) remains as one the most prevalent cancers diagnosed in industrialised countries. Although the overall survival rate is high, the dissemination of BRCA cells to distant organs correlates with a significantly poor prognosis. This is due to the fact that there are no efficient therapeutic strategies designed to overcome the progression of the metastasis. Over the past decade, critical associations between stress and the prevalence of BRCA metastases were uncovered. Chronic stress and the concomitant sympathetic hyperactivation have been shown to accelerate the progression of the disease and the metastases incidence, specifically to the bone. In this review, we provide a summary of the sympathetic profile on BRCA. Additionally, the current knowledge regarding the sympathetic hyperactivity, and the underlying adrenergic signalling pathways, involved on the development of BRCA metastasis to distant organs (i.e., bone, lung, liver and brain) will be revealed. Since bone is a preferential target site for BRCA metastases, greater emphasis will be given to the contribution of α2- and β-adrenergic signalling in BRCA bone tropism and the occurrence of osteolytic lesions.

17β-Estradiol Concentration and Direct β2-Adrenoceptor Inhibition Determine Estrogen-Mediated Reversal of Adrenergic Immunosuppression.

Background:Sympathetic innervation of lymphoid organs, and the presence of 17β-estradiol (estrogen or E2) and adrenergic receptors (ARs) on lymphocytes, suggests that sympathetic stimulation and hormonal activation may influence immune functions.Purpose:Modeling and simulating these pathways may help to understand the dynamics of neuroendocrine-immune modulation at the cellular and molecular levels.Methods:Dose- and receptor-dependent effects of E2 and AR subtype-specific agonists were established in vitro on lymphocytes from young male Sprague-Dawley rats and were modeled in silico using the MATLAB Simbiology toolbox. Kinetic principles were assigned to define receptor–ligand dynamics, and concentration/time plots were obtained using Ode15s solvers at different time intervals for key regulatory molecules. Comparisons were drawn between in silico and in vitro data for validating the constructed model with sensitivity analysis of key regulatory molecules to assess their individual impacts on the dynamics of the system. Finally, docking studies were conducted with key ligands E2 and norepinephrine (NE) to understand the mechanistic principles underlying their interactions.Results:Adrenergic activation triggered proapoptotic signals, while E2 enhanced survival signals, showing opposing effects as observed in vitro. Treatment of lymphocytes with E2 shows a 10-fold increase in survival signals in a dose-dependent manner. Cyclic adenosine monophosphate (cAMP) activation is crucial for the activation of survival signals through extracellular signal-regulated kinase (p-ERK) and cAMP responsive element binding (p-CREB) protein. Docking studies showed the direct inhibition of ERK by NE and β2-AR by E2 explaining how estrogen signaling overrides NE-mediated immunosuppression in vitro.Conclusion:The cross-talk between E2 and adrenergic signaling pathways determines lymphocyte functions in a receptor subtype and coactivation-dependent manner in health and disease.