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[Objectives] To explore the molecular mechanism of Zhizi Ganjiang Decoction in the treatment of liver cirrhosis based on the network pharmacology. [Methods] The BATMAN-TCM server was used to predict the potential targets of Zhizi Ganjiang Decoction, and the Gen-eCards database searched for targets related to liver cirrhosis; Cytoscape 3.5.1 software was used to construct compound-cirrhosis target interaction network and protein interaction network; then gene ontology (GO) enrichment analysis, Reactome pathway enrichment analysis, and KEGG-based biological pathway enrichment analysis were performed. [Results] The compound-disease-target network of Zhizi Ganjiang Decoction was constructed. The PPI network of Zhizi Ganjiang Decoction targets constructed based on String contained 130 nodes and 689 interaction relationships. The key nodes mainly involved nuclear hormone receptor-like domain superfamily and ligand binding domain, serpentine type7TM GPCR chemoreceptor and chemoreceptor Six, rhodopsin family transmembrane receptors, zinc finger NHR/GATA type nuclear hormone receptors and ligand binding domains, PI3-kinase family p85 binding domain, phosphoinositide (PI) 3-kinase catalytic domain and other categories. GO enrichment analysis pathway related entries mainly involved steroid hormone receptor activity, nuclear receptor activity, transcription factor activity, direct ligands regulation sequence-specific DNA binding, G protein-coupled amine receptor activity, steroid binding, catecholamine binding, neurotransmitter receptor activity, adrenergic receptor activity, ammonium ion binding, and oxidoreductase activity, etc. KEGG channel analysis mainly involved neuroactive ligand-receptor interaction, aldosterone regulates sodium reabsoiption, regulates lipolysis in adipocytes, regulates inflammatory mediators of TRP channels, tyrosine metabolism, calcium signaling pathway, cAMP signaling pathway, and nonalcoholic fatty liver diseases. [Conclusions] The research results suggest that Zhizi Ganjiang Decoction regulates the process of liver cirrhosis mainly through aldosterone regulation of sodium reabsorption, regulation of lipolysis in adipocytes, regulation of inflammatory mediators of TRP channels, calcium signaling pathways, and nonalcoholic fatty liver diseases. This reflects the multi-target and holistic action characteristics of the Chinese herbal compounds, and is expected to provide new ideas for further research on the molecular mechanism of Zhizi Ganjiang Decoction. [ABSTRACT FROM AUTHOR]

Background and Objective: Antidepressant use in older adults (≥ 65 years) is understudied in large population-based samples, particularly in recent years and regarding user characteristics. We aimed to describe the trends, patterns, and associated user characteristics of all antidepressant prescriptions redeemed by older adults at community pharmacies in Denmark during 2015–2019. Methods: This register-based study used a cross-sectional design to characterize antidepressant prescription trends and patterns, and a cohort design to describe user characteristics associated with antidepressant prescription initiation. We used descriptive statistics to characterize trends and patterns, and Poisson regression for analyzing user characteristics. Results: During the years 2015–2019, 17.9% of 1.2 million older adults redeemed 4.84 million antidepressant prescriptions, where 48.5% were selective serotonin reuptake inhibitors, followed by noradrenergic and specific serotonergic antidepressants (26.2%), serotonin-norepinephrine reuptake inhibitors (12.7%), tricyclic antidepressants (11.2%), and others (1.4%). Amitriptyline and nortriptyline, considered potentially inappropriate medications, were among the 10 most frequently redeemed antidepressants. Only 60.5% of prescriptions had a treatment indication of depression. Prescription-proportion trends by drug classes and individual antidepressants remained consistent. A higher incidence rate ratio (IRR) and 95% confidence interval (CI) of initiating antidepressants was associated with female sex (IRR 1.20, 95% CI 1.07–1.34), older age (e.g., 81–85 years vs. 65–70 years: IRR 1.74, 95% CI 1.44–2.11), living in rural areas (North Denmark vs. Capital Region: IRR 1.31, 95% CI 1.09–1.58), and having somatic and psychiatric diagnoses (e.g., per one psychiatric diagnosis: IRR 1.10, 95% CI 1.05–1.15), while a lower ratio was associated with being non-Western (vs. Danish: IRR 0.50, 95% CI 0.28–0.89) and having hospital contacts for psychiatric treatment (per each contact: IRR 0.96, 95% CI 0.93–1.00). Conclusion: SSRIs were the most commonly redeemed antidepressants, with consistent trends in Danish older adults. Besides clinical conditions, sociodemographics, e.g., sex, age, ethnicity, and place of residence, may influence antidepressant use. [ABSTRACT FROM AUTHOR]

Valbenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors approved for tardive dyskinesia. The clinical activity of valbenazine is primarily attributed to its only dihydrotetrabenazine (HTBZ) metabolite, [+]‐α‐HTBZ. Deutetrabenazine is a deuterated form of tetrabenazine and is metabolized to four deuterated HTBZ metabolites: [+]‐α‐deuHTBZ, [+]‐β‐deuHTBZ, [−]‐α‐deuHTBZ, and [−]‐β‐deuHTBZ. An open‐label, crossover study characterized the pharmacokinetic profiles of the individual deuHBTZ metabolites, which have not been previously reported. VMAT2 inhibition and off‐target interactions of the deuHTBZ metabolites were evaluated using radioligand binding. The only valbenazine HTBZ metabolite, [+]‐α‐HTBZ, was a potent VMAT2 inhibitor, with negligible affinity for off‐target dopamine, serotonin, and adrenergic receptors. Following deutetrabenazine administration, [−]‐α‐deuHTBZ represented 66% of circulating deuHTBZ metabolites and was a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine (D2S, D3) and serotonin (5‐HT1A, 5‐HT2B, 5‐HT7) receptors. [+]‐β‐deuHTBZ was the most abundant deuHTBZ metabolite that potently inhibited VMAT2, but it represented only 29% of total circulating deuHTBZ metabolites. The mean half‐life of [+]‐α‐HTBZ (22.2 hours) was ∼3× longer than that of [+]‐β‐deuHTBZ (7.7 hours). These findings are similar to studies with tetrabenazine, in that deutetrabenazine is metabolized to four deuHTBZ stereoisomers, the most abundant of which has negligible interaction with VMAT2 in vitro and appreciable affinity for several off‐target receptors. In contrast, valbenazine's single HTBZ metabolite is a potent VMAT2 inhibitor in vitro with no discernible off‐target activity. Determination of the effects of intrinsic/extrinsic variables on deutetrabenazine's safety/efficacy profile should incorporate assessment of the effects on all deuHTBZ metabolites. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) is an easily accessible dietary supplement gaining notoriety in medicine for its use as a surrogate form of self-driven opioid use disorder treatment, albeit one with a lack of evidence and significant risks. Both misuse and withdrawal from kratom have been appreciated in the literature and addressed in a fashion analogous to that of opioids. Because of this, it has largely been studied through the looking glass of its properties of agonizing μ-opioid and likely α2-adrenergic receptors. While an important area of study, the correlation with kratom and stimulant use, reflected in the National Survey on Drug Use and Health, is one that often gets neglected clinically. In our manuscript we present three unique cases, demonstrative of the overlap kratom misuse may have with stimulant use disorders in distinct settings. We provide a discussion and review of this correlation in light of kratom use increasing in the United States. [ABSTRACT FROM AUTHOR]

Abstract: Alpha-1 adrenoceptors are overexpressed in the epidermis of a subgroup of patients with complex regional pain syndrome (CRPS). Activating α 1 -adrenoceptors in epidermal cells increases production of the proinflammatory cytokine interleukin-6 (IL-6), a mediator of inflammation. To investigate whether this might exacerbate inflammation in CRPS, primary keratinocytes or dermal fibroblasts were cultured from skin biopsies obtained from the affected limb of 25 patients and a similar site in 28 controls. The fundamental proinflammatory cytokine, tumor necrosis factor alpha, was administered for 24 hours to initiate inflammation. After this, cells were incubated for 6 hours with the α 1 -adrenoceptor agonist phenylephrine. Exposure to tumor necrosis factor alpha induced proinflammatory cytokine mRNA production and protein secretion in keratinocytes and fibroblasts and enhanced α 1B -adrenoceptor mRNA expression in keratinocytes. Additional stimulation of α 1 adrenoceptors with phenylephrine increased the production of IL-6 mRNA and protein secretion in both cell types. Under all conditions, gene and protein α 1 -adrenoceptor levels and cytokine gene expression and protein secretion were similar, overall, in patients and controls, except for abnormally high α 1 -adrenoceptor protein levels in the keratinocytes of 3 of 17 patients. These findings suggest that persistent inflammation in CRPS is not due to dysfunction of skin cells but is a normal response to extrinsic signals. After α 1 -adrenoceptor stimulation of keratinocytes, increases in IL-6 mRNA but not protein were proportional to basal α 1 -adrenoceptor protein levels. Skin cells play an important role in persistent inflammation in CRPS. Potentially, a positive feedback loop between α 1 -adrenoceptors and IL-6 production in skin cells contributes to this inflammatory state. [ABSTRACT FROM AUTHOR]

The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [11C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device. Microdialysis probes were placed in the thalamus, striatum and cortex and dialysis samples were collected every 10 min. Three 90 min [11C]yohimbine scans were acquired: at baseline and at two timepoints after the administration of amphetamine (1–10 mg/kg), a non-specific releaser of dopamine and noradrenaline, or nisoxetine (1 mg/kg), a specific noradrenaline transporter inhibitor. [11C]yohimbine volumes of distribution (VT) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine VT, with time courses reflecting their different mechanisms of action. Dialysis samples revealed a significant increase in noradrenaline extracellular concentrations after challenge and an inverse correlation with changes in yohimbine VT. These data suggest that [11C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges. [ABSTRACT FROM AUTHOR]

The sympathetic nervous system (SNS), particularly through the β2 adrenergic receptor (β2-AR), has been linked with breast cancer (BC) and the development of metastatic BC, specifically in the bone. Nevertheless, the potential clinical benefits of exploiting β2-AR antagonists as a treatment for BC and bone loss-associated symptoms remain controversial. In this work, we show that, when compared to control individuals, the epinephrine levels in a cohort of BC patients are augmented in both earlier and late stages of the disease. Furthermore, through a combination of proteomic profiling and functional in vitro studies with human osteoclasts and osteoblasts, we demonstrate that paracrine signaling from parental BC under β2-AR activation causes a robust decrease in human osteoclast differentiation and resorption activity, which is rescued in the presence of human osteoblasts. Conversely, metastatic bone tropic BC does not display this anti-osteoclastogenic effect. In conclusion, the observed changes in the proteomic profile of BC cells under β-AR activation that take place after metastatic dissemination, together with clinical data on epinephrine levels in BC patients, provided new insights on the sympathetic control of breast cancer and its implications on osteoclastic bone resorption. [ABSTRACT FROM AUTHOR]

Chronic and acute stress caused by emotional or physical insults can affect the function of other organs via the brain-body axis. As one of the smallest organs in mammalian, hair follicles are highly susceptible to stress. Under stress, the sympathetic nerves release norepinephrine (NA), which acts directly on the β-2 adrenergic receptors on melanocyte stem cells (MeSCs) within the hair follicles, causing the MeSCs to lose quiescence and enter a rapid proliferation state followed by differentiation and migration, leading to rapid loss of MeSCs and, ultimately, grey hair. Here, we screened out β-2 blockers forming the ZINC 15 compound database, found a natural product isoliensinine, and was effective in preventing stress-induced hair greying in mice. The study sheds light on the development of products that use natural compounds to prevent stress-induced hair greying. [ABSTRACT FROM AUTHOR]

Alcohol Use Disorder (AUD) ranks among the most prevalent mental disorders, extracting $250 billion/year in the US alone and producing myriad medical and social harms. Also, the number of deaths related to problem drinking has been increasing dramatically. Compulsive alcohol drinking, characterized by intake that persists despite negative consequences, can be particularly important and a major obstacle to treatment. With the number of people suffering from AUD increasing during the past years, there is a critical need to understand the neurobiology related to compulsive drives for alcohol, as well as the development of novel AUD pharmacological therapies. Here we discuss rodent compulsion-like alcohol drinking (CLAD) models, focusing on the two most widely used adverse stimuli to model rodent compulsion-like responding, quinine adulteration of alcohol and footshook-resistant alcohol intake. For both cases, the goal is to uncover behavior patterns and brain circuits that underlie drive for alcohol even in the face of negative consequences. We discuss caveats, benefits, and potential brain mechanisms, of models for consequence-resistant responding for alcohol more generally, and especially highlight some advantages of quinine-resistance over footshook-resistance. Further, since this review contributes to a Special issue focused on Molecular Aspects of Compulsive Drug Use, we discuss our new findings showing how the noradrenergic system is related to CLAD responding. In particular, we comment on the importance of al and p adrenergic receptors (ARs) as potential targets for treating AUD. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) is considered a public health problem. According to the World Health Organization, MI is a leading cause of death and comorbidities worldwide. Activation of the α1A adrenergic receptor is a contributing factor to the development of MI. Tamsulosin, an α1A adrenergic blocker, has gained wide popularity as a medication for the treatment of benign prostatic hyperplasia. Limited evidence from previous studies has revealed the potential cardioprotective effects of tamsulosin, as its inhibitory effect on the α1A adrenoceptor protects the heart by acting on the smooth muscle of blood vessels, which results in hypotension; however, its effect on the infarcted heart is still unclear. The mechanisms of the expected cardioprotective effects mediated by tamsulosin are not yet understood. Transforming growth factor-beta (TGF-β), a mediator of fibrosis, is considered an attractive therapeutic target for remodeling after MI. The role of α1A adrenoceptor inhibition or its relationships with integrin-linked kinase (ILK) and TGF-β/small mothers against decapentaplegic (Smad) signaling pathways in attenuating MI are unclear. The present study was designed to investigate whether tamsulosin attenuates MI by modulating an ILK-related TGF-β/Smad pathway. Methods: Twenty-four adult male Wistar rats were randomly divided into 4 groups: control, ISO, TAM, and ISO + TAM. ISO (150 mg/kg, intraperitoneally) was injected on Days 20 and 21 to induce MI. Tamsulosin (0.8 mg/kg, orally) was administered for 21 days, prior to ISO injection for 2 consecutive days. Heart-to-body weight ratios and cardiac and fibrotic biomarker levels were subsequently determined. ILK, TGF-β1, p-Smad2/3, and collagen III protein expression levels were determined using biomolecular methods. Results: Tamsulosin significantly attenuated the relative heart-to-body weight index (p < 0.5) and creatine kinase-MB level (p < 0.01) compared with those in the ISO control group. While ISO resulted in superoxide anion production and enhanced oxidative damage, tamsulosin significantly prevented this damage through antioxidant defense mechanisms, increasing glutathione and superoxide dismutase levels (p < 0.05) and decreasing lipid peroxide oxidation levels (p < 0.01). The present data revealed that tamsulosin reduced TGF-β/p-Smad2/3 expression and enhanced ILK expression. Conclusion: Tamsulosin may exert a cardioprotective effect by modulating the ILK-related TGF-β/Smad signaling pathway. Thus, tamsulosin may be a useful therapeutic approach for preventing MI. [ABSTRACT FROM AUTHOR]

In the inflamed uterus, the production and secretion of prostaglandins (PGs) and noradrenergic innervation pattern are changed. Receptor-based control of prostaglandin E2 (PGE2) production and secretion by noradrenaline during uterine inflammation is unknown. The aim of this study was to determine the role of α1-, α2- and β-adrenoreceptors (ARs) in noradrenaline-influenced PG-endoperoxidase synthase-2 (PTGS-2) and microsomal PTGE synthase-1 (mPTGES-1) protein levels in the inflamed pig endometrium, and in the secretion of PGE2 from this tissue. E. coli suspension (E. coli group) or saline (CON group) was injected into the uterine horns. Eight days later, severe acute endometritis developed in the E. coli group. Endometrial explants were incubated with noradrenaline and/or α1-, α2- and β-AR antagonists. In the CON group, noradrenaline did not significantly change PTGS-2 and mPTGES-1 protein expression and increased PGE2 secretion compared to the control values (untreated tissue). In the E. coli group, both enzyme expression and PGE2 release were stimulated by noradrenaline, and these values were higher versus the CON group. The antagonists of α1- and α2-AR isoforms and β-AR subtypes do not significantly alter the noradrenaline effect on PTGS-2 and mPTGES-1 protein levels in the CON group, compared to noradrenaline action alone. In this group, α1A-, α2B- and β2-AR antagonists partly eliminated noradrenaline-stimulated PGE2 release. Compared to the noradrenaline effect alone, α1A-, α1B-, α2A-, α2B-, β1-, β2- and β3-AR antagonists together with noradrenaline reduced PTGS-2 protein expression in the E. coli group. Such effects were also exerted in this group by α1A-, α1D-, α2A-, β2- and β3-AR antagonists with noradrenaline on mPTGES-1 protein levels. In the E. coli group, the antagonists of all isoforms of α1-ARs and subtypes of β-ARs as well as α2A-ARs together with noradrenaline decreased PGE2 secretion versus noradrenaline action alone. Summarizing, in the inflamed pig endometrium, α1(A, B)-, α2(A, B)- and β(1, 2, 3)-ARs mediate the noradrenaline stimulatory effect on PTGE-2 protein expression, while noradrenaline via α1(A, D)-, α2A- and β(2, 3)-ARs increases mPTGES-1 protein expression and α1(A, B, D)-, α2A- and β(1, 2, 3)-ARs are involved in PGE2 release. Data suggest that noradrenaline may indirectly affect the processes regulated by PGE2 by influencing its production. Pharmacological modulation of particular AR isoforms/subtypes can be used to change PGE2 synthesis/secretion to alleviate inflammation and improve uterine function. [ABSTRACT FROM AUTHOR]

Background: Noradrenergic neurons in the locus coeruleus (LC) are the primary source of norepinephrine (NE) in the brain and degeneration of these neurons is reported in the early stages of Parkinson's disease (PD), even prior to dopaminergic neuron degeneration in the substantia nigra (SN), which is a hallmark of PD pathology. NE depletion is generally associated with increased PD pathology in neurotoxin-based PD models. The effect of NE depletion in other models of PD-like α-synuclein-based models is largely unexplored. In PD models and in human patients, β-adrenergic receptors' (AR) signaling is associated with a reduction of neuroinflammation and PD pathology. However, the effect of NE depletion in the brain and the extent of NE and β-ARs signaling involvement in neuroinflammation, and dopaminergic neuron survival is poorly understood. Methods: Two mouse models of PD, a 6OHDA neurotoxin-based model and a human α-synuclein (hα-SYN) virus-based model of PD, were used. DSP-4 was used to deplete NE levels in the brain and its effect was confirmed by HPLC with electrochemical detection. A pharmacological approach was used to mechanistically understand the impact of DSP-4 in the hα-SYN model of PD using a norepinephrine transporter (NET) and a β-AR blocker. Epifluorescence and confocal imaging were used to study changes in microglia activation and T-cell infiltration after β1-AR and β2-AR agonist treatment in the hα-SYN virus-based model of PD. Results: Consistent with previous studies, we found that DSP-4 pretreatment increased dopaminergic neuron loss after 6OHDA injection. In contrast, DSP-4 pretreatment protected dopaminergic neurons after hα-SYN overexpression. DSP-4-mediated protection of dopaminergic neurons after hα-SYN overexpression was dependent on β-AR signaling since using a β-AR blocker prevented DSP-4-mediated dopaminergic neuron protection in this model of PD. Finally, we found that the β-2AR agonist, clenbuterol, reduced microglia activation, T-cell infiltration, and dopaminergic neuron degeneration, whereas xamoterol a β-1AR agonist showed increased neuroinflammation, blood brain barrier permeability (BBB), and dopaminergic neuron degeneration in the context of hα-SYN-mediated neurotoxicity. Conclusions: Our data demonstrate that the effects of DSP-4 on dopaminergic neuron degeneration are model specific, and suggest that in the context of α-SYN-driven neuropathology, β2-AR specific agonists may have therapeutic benefit in PD. [ABSTRACT FROM AUTHOR]

Dopamine has effects on the mammalian heart. These effects can include an increase in the force of contraction, and an elevation of the beating rate and the constriction of coronary arteries. Depending on the species studied, positive inotropic effects were strong, very modest, or absent, or even negative inotropic effects occurred. We can discern five dopamine receptors. In addition, the signal transduction by dopamine receptors and the regulation of the expression of cardiac dopamine receptors will be of interest to us, because this might be a tempting area of drug development. Dopamine acts in a species-dependent fashion on these cardiac dopamine receptors, but also on cardiac adrenergic receptors. We will discuss the utility of drugs that are currently available as tools to understand cardiac dopamine receptors. The molecule dopamine itself is present in the mammalian heart. Therefore, cardiac dopamine might act as an autocrine or paracrine compound in the mammalian heart. Dopamine itself might cause cardiac diseases. Moreover, the cardiac function of dopamine and the expression of dopamine receptors in the heart can be altered in diseases such as sepsis. Various drugs for cardiac and non-cardiac diseases are currently in the clinic that are, at least in part, agonists or antagonists at dopamine receptors. We define the research needs in order to understand dopamine receptors in the heart better. All in all, an update on the role of dopamine receptors in the human heart appears to be clinically relevant, and is thus presented here. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is a crucial risk factor for hypertensive disorders during pregnancy, but its progression during pregnancy remains unclear. We previously showed cardiac hypertrophy in a pregnancy-associated hypertensive (PAH) mouse model, in which an increase in angiotensin II (Ang II) levels was induced by human renin and human angiotensinogen, depending on pregnancy conditions. Here, to elucidate the factors involved in the progression of cardiac hypertrophy, we performed a comprehensive analysis of changes in gene expression in the hearts of PAH mice and compared them with those in control mice. We found that alpha-1A adrenergic receptor (Adra1a) mRNA levels in the heart were significantly reduced under PAH conditions, whereas the renin-angiotensin system was upregulated. Furthermore, we found that Adra1a-deficient PAH mice exhibited more severe cardiac hypertrophy than PAH mice. Our study suggests that Adra1a levels are regulated by renin-angiotensin system and that changes in Adra1a expression are involved in progressive cardiac hypertrophy in PAH mice. [ABSTRACT FROM AUTHOR]

Noradrenergic neurotransmission is a critical mediator of stress responses. In turn, exposure to stress induces noradrenergic system adaptations, some of which are implicated in the etiology of stress‐related disorders. Adrenergic receptors (ARs) in the ventral tegmental area (VTA) have been demonstrated to regulate phasic dopamine (DA) release in the forebrain, necessary for behavioral responses to conditional cues. However, the impact of stress on noradrenergic modulation of the VTA has not been previously explored. We demonstrate that ARs in the VTA regulate dopaminergic activity in the VTA–BLA (basolateral amygdala) circuit, a key system for processing stress‐related stimuli; and that such control is altered by acute stress. We utilized fast‐scan cyclic voltammetry to assess the effects of intra‐VTA microinfusion of α1‐AR and α2‐AR antagonists (terazosin and RX‐821002, respectively), on electrically evoked phasic DA release in the BLA in stress‐naïve and stressed (unavoidable electric shocks – UES) anesthetized male Sprague–Dawley rats. In addition, we used western blotting to explore UES‐induced alterations in AR protein level in the VTA. Intra‐VTA terazosin or RX‐821002 dose‐dependently attenuated DA release in the BLA. Interestingly, UES decreased the effects of intra‐VTA α2‐AR blockade on DA release (24 h but not 7 days after stress), while the effects of terazosin were unchanged. Despite changes in α2‐AR physiological function in the VTA, UES did not alter α2‐AR protein levels in either intracellular or membrane fractions. These findings demonstrate that NA‐ergic modulation of the VTA–BLA circuit undergoes significant alterations in response to acute stress, with α2‐AR signaling indicated as a key target. [ABSTRACT FROM AUTHOR]

Neurological impairments due to traumatic, vascular, or neurodegenerative brain diseases have a high prevalence worldwide. Among them are motor, cognitive, and mental disorders, which have a serious negative impact on the working and social activities of the patients. This calls for the search and development of novel effective neuroprotective agents. Previous studies have shown the pyrimidine-derived α2-adrenergic agonist mafedine to be highly effective for the amelioration of neurological deficits in experimental traumatic brain injury (TBI) in rats. Despite the results of the previous works favouring the major role of the α2 adrenergic receptor activation in the mechanism of action of mafedine, the search for additional molecular targets is an important part of the development of any drug to be used in clinical practice. In this work, we evaluated the effects of 7 day-long course administration of mafedine (2.5 mg/kg b.w.) on the expression of brain-derived neurotrophic factor (BDNF), the proinflammatory cytokines interleukin (IL)-1β, -6, tumour necrosis factor (TNF)-α, and the α2A, α2B, and α2C α2-adrenergic receptor subtypes in the brain cortex of rats subjected to TBI, using the reverse-transcription real-time polymerase chain reaction method. TBI was modelled by the controlled cortical impact technique in an open area of sensorimotor cortex of the left brain hemisphere. Behavioural alterations in the injured animals were assessed in the Open field test, and the fore- and hindlimb motor function, in the Limb placing, Cylinder, and Beam walking tests. Our experiments show that TBI causes severe motor impairments as well as decreases exploration in rats. Besides, at post-TBI day 7, a reduction in the expression of all analyzed genes is seen, which is the most pronounced in the contralateral (uninjured) hemisphere. Course administration of mafedine (2,5 mg/kg b.w.) resulted in moderate stimulation of the injured rats' behaviour, increased exploratory activity compared to controls, and improved sensorimotor deficit as assessed by the Beam walking test. Gene expression analysis results indicated that mafedine decreased α2B-adrenergic receptor, TNF-α, and IL-6 expression in the injured hemisphere. At the same time, compared to rats with TBI having received no treatment, mafedine-treated animals exhibited higher α2B-adrenergic receptor and IL-1β expression in the injured rather than the intact hemisphere. These results confirm the previously observed neuroprotective activity of mafedine and imply that it may exert its effects via suppression of α2B-adrenergic receptor and proinflammatory cytokine expression in the injured brain hemisphere, at the same time increasing their expression in the intact one. [ABSTRACT FROM AUTHOR]

Catecholamine, along with adrenergic receptor (ARs), plays a pivotal role in mediating the immune function of vertebrates under stressful environment. However, the immunomodulatory role of adrenergic receptors in invertebrates remains largely unknown, hindering the development of effective stress management strategies in invertebrate aquaculture. In the present study, an α2 type adrenergic receptor, designated as Mg α2AR, was identified in an economically important species, the Pacific oyster Magallana gigas. The Mg α2AR was consisted of seven transmembrane domains and one short carboxyl terminus. The mRNA transcript of Mg α2AR was expressed in haemocytes and all the examined tissues, with the highest expression level in haemocytes, particularly in granulocyte (9.28-fold of that in agranulocyte, p < 0.05). By immunofluorescence analysis, Mg α2AR was found primarily localized in the cytoplasmic membrane of granulocytes. The mRNA expression of Mg α2AR in haemocytes increased significantly at 6 h, and peaked at 12 h (4.71-fold of that in control group, p < 0.01) after LPS stimulation in vivo. After transfection and expression of Mg α2AR in HEK293T cells, a significant decrease in cAMP concentration, rather than in Ca2+ concentration, was observed upon treatment with the agonist NE (p < 0.05), while the administration of the α2 adrenergic receptor antagonist (Ida) yielded opposite results. The expressions of Mg IL17–5, Mg TNF-1, and Mg TNF-2 in oyster haemocytes were also downregulated following treatment with α2AR antagonist Ida, which was 0.44-fold, 0.54-fold, and 0.32-fold of that in the NE+ LPS group (p < 0.01), respectively. After Mg α2AR was knockdown by RNAi, the transcripts of Mg IL17–5, Mg TNF-1, and Mg TNF-2 significantly decreased. These results collectively suggested that the granulocytes highly-expressed Mg α2AR could induce the expressions of TNFs and IL-17 by reducing the intracellular cAMP level in the immune response of oysters. These findings provide a novel insight into the immunomodulatory role of adrenergic receptors in mollusks, and also offer valuable information for the development of effective stress management strategies in aquaculture. • An α2 type adrenergic receptor expressed in oyster granulocytes was identified. • Mg α2AR could respond to LPS stimulation during the early stage of immune response. • Mg α2AR down-regulated cAMP concentration and induce the expression of cytokines. [ABSTRACT FROM AUTHOR]

We studied the effect of α2-adrenoreceptor stimulation after preliminary If blockade on the function of the Langendorff-isolated rat heart in the acute stage of experimental myocardial infarction. Stimulation of α2-adrenoreceptors with clonidine (10—6 M) against the background of If blockade with ZD7288 (10—9 M) reduced the contractility of the left ventricular myocardium, HR, coronary blood flow, and the duration of the left ventricular myocardium contraction in sham-operated rats and animals with acute myocardial infarction. The duration of relaxation and contraction cycle during α2-adrenoreceptor stimulation after preliminary If blockade (10—9 M) was increased in sham-operated rats and in animals with acute myocardial infarction. Stimulation of adrenoreceptors against the background of application of ZD7288 in a concentration of 10—5 M decreased the left ventricular pressure, HR, coronary blood flow, and the duration of left ventricular myocardial contraction in both groups. The duration of the relaxation and contraction cycle during α2-adrenoreceptor stimulation against the background of If blockade (10—5 M) increased in sham-operated rats and animals with acute myocardial infarction. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans, playing a crucial role in regulating diverse cellular processes and serving as primary drug targets. Traditional drug design has primarily focused on ligands that uniformly activate or inhibit GPCRs. However, the concept of biased agonism—where ligands selectively stabilize distinct receptor conformations, leading to unique signaling outcomes—has introduced a paradigm shift in therapeutic development. Despite the promise of biased agonists to enhance drug efficacy and minimize side effects, a comprehensive understanding of the structural and biophysical mechanisms underlying biased signaling is essential. Recent advancements in GPCR structural biology have provided unprecedented insights into ligand binding, conformational dynamics, and the molecular basis of biased signaling. These insights, combined with improved techniques for characterizing ligand efficacy, have driven the development of biased ligands for several GPCRs, including opioid, angiotensin, and adrenergic receptors. This review synthesizes these developments, from mechanisms to drug discovery in biased signaling, emphasizing the role of structural insights in the rational design of next-generation biased agonists with superior therapeutic profiles. Ultimately, these advances hold the potential to revolutionize GPCR-targeted drug discovery, paving the way for more precise and effective treatments. [ABSTRACT FROM AUTHOR]

• Appropriate mechanical stimulation favors fracture healing. • PIEZO1 of macrophage is essential for mechanical stimulation-induced bone repair. • PIEZO1-activated macrophages secrete extracellular vesicles to promote osteogenesis. • Extracellular vesicles enriched microRNAs regulate adrenergic receptor signaling. • Adrb2 of osteoblast could be a target to promote fracture healing. Appropriate mechanical loading (ML) accelerates fracture healing. Macrophages, being the primary mechanosensitive immune cells, play a pivotal role in the regulation of bone formation. However, the exact mechanism through which macrophages respond to ML during the fracture healing process remains unclear. The current study revealed that conditional knockout of Piezo1 in macrophages impairs the infiltration and alternative activation of macrophages during fracture healing. In addition, ML activates PIEZO1 in macrophages to release small extracellular vesicles (sEVs) to foster osteogenesis. sEVs deriving from ML-treated macrophages (ML-Mφ-sEVs) enriched miRNAs in regulating adrenergic receptor signaling pathway. We next discovered that selected miRNAs within ML-Mφ-sEVs could target the expression of Adrb2 , thereby impeding β2 -adrenergic receptor signaling in osteoblasts during fracture healing. Conditional knockout of Adrb2 in osteoblasts increased mineralization in the callus, indicating that ML-Mφ-sEVs promote fracture healing through confining ADRB2 of osteoblasts. Based on these discoveries, we introduced engineered sEVs in the treatment of bone fracture, revealing that the osteoblasts targeting sEVs accelerated bone formation and ameliorated mechanical unloading-induced fracture delayed union. Collectively, our results reveal the relationship between ML-induced Mφ-sEVs and osteogenesis, which provides a potential therapeutic strategy for fracture management via targeting Adrb2 in osteoblasts. [ABSTRACT FROM AUTHOR]

Capsaicin, a polyphenol, is known to regulate energy expenditure and thermogenesis in adipocytes and muscles. However, its role in modulating uncoupling proteins (UCPs) and adenosine triphosphate (ATP)-dependent thermogenesis in muscles remains unclear. This study investigated the mechanisms underlying the role of capsaicin in modulating the UCP- and ATP-dependent thermogenesis in C2C12 myoblasts, as well as the gastrocnemius (GM) and soleus muscles (SM) of mice. We employed molecular dynamics (MD), quantitative real-time polymerase chain reactions (qRT-PCR), immunoblots, staining methods, and assay kits to investigate the role of capsaicin on thermogenesis and its modulatory roles on the transient receptor potential cation channel subfamily V member 1 (TRPV1) and α-/β-adrenergic receptors (ARs) using in vitro and in vivo models. Our findings demonstrate that capsaicin treatment in high-fat diet-induced obese mice reduces weight gain and elevates the expression of UCP- and ATP-dependent thermogenic effectors through ATP-consuming calcium and creatine futile cycles. In vitro and in vivo models capsaicin treatment elevated the expression of sarcoendoplasmic/endoplasmic reticulum calcium ATPases (SERCA-1 and -2), ryanodine receptors (RYR-1 and -2), uncoupling proteins (UCP-2 and -3), creatine kinase B (CKB), and creatine kinase mitochondrial 2 (CKMT2), through activation of TRPV1, α1-, β2-, and β3-AR as well as the suppressed expression of α2-AR. Furthermore, our results also indicate that capsaicin promotes myotube development and enhances lipid metabolism in C2C12 cells. We found that capsaicin increased intracellular Ca2+ levels and the expression of the voltage-dependent anion channel (VDAC) and mitochondrial calcium uniporter (MCU), suggesting that elevated mitochondrial Ca2+ levels boost the expression of oxidative phosphorylation protein complexes via the activation of the ATP-futile cycle. Mechanistic studies in C2C12 cells revealed that TRPV1 is likely dispensable for capsaicin-induced thermogenesis, and TRPV1 and α1-AR may synergistically induce thermogenesis. Collectively, our findings have uncovered a novel mechanism of UCP- and ATP-dependent thermogenesis and its associated pathways in both cellular and animal models which is crucial for designing therapeutic strategies to address obesity and associated metabolic diseases. Suggested molecular mechanism for uncoupling protein (UCP)- and adenosine triphosphate (ATP)-dependent capsaicin-mediated thermogenesis. To induce thermogenesis, capsaicin may involve mainly five interacting parts; first and second, capsaicin induces thermogenesis by increasing cytosolic Ca2+ levels and activating the α1-adrenergic receptor (AR)/transient receptor potential vanilloid (TRPV)1/Ca2+/calmodulin-dependent protein kinase-II (CaMKII)/adenosine monophosphate-activated protein kinase (AMPK)/Sirtuin (SIRT)1 pathway; third, capsaicin inhibits the expression of α2-AR; fourth and fifth, via β3/β2-AR/protein kinase A (PKA)/p38 pathway. Sharp arrows refer to stimulation and blunt arrows indicate inhibition. [Display omitted] • Capsaicin elevates the expression of UCP- and ATP-dependent thermogenic proteins in muscle. • Capsaicin increases calcium levels, which boosts the expression of oxidative phosphorylation protein complexes. • TRPV1 may dispensable and α/β-AR may involve in capsaicin-mediated thermogenesis. • TRPV1 and α1-AR work together to induce capsaicin-mediated thermogenesis. [ABSTRACT FROM AUTHOR]

Background: Anxiety disorders constitute the most widespread category of psychiatric conditions which can result from adverse life events and involve stress response generalization. The pursuit of innovative pharmaceutical interventions for these disorders is motivated by the escalating demand. The noradrenergic system is involved in the regulation of many physiological and psychological processes, including the modulation of mood. a2A adrenergic receptors (a2A-ARs) are both expressed on pre- and post-synaptic, which could regulate calcium-dependent transmitter release as well as the firing rate of the neuron. Research with animal models has shed light on potential anti-anxiety effects by intervening a2A-AR. Mice with a2A-AR knockout exhibited anxiety-like behavior, and inhibiting a2A-AR on the bed nucleus of the stria terminalis (BNST) elicits anxiety-like behavior in the elevated plus maze. However, the neuron basis of a2A-AR populations and their contributions to behavior remain unknown. As we all know, the hypothalamic-pituitary-adrenal (HPA)axis is the main way an organism responds to stress. A recent study demonstrated that the BNST? hypothalamic paraventricular nucleus(PVN) project may be a crucial circuit regulating a variety of stressful conditions. Therefore, we speculate that a2A-AR acts on the BNST and ultimately controls the HPA axis through specific projections, thereby modulating mice behavior. Aims: Elaborate further on the pivotal regulatory role of a2A-AR in anxiety behavior induced by chronic stress, elucidating the underlying neural circuitry that ultimately impacts the HPA axis. Method: We adopted a 7-day restraint stress model to induce anxiety-like behavior in mice, with the a 2A-AR agonistdexmedetomidine (DEX) or saline (SAL) injected at the last 3 days of restraint. Then open field test (OFT), new object recognition (NOC), light-dark box(LDB) and elevated plus maze(EPM) were assessed after the restraint procedure. Mice were placed back in their home cage for an additional 60 minutes before being sacrificed for cFos expression. Blood glucocorticoids were tested as well. We will further co-label a2A-AR, cFos, and subtype of neurons, manipulating a2A-AR expressed by virus injection at specific ensembles at BNST. Then neural circuits will be explored by electrophysiology in vitro, optogenetics, and fiber photometry. Results: Mice after chronic restraint stress exhibited anxiety-like behavior which can be improved by DEX (Figure 1). Mice administrated with DEX had less neuron activation at the PVN area but an independent ensemble of activation at BNST (Figure 2), fiber photometry during EPM similarly demonstrates a corresponding trend. Discussion: The a2A-AR agonist effectively alleviates anxiety-like behavior induced by chronic stress in mice, while its neural circuit mechanism requires further clarification. This groundwork will pave the way for the identification of potential targets in the development of anti-anxiety medications. [ABSTRACT FROM AUTHOR]

The Journal of Neuroscience published an article on a potential new treatment target for chemotherapy-induced neuropathic pain, focusing on mitochondrial receptors. The study found that targeting the A3 adenosine receptor on rat mitochondria during chemotherapy prevented neuropathic pain and abnormal nerve activity. Another article in the journal explored how noradrenaline and corticosterone modulate stress-induced CRH release at CRH neuron terminals, shedding light on the HPA axis activity. These findings provide valuable insights for future animal model studies and clinical work in the field of neuropathic pain and stress response modulation. [Extracted from the article]

Purpose: Resting beat-to-beat blood pressure variability is a strong predictor of cardiovascular events and mortality. However, its underlying mechanisms remain incompletely understood. Given that the sympathetic nervous system plays a pivotal role in cardiovascular regulation, we hypothesized that alpha-1 adrenergic receptors (the main sympathetic receptor controlling peripheral vasoconstriction) may contribute to resting beat-to-beat blood pressure variability.Beat-to-beat heart rate (electrocardiography) and blood pressure (photoplethysmography) were continuously measured before and 2 h following, selective blockade of alpha-1 adrenergic receptors via oral administration of prazosin (1 mg/20 kg) in ten young healthy adults (two women). Cardiac output and total peripheral resistance were estimated using the ModelFlow method.Selective blockade of alpha-1 adrenergic receptors was confirmed by the marked reduction in the pressor response to intravenous infusion of phenylephrine hydrochloride (−80 ± 15%, P = 0.001 versus pre-prazosin). The blockade significantly decreased the standard deviation of the systolic (pre-prazosin versus post-prazosin: 5.6 ± 1.4 versus 3.8 ± 0.7 mmHg, P = 0.002), diastolic (3.2 ± 1.2 versus 2.2 ± 0.5 mmHg, P = 0.022), and mean blood pressure (3.7 ± 1.2 versus 2.5 ± 0.5 mmHg, P = 0.009), as well as total peripheral resistance (0.8 ± 0.5 versus 0.5 ± 0.1 mmHg/L/min, P = 0.047), but not cardiac output (521 ± 188 versus 453 ± 160 mL/min, P = 0.321). Similar results were found using different indices of variability.These findings indicate that alpha-1 adrenergic receptors play a significant role in regulating resting beat-to-beat blood pressure variability in young, healthy adults.Methods: Resting beat-to-beat blood pressure variability is a strong predictor of cardiovascular events and mortality. However, its underlying mechanisms remain incompletely understood. Given that the sympathetic nervous system plays a pivotal role in cardiovascular regulation, we hypothesized that alpha-1 adrenergic receptors (the main sympathetic receptor controlling peripheral vasoconstriction) may contribute to resting beat-to-beat blood pressure variability.Beat-to-beat heart rate (electrocardiography) and blood pressure (photoplethysmography) were continuously measured before and 2 h following, selective blockade of alpha-1 adrenergic receptors via oral administration of prazosin (1 mg/20 kg) in ten young healthy adults (two women). Cardiac output and total peripheral resistance were estimated using the ModelFlow method.Selective blockade of alpha-1 adrenergic receptors was confirmed by the marked reduction in the pressor response to intravenous infusion of phenylephrine hydrochloride (−80 ± 15%, P = 0.001 versus pre-prazosin). The blockade significantly decreased the standard deviation of the systolic (pre-prazosin versus post-prazosin: 5.6 ± 1.4 versus 3.8 ± 0.7 mmHg, P = 0.002), diastolic (3.2 ± 1.2 versus 2.2 ± 0.5 mmHg, P = 0.022), and mean blood pressure (3.7 ± 1.2 versus 2.5 ± 0.5 mmHg, P = 0.009), as well as total peripheral resistance (0.8 ± 0.5 versus 0.5 ± 0.1 mmHg/L/min, P = 0.047), but not cardiac output (521 ± 188 versus 453 ± 160 mL/min, P = 0.321). Similar results were found using different indices of variability.These findings indicate that alpha-1 adrenergic receptors play a significant role in regulating resting beat-to-beat blood pressure variability in young, healthy adults.Results: Resting beat-to-beat blood pressure variability is a strong predictor of cardiovascular events and mortality. However, its underlying mechanisms remain incompletely understood. Given that the sympathetic nervous system plays a pivotal role in cardiovascular regulation, we hypothesized that alpha-1 adrenergic receptors (the main sympathetic receptor controlling peripheral vasoconstriction) may contribute to resting beat-to-beat blood pressure variability.Beat-to-beat heart rate (electrocardiography) and blood pressure (photoplethysmography) were continuously measured before and 2 h following, selective blockade of alpha-1 adrenergic receptors via oral administration of prazosin (1 mg/20 kg) in ten young healthy adults (two women). Cardiac output and total peripheral resistance were estimated using the ModelFlow method.Selective blockade of alpha-1 adrenergic receptors was confirmed by the marked reduction in the pressor response to intravenous infusion of phenylephrine hydrochloride (−80 ± 15%, P = 0.001 versus pre-prazosin). The blockade significantly decreased the standard deviation of the systolic (pre-prazosin versus post-prazosin: 5.6 ± 1.4 versus 3.8 ± 0.7 mmHg, P = 0.002), diastolic (3.2 ± 1.2 versus 2.2 ± 0.5 mmHg, P = 0.022), and mean blood pressure (3.7 ± 1.2 versus 2.5 ± 0.5 mmHg, P = 0.009), as well as total peripheral resistance (0.8 ± 0.5 versus 0.5 ± 0.1 mmHg/L/min, P = 0.047), but not cardiac output (521 ± 188 versus 453 ± 160 mL/min, P = 0.321). Similar results were found using different indices of variability.These findings indicate that alpha-1 adrenergic receptors play a significant role in regulating resting beat-to-beat blood pressure variability in young, healthy adults.Conclusion: Resting beat-to-beat blood pressure variability is a strong predictor of cardiovascular events and mortality. However, its underlying mechanisms remain incompletely understood. Given that the sympathetic nervous system plays a pivotal role in cardiovascular regulation, we hypothesized that alpha-1 adrenergic receptors (the main sympathetic receptor controlling peripheral vasoconstriction) may contribute to resting beat-to-beat blood pressure variability.Beat-to-beat heart rate (electrocardiography) and blood pressure (photoplethysmography) were continuously measured before and 2 h following, selective blockade of alpha-1 adrenergic receptors via oral administration of prazosin (1 mg/20 kg) in ten young healthy adults (two women). Cardiac output and total peripheral resistance were estimated using the ModelFlow method.Selective blockade of alpha-1 adrenergic receptors was confirmed by the marked reduction in the pressor response to intravenous infusion of phenylephrine hydrochloride (−80 ± 15%, P = 0.001 versus pre-prazosin). The blockade significantly decreased the standard deviation of the systolic (pre-prazosin versus post-prazosin: 5.6 ± 1.4 versus 3.8 ± 0.7 mmHg, P = 0.002), diastolic (3.2 ± 1.2 versus 2.2 ± 0.5 mmHg, P = 0.022), and mean blood pressure (3.7 ± 1.2 versus 2.5 ± 0.5 mmHg, P = 0.009), as well as total peripheral resistance (0.8 ± 0.5 versus 0.5 ± 0.1 mmHg/L/min, P = 0.047), but not cardiac output (521 ± 188 versus 453 ± 160 mL/min, P = 0.321). Similar results were found using different indices of variability.These findings indicate that alpha-1 adrenergic receptors play a significant role in regulating resting beat-to-beat blood pressure variability in young, healthy adults. [ABSTRACT FROM AUTHOR]

[Display omitted] • Induction of ARS for 4 h caused anxiety-like behavior and neuronal lesion in the prefrontal cortex. • I.c.v. infusion of ACPA and clonidine induced anxiolytic-like behavior in the NARS and ARS mice. • I.c.v. microinjection of yohimbine produced an anxiogenic-like effect in the NARS and ARS mice. • Co-infusion of ACPA along with clonidine or yohimbine caused an anxiolytic-like effect. • There is a synergistic effect between ACPA and clonidine for induction of anxiolytic behavior. The present research examined the possible role of α-2 adrenergic receptor drugs (clonidine, selective α-2 adrenergic receptor agonist, and yohimbine, competitive α-2 adrenoreceptor antagonist,) on the effect of arachidonylcyclopropylamide (ACPA), a cannabinoid CB1 receptor agonist, in non-acute restraint stress (NARS) and acute restraint stress (ARS) mice. The animals were unilaterally implanted with a cannula in the left lateral ventricle. ARS was carried out by movement restraint at a period of 4 h. An elevated plus-maze (EPM) apparatus was used to evaluate anxiety-like behaviors. The results indicated that induction of ARS for 4 h induced anxiogenic-like behavior due to the reduction of %OAT (the percentage of time spent in the open arms) in male mice. Additionally, ARS caused neuronal degeneration in the prefrontal cortex. On the other hand, alone intracerebroventricularly (i.c.v.) infusions of ACPA (0.5 µg/mouse) and clonidine (0.5 µg/mouse) increased %OAT, indicating an anxiolytic-like response in the NARS and ARS mice. In contrast, alone i.c.v. infusions of yohimbine (0.5 µg/mouse) decreased %OAT and %OAE (the percentage of entries to the open arms), proposing an anxiogenic-like effect in the NARS and ARS mice. When the subthreshold dose of ACPA and different doses of clonidine were co-injected, ACPA potentiated the anxiolytic-like behavior produced by clonidine in the ARS mice. On the other hand, when the ineffective dosage of ACPA and different dosages of yohimbine were co-infused, ACPA reversed the anxiogenic-like effect induced by yohimbine in the NARS and ARS mice. Moreover, the results revealed a synergistic effect between ACPA and clonidine upon induction of anxiolytic-like behaviors. It can be concluded that the interaction between clonidine and ACPA modulates the anxiety-like behaviors induced by stress in male mice. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that norepinephrine (NE) released during chronic stress promotes breast cancer (BC) metastasis via adrenergic receptors (ARs). However, the effect of NE on tumor-associated macrophage polarization and the underlying mechanisms remain largely unknown. In this study, we aimed to investigate the influence of NE on M2 macrophage polarization, with a particular focus on the crosstalk between macrophages and BC cells. Our results demonstrated that, although NE alone did not directly induce the expression of M2 macrophage markers, conditioned medium from NE-treated MDA-MB-231 human BC cells (NE CM) significantly promoted M2 macrophage polarization in THP-1 macrophages. We found that NE stimulated IL-6 production in MDA-MB-231 cells via β2-AR/NF-κB pathway, which activated STAT3 in THP-1 cells to induce M2 macrophage polarization. NE failed to induce IL-6 production and NF-κB activation when ADRB2 was knocked down in MDA-MB-231 cells. Furthermore, ADRB2 knockdown in cancer cells suppressed NE CM-induced M2 macrophage polarization, as well as M2 macrophage-induced cancer cell migration. Taken together, our results suggest that NE stimulates M2 macrophage polarization by inducing IL-6 secretion from BC cells through a β2-AR-dependent mechanism, which subsequently promotes cancer cell migration. Targeting β2-AR may represent a promising strategy to prevent chronic stress-induced BC metastasis. • Conditioned medium from NE-treated cancer cells promotes M2 macrophage polarization. • NE stimulates IL-6 production in breast cancer cells via β2-AR/NF-κB pathway. • IL-6 activates STAT3 in macrophages to induce M2 macrophage polarization. • β2-AR knockdown in cancer cell suppresses M2 macrophage-driven cancer cell migration. • β2-AR can be a promising target to prevent chronic stress-induced cancer metastasis. [ABSTRACT FROM AUTHOR]

Social isolation (SI) in humans can lead to various psychological and physical abnormalities. However, the molecular mechanisms and potential drug treatments for this illness are not well understood. Drosophila , a social organism, exhibits distinct behavioral defects under SI conditions, such as reduced sleep and loss of sugar intake preference. By examining the transcriptional profiles of SI flies, we discovered significant impacts on metabolic pathways. Notably, serotonin (5-HT) levels were reduced in the brains of SI flies. Treatment with 5-HT reversed the behavioral defects in SI flies. 5-HT is known to regulate mitochondrial synthesis in mouse brain, and we found it also enhances mitochondrial biogenesis in flies. Further investigation revealed that the 5-HT 7 receptor subtype was involved in SI behavior. To activate mitochondrial metabolism, we overexpressed phosphoglycerate kinase (Pgk), an enzyme in the glycolytic pathway, in neurons. This overexpression rescued the behavioral defects in SI flies. Additionally, terazosin, an alpha-1 adrenergic receptor antagonist known to activate Pgk, produced a similar rescue effect. Our study elucidates a key principle of SI-induced psychological damage and proposes a drug targeting strategy for future validation. • Social isolation reduces mitochondrial function; Pgk activation rescues this deficit. [ABSTRACT FROM AUTHOR]

[Display omitted] Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disorder characterized by the accumulation of extracellular matrix and collagen, resulting in significant parenchymal scarring and respiratory failure that leads to mortality. Yohimbine (YBH) is an α-2 adrenergic receptor antagonist with anti-oxidant and anti-inflammatory properties. In the current study, we aimed to investigate the anti-inflammatory, anti-oxidant and anti-fibrotic activity of YBH against LPS/TGF-β-induced differentiation in BEAS-2B/LL29 cells and bleomycin (BLMN) induced pulmonary fibrosis model in rats. Network pharmacology, gene expression, Western-blot analysis, immune-cytochemistry/immunohistochemistry, lung functional analysis, and histology techniques were used to assess the fibrotic marker expression/levels in cells or rat lung tissues. YBH treatment significantly attenuated the LPS-induced pro-inflammatory (identified through a network-pharmacology approach) and oxidative stress markers expression in lung epithelial cells. TGF-β stimulation significantly elevated the fibrotic cascade of markers and treatment with YBH attenuated these markers' expression/levels. Intra-tracheal administration of BLMN caused a significant elevation of various inflammatory/oxidative stress and fibrotic markers expression in lung tissues and treatment with YBH significantly mitigated the same. Ashcroft score analysis revealed that BLMN exhibited severe distortion of the lungs, elevation of thickness of the alveolar walls and accumulation of collagen in tissues, further treatment with YBH significantly suppressed these events and improved the lung architecture. Lung functional parameters demonstrated that BLMN-induced stiffness and resistance were reduced considerably upon YBH treatment and restored lung function dose-dependently. Overall, this study reveals that YBH treatment significantly attenuated the BLMN-induced fibrosis by regulating the MAPK pathway and provided insightful information for progressing towards translational outcomes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Thr164Ile variant in β2AR leads to poor β2 agonist binding, causing refractoriness in asthma. • Our modeling studies showed CACPD2011a-0001278239 promiscuously binds both wild and T164I β2AR. • Present cell line-based studies confirm promiscuity of CACPD2011a-0001278239 in both receptors. • In vitro toxicity assays showed CACPD2011a-0001278239 to be non-toxic. Inhaled β2 agonists form the first-line treatment for bronchial asthma due to their superior bronchodilator effects. In our previous studies, we have identified a significant association of Thr164Ile (T164I) polymorphism (C491T, rs1800088) in the β2 adrenergic receptor (β2AR) with refractoriness to β2 agonists like salbutamol. Utilizing molecular modeling approaches, we have demonstrated the suboptimal binding of salbutamol as a plausible rationale behind the refractoriness observed in asthmatics. Furthermore, our high throughput virtual screening studies led to the identification of high-affinity agonist, (5-[[2-[4-(4-hydroxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]acetyl]amino]benzene-1,3-dicarboxamide), referred to as "CACPD2011a-0001278239" in the Phase database. This compound exhibited promiscuous and high-affinity binding to both the wild type and T164I β2AR variants. The present study aims to evaluate the efficacy and toxicity of CACPD2011a-0001278239 in In vitro systems. Promiscuous and high-affinity properties of CACPD2011a-0001278239 were assessed in MRC-5 lung fibroblasts expressing wild β2AR and T164Iβ2AR transfected CHW-1102 cells. In both cells, CACPD2011a-0001278239 exhibited superior potency with appreciable EC 50 values compared to salbutamol, indicating its promiscuity and superior binding potential for β2AR isoforms. Further, toxicity studies of CACPD2011a-0001278239 were conducted by assessing the cytotoxicity (MTT assay), mutagenicity (reverse-mutation assay), and genotoxicity (chromosomal aberrations and micronucleus test). In all these investigations, CACPD2011a-0001278239 demonstrated non-cytotoxic, non-mutagenic, and non-genotoxic properties. In conclusion, the present biological investigations confirm that CACPD2011a-0001278239 possesses high affinity and promiscuous binding properties while exhibiting a favorable safety profile. These findings suggest CACPD2011a-0001278239 as a potential promiscuous agonist for addressing refractoriness in asthmatics, regardless of whether they harbor wild type or T164I β2AR variant. [ABSTRACT FROM AUTHOR]

Cancer neuroscience, as an emerging converging discipline, provides us with new perspectives on the interactions between the nervous system and cancer progression. As the sympathetic nervous system, in particular adrenergic signaling, plays an important role in the regulation of tumor activity at every hierarchical level of life, from the tumor cell to the tumor microenvironment, and to the tumor macroenvironment, it is highly desirable to dissect its effects. Considering the far-reaching implications of drug repurposing for antitumor drug development, such a large number of adrenergic receptor antagonists on the market has great potential as one of the means of antitumor therapy, either as primary or adjuvant therapy. Therefore, this review aims to summarize the impact of adrenergic signaling on cancer development and to assess the status and prospects of intervening in adrenergic signaling as a therapeutic tool against tumors. [ABSTRACT FROM AUTHOR]

Exposure of organisms to extremely low-frequency electromagnetic field (ELF-EMF; 50 Hz) has been increasing in recent decades, which is connected with dynamic technological development. ELF-EMF is considered a stress factor and its effects on organisms are still being investigated. We aimed to determine its impact on the locus coeruleus–noradrenergic (LC-NA) system enabling adaptation to stressful conditions. For this purpose, we exposed rats to 50 Hz ELF-EMF of 1 and 7 mT, 1 h/day for 7 days. The procedure was repeated three times to examine the organism's adaptive capabilities. Subsequently, the concentration of adrenaline, noradrenaline and its metabolite MHPG as well as the expression of the β2-adrenergic receptor was assessed. After the end of each exposure, part of the animals were subjected to a behavioural test to assess the influence of repeated ELF-EMF exposure on stress response to subsequent stress factors. Our research proved that mechanisms underlying the effects of ELF-EMF on stress response include the LC-NA system. ELF-EMF of 1 mT induced adaptive changes in the NA-LC system. However, exposure to 7 mT caused increased activity of the stress system which resulted in sensitization to subsequent, heterotypic (different from the one previously acting) stress factor. As ELF-EMF of 7 mT caused a profound decrease in β2-AR level would strongly inhibit the potential for neuroplastic processes in the hippocampus. Moreover, rats exposed to ELF-EMF of 7 mT showed moderately increased anxiety-related behaviour. Disturbances in NA-LC transmission may underlie the development of some neurodegenerative and psychiatric diseases which indicates the possible involvement of ELF-EMF in the pathogenesis of these disorders. [Display omitted] • he effect of the extremely low-frequency electromagnetic field effect on LC-NA activity is hormetic. • High dose of ELF-ELF-EMF (7 mT) causes hyperreactivity of the adrenergic system. • The repeated exposure to ELF-EMF change the response to another stress factor. • Rats exposed to ELF-EMF of 7 mT showed disturbed anxiety-related behaviour. • 7 mT ELF-EMF caused a decrease in β2-AR thus can inhibit the neuroplastic processes in the hippocampus. [ABSTRACT FROM AUTHOR]

Stigmasterol is a sterol compound found in various traditional Chinese medicines; however, its effects on glioma remain unclear. The present study aimed to investigate the effects of stigmasterol on the biological behaviors of glioblastoma (GBM) cells and to explore the underlying mechanisms. In vitro experiments assessed its effects on GBM cell proliferation, apoptosis, cell cycle progression, invasion, migration and vasculogenic mimicry (VM). The potential targets for stigmasterol in treating GBM were identified using databases and Venn diagram analysis, followed by enrichment analysis using R language. A prognostic model related to the target genes of stigmasterol was developed through univariate Cox regression and least absolute shrinkage and selection operator analyses. Stigmasterol was found to suppress the proliferation of GBM cells in a dose- and time-dependent manner, to induce apoptosis, and to inhibit invasion, migration and VM formation. Additionally, 31 potential targets of stigmasterol were identified, linked to lipid metabolism and the G protein-coupled receptor signaling pathway. Lipid metabolism assays revealed that stigmasterol significantly reduced free fatty acids and total cholesterol levels. Furthermore, two prognosis-related target genes, fatty acid binding protein 5 and α-1B adrenergic receptor, were selected, and the prognostic model effectively predicted GBM outcomes. Moreover, molecular docking revealed strong binding affinities between stigmasterol and the target proteins. Overall, these findings suggested that stigmasterol may exert anti-glioma effects, which could be potentially mediated through the regulation of lipid metabolism. [ABSTRACT FROM AUTHOR]

Abstract Background/objectives Visceral obesity is one of the key features of metabolic syndrome. High-intensity interval training (HIIT) could effectively reduce visceral fat, but its effects show strong heterogeneity in populations with different degrees of obesity. The mechanism may be related to the differential adaptation to training between obesity phenotypes, namely obesity prone (OP) and obesity resistant (OR). The aim of the present study was to compare adaptive changes of visceral adipose lipolysis adaptation to HIIT between OP and OR animals and further explore the upstream pathway. Methods OP and OR Sprague Dawley rats were established after feeding a high-fat diet for 6 weeks; they were then divided into HIIT (H-OP and H-OR) and control (C-OP and C-OR) groups. After 12 weeks of HIIT or a sedentary lifestyle, animals were fasted for 12 h and then sacrificed for histology as well as gene and protein analysis. Visceral adipocytes were isolated without fasting for catecholamine stimulation and β3-adrenergic receptor (β3-AR) blockade in vitro to evaluate the role of upstream pathways. Results After training, there were no differences in weight loss or food intake between OP and OR rats (P > 0.05). However, the visceral fat mass, adipocyte volume, serum triglycerides and liver lipids of OP rats decreased by more than those of OR rats (P 0.05), the cell sensitivity to catecholamine increased significantly in the OP compared with OR groups (P

Abnormalities in the peripheral immune system are involved in the pathophysiology of fibromyalgia, although their contribution to the painful symptoms remains unknown. Our previous study reported the ability of splenocytes to develop pain-like behavior and an association between the central nervous system (CNS) and splenocytes. Since the spleen is directly innervated by sympathetic nerves, this study aimed to examine whether adrenergic receptors are necessary for pain development or maintenance using an acid saline-induced generalized pain (AcGP) model (an experimental model of fibromyalgia) and whether the activation of these receptors is also essential for pain reproduction by the adoptive transfer of AcGP splenocytes. The administration of selective β2-blockers, including one with only peripheral action, prevented the development but did not reverse the maintenance of pain-like behavior in acid saline-treated C57BL/6J mice. Neither a selective α1-blocker nor an anticholinergic drug affects the development of pain-like behavior. Furthermore, β2-blockade in donor AcGP mice eliminated pain reproduction in recipient mice injected with AcGP splenocytes. These results suggest that peripheral β2-adrenergic receptors play an important role in the efferent pathway from the CNS to splenocytes in pain development. [ABSTRACT FROM AUTHOR]

Hypertension is a major risk factor for cardiovascular diseases, such as strokes and myocardial infarctions. Nearly 70% of hypertension onsets in adults can be attributed to obesity, primarily due to sympathetic overdrive and the dysregulated renin-angiotensin system. Sympathetic overdrive increases vasoconstriction via α1-adrenoceptor activation on vascular cells. Despite the fact that a sympathetic outflow increases in individuals with obesity, as a rule, there is a cohort of patients with obesity who do not develop hypertension. In this study, we investigated how adrenoceptors' expression and functioning in adipose tissue are affected by obesity-driven hypertension. Here, we demonstrated that α1A is a predominant isoform of α1-adrenoceptors expressed in the adipose tissue of patients with obesity, specifically by multipotent mesenchymal stromal cells (MSCs). These cells respond to prolonged exposure to noradrenaline in the model of sympathetic overdrive through the elevation of α1A-adrenoceptor expression and signaling. The extent of MSCs' response to noradrenaline correlates with a patient's arterial hypertension. scRNAseq analysis revealed that in the model of sympathetic overdrive, the subpopulation of MSCs with contractile phenotype expanded significantly. Elevated α1A-adrenoceptor expression is triggered specifically by beta3-adrenoceptors. These data define a novel pathophysiological mechanism of obesity-driven hypertension by which noradrenaline targets MSCs to increase microvessel constrictor responsivity. [ABSTRACT FROM AUTHOR]

Asthma is a common respiratory disease characterized by chronic airway inflammation. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, has been shown to participate in regulating inflammatory states and thus exert organ protective actions. However, the potential of DEX in asthma is still unknown. This study is aimed at investigating the role of DEX in a mouse model of house dust mite- (HDM-) induced asthma and exploring its underlying mechanism. Here, we found that DEX treatment significantly ameliorated airway hyperresponsiveness, airway inflammation, and airway remodeling in the asthmatic mice, which were similar to the efficacy of the reference anti-inflammatory drug dexamethasone. In addition, DEX reversed the increased expression of toll-like receptor 4 (TLR4) and its downstream signaling adaptor molecule nuclear factor-κB (NF-κB) in the lung tissue of asthmatic mice. Furthermore, these protective effects of DEX were abolished by yohimbine, an α2 adrenergic receptor antagonist. These results indicate that DEX is capable of ameliorating airway inflammation and remodeling in asthmatic mice, and this protective effect is associated with the inhibition of the TLR4/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

While positive social-behavioral factors predict longer survival in cancer patients, the underlying mechanisms are unknown. Since tumor metastasis are the major cancer mortality factor, we investigated how an enriched environment (EE) conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in lungs following intravasation in the circulation. We find that mice housed in EE exhibited reduced number of lung metastatic foci compared to control mice housed in a standard environment (SE). Compared to SE mice, EE mice increased lung inflammation as early as 4 days after circulating tumor cells extravasation. The impact of environmental signals on lung metastasis is independent of adrenergic receptors signaling. By contrast, we find that serum corticosterone levels are lower in EE mice and that glucocorticoid receptor (GR) antagonist reduces the number of lung metastasis in SE mice. In addition, the difference of the number of lung metastasis between SE and EE mice is abolished when inflammatory monocytes are rendered deficient in GR signaling. This decreased GR signaling in inflammatory monocytes of SE mice results in an exacerbated inflammatory profile in the lung. Our study shows that not only EE reduces late stages of metastatic progression in lungs but disclose a novel anti-tumor mechanism whereby GR-dependent reprogramming of inflammatory monocytes can inhibit metastatic progression in lungs. Moreover, while inflammatory monocytes have been shown to promote cancer progression, they also have an anti-tumor effect, suggesting that their role is more complex than currently thought. [ABSTRACT FROM AUTHOR]

The neurotoxin β-N-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by cyanobacteria. Non-neuronal toxicity of BMAA is poorly studied with a reported increase in reactive oxygen species and a decrease in the antioxidant capacity of liver, kidney, and colorectal adenocarcinoma cells. The aim of this research is to study the toxicity of BMAA (0.1–1 mM) on mitochondria and submitochondrial particles with ATPase activity, on the semicarbazide-sensitive amino oxidases (SSAOs) activity of rat liver, and on an in vitro model containing functionally active excitable tissues—regularly contracting heart muscle preparation with a preserved autonomic innervation. For the first time the BMAA-dependent inhibition of SSAO activity, the elimination of the positive inotropic effect of adrenergic innervation, and the direct and reversible inhibition of adrenaline signaling in ventricular myocytes with 1 mM BMAA were observed. Additionally, it is confirmed that 1 mM BMAA can activate mitochondrial ATPase indirectly. It is concluded that a higher dose of BMAA may influence multiple physiological and pathological processes as it slows down the degradation of biogenic amines, downregulates the sympathetic neuromediation, and embarrasses the cell signaling of adrenergic receptors. [ABSTRACT FROM AUTHOR]

Simple Summary: Nine types of complete adrenergic receptor (ADR) gene sequences were analyzed, wherein twenty-four specific mutation sites were found as a result of the artificial selection of Shaver Brown and Shamo chickens. From the analysis, Shamo- and Shaver Brown-specific mutations, and those common to both breeds, could be separated into three groups. The results confirmed that eight mutation sites may be affected by artificial selection. Furthermore, the evolutionary analysis revealed that the identified mutations were not ancestral. These results confirmed that the eight mutations at these sites were artificially selected by domestication and breed specificity. NST population analysis confirmed that there is a difference in the degree of genetic differentiation between the two populations. In particular, the NST rate of ADRA1D (0.064) was most affected by artificial selection. This suggests that these mutations may exert different effects on vasoconstriction, smooth muscles, and the action of the digestive system relevant to the breed's specific characteristics. Associations between neurotransmitters, adrenergic receptor (ADR) mutations, and behaviors in chickens produced and domesticated by artificial selection remain unclear. This study investigates the association of neurotransmitters and ADR mutations with egg laying and cockfighting—behaviors associated with significantly different breeding backgrounds—in Shaver Brown and Shamo chickens. Accordingly, the whole sequences of nine ADR genes were determined, and nine amino acid-specific mutation sites from five genes (ADRα1A: S365G, ADRα1D: T440N, ADRα2A: D273E, ADRβ1: N443S, S445N, ADRβ3: R342C, Q404L, and P406S) were extracted. Evolutionary analysis showed that these mutations were not ancestrally derived. These results confirm that the mutations at these sites were artificially selected for domestication and are breed specific. NST population analysis confirmed a difference in the degree of genetic differentiation between the two populations in seven genes. The results further confirm differences in the degree of genetic differentiation between the two populations in Shaver Brown (ADRA1B and ADRA1D) and Shamo (ADRA1A and ADRA2B) chickens, indicating that the ADR gene differs between the two breeds. The effects of artificial selection, guided by the human-driven selection of desirable traits, are reflected in adrenaline gene mutations. Furthermore, certain gene mutations may affect domestication, while others may affect other traits in populations or individuals. [ABSTRACT FROM AUTHOR]

Shock is a severe, life-threatening medical condition with a high mortality rate worldwide. All four major categories of shock (along with their various subtypes)—hypovolemic, distributive, cardiogenic, and obstructive, involve a dramatic mismatch between oxygen supply and demand, and share standard features of decreased cardiac output, reduced blood pressure, and overall hypoperfusion. Immediate and appropriate intervention is required regardless of shock type, as a delay can result in cellular dysfunction, irreversible multiple organ failure, and death. Studies have shown that dysfunction and downregulation of adrenergic receptors (ARs) are often implicated in these shock conditions; for example, their density is shown to be decreased in hypovolemic and cardiogenic shock, while their reduced signaling in the brain and vasculature decrease blood perfusion and oxygen supply. There are two main categories of ARs, α, and β, each with its subtypes and distributions. Our group has demonstrated that a dose of .02 mg/kg body wt of centhaquine (CQ) specifically activates α2B ARs on venous circulation along with the central α2A ARs after hypovolemic/hemorrhagic shock. Activating these receptors by CQ increases cardiac output (CO) and reduces systemic vascular resistance (SVR), with a net increase in blood pressure and tissue perfusion. The clinical trials of CQ conducted by Pharmazz Inc. in India have demonstrated significantly improved survival in shock patients. CQ improved blood pressure and shock index, indicating better blood circulation, and reduced lactate levels in the blood compared to in-use standard resuscitative agents. After successful clinical trials, CQ is being marketed as a drug (Lyfaquin®) for hypovolemic/ hemorrhagic shock in India, and United States FDA has approved the phase III IND application. It is anticipated that the phase III trial in the United States will begin in 2023. Thus, we have demonstrated that α2 ARs could be suitable targets for treating or managing hypovolemic/hemorrhagic shock. Further understanding of ARs in shock would help find new potential pharmacological targets. [ABSTRACT FROM AUTHOR]

Spike-wave discharges are the hallmark of idiopathic generalized epilepsy. They are caused by a disorder in the thalamocortical network. Commercially available anti-epileptic drugs have pronounced side effects (i.e., sedation and gastroenterological concerns), which might result from a low selectivity to molecular targets. We suggest a specific subtype of adrenergic receptors (ARs) as a promising anti-epileptic molecular target. In rats with a predisposition to absence epilepsy, alpha2 ARs agonists provoke sedation and enhance spike-wave activity during transitions from awake/sedation. A number of studies together with our own observations bring evidence that the sedative and proepileptic effects require different alpha2 ARs subtypes activation. Here we introduce a new concept on target pharmacotherapy of absence epilepsy via alpha2B ARs which are presented almost exclusively in the thalamus. We discuss HCN and calcium channels as the most relevant cellular targets of alpha2 ARs involved in spike-wave activity generation. [ABSTRACT FROM AUTHOR]

G-protein-coupled receptors (GPCRs) are cell membrane proteins of relevance as therapeutic targets, and are associated to the development of treatments for illnesses such as diabetes, Alzheimer's, or even cancer. Therefore, comprehending the underlying mechanisms of the receptor functional properties is of particular interest in pharmacoproteomics and in disease therapy at large. Their interaction with ligands elicits multiple molecular rearrangements all along their structure, inducing activation pathways that distinctly influence the cell response. In this work, we studied GPCR signaling pathways from molecular dynamics simulations as they provide rich information about the dynamic nature of the receptors. We focused on studying the molecular properties of the receptors using deep-learning-based methods. In particular, we designed and trained a one-dimensional convolution neural network and illustrated its use in a classification of conformational states: active, intermediate, or inactive, of the β 2 -adrenergic receptor when bound to the full agonist BI-167107. Through a novel explainability-oriented investigation of the prediction results, we were able to identify and assess the contribution of individual motifs (residues) influencing a particular activation pathway. Consequently, we contribute a methodology that assists in the elucidation of the underlying mechanisms of receptor activation–deactivation. [ABSTRACT FROM AUTHOR]

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings. [ABSTRACT FROM AUTHOR]

Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to "uncoupling" of endothelial nitric oxide synthase (eNOS). Stimulation of β3 adrenergic receptors (β3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of β3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective β3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)–pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RV–PA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p < 0.0001) and Sugen hypoxic mice (p < 0.0001). CL316243 reduced RV systolic pressure, to a similar degree to riociguat and sildenafil, in both hypoxia (p < 0.0001) and Sugen hypoxia models (p < 0.03). CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RV–PA coupling efficiency and reduced RV stiffness, hypertrophy, and fibrosis. Although all treatments decreased oxidative stress, CL316243 significantly reduced eNOS glutathionylation. β3 AR stimulation improved RV hemodynamics and led to beneficial RV–PA remodeling in experimental models of PAH. β3 AR agonists may be effective therapies in PAH. [ABSTRACT FROM AUTHOR]

Early-life attachment disruption appears to sensitize neuroinflammatory signaling to increase later vulnerability for stress-related mental disorders, including depression. How stress initiates this process is unknown, but studies with adult rats and mice suggest sympathetic nervous system activation and/or cortisol elevations during the early stress are key. Guinea pig pups isolated from their mothers exhibit an initial active behavioral phase characterized by anxiety-like vocalizing. This is followed by inflammatory-dependent depressive-like behavior and fever that sensitize on repeated isolation. Using strategies that have been successful in adult studies, we assessed whether sympathetic nervous system activity and cortisol contributed to the sensitization process in guinea pig pups. In Experiment 1, the adrenergic agonist ephedrine (3 or 10 mg/kg), either alone or with cortisol (2.5 mg/kg), did not increase depressive-like behavior or fever during initial isolation the following day as might have been expected to if this stimulation was sufficient to account for the sensitization process. In Experiment 2, both depressive-like behavior and fever sensitized with repeated isolation, but beta-adrenergic receptor blockade with propranolol (10 or 20 mg/kg) did not affect either of these responses or their sensitization. The high dose of propranolol did, however, reduce vocalizing. These results suggest sympathetic nervous system activation is neither necessary nor sufficient to induce the presumptive neuroinflammatory signaling underlying sensitization of depressive-like behavioral or febrile responses in developing guinea pigs. Thus, processes mediating sensitization of neuroinflammatory-based depressive-like behavior following early-life attachment disruption in this model appear to differ from those previously found to underlie neuroinflammatory priming in adults. [ABSTRACT FROM AUTHOR]

Background: Preterm labour (PTL) is any delivery after 20 weeks and before the end of 37 weeks' gestation. In PTL, using tocolytic drugs has been proven to prolong pregnancy. A commonly tocolytic drug as nifedipine, which appears to be more effective than ß2-adrenergic-receptor agonists and magnesium sulfate. The aim of the present study was to study the tocolytic action of nifedipine combined with sildenafil citrate and if the combination is more effective than nifedipine alone in inhibiting threatened PTL. Methods: This interventional study was conducted at Obstetrics and Gynecology Department, Zagazig University, from April 2019 to February 2020. Included 96 pregnant women who suffered from threatened PTL. They were divided into two classes, class (A) included 48 cases who received nifedipine only and class (B) included 48 cases who received nifedipine with sildenafil. Results: our study showed that a statistically significant difference according to maternal heart rate and mean blood pressure before and after treatment in nifedipine with sildenafil group. But in nifedipine only group, there was no statistically significant difference according to maternal heart rate before and after treatment. There was statistically significant difference between the two studied classes in delivery 24,48 and 72 hours after admission with less early deliveries among the nifedipine with sildenafil group. Regarding mode of delivery, there was no statistically significant difference between nifedipine and nifedipine with sildenafil groups. Conclusions: Vaginal sildenafil citrate (SC) combined with nifedipine is more effective tocolytic therapy during threatened PTL. [ABSTRACT FROM AUTHOR]

Compelling evidence supports the hypothesis that stress negatively impacts cancer development and prognosis. Irrespective of its physical, biological or psychological source, stress triggers a physiological response that is mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic adrenal medullary axis. The resulting release of glucocorticoids and catecholamines into the systemic circulation leads to neuroendocrine and metabolic adaptations that can affect immune homeostasis and immunosurveillance, thus impairing the detection and eradication of malignant cells. Moreover, catecholamines directly act on β-adrenoreceptors present on tumor cells, thereby stimulating survival, proliferation, and migration of nascent neoplasms. Numerous preclinical studies have shown that blocking adrenergic receptors slows tumor growth, suggesting potential clinical benefits of using β-blockers in cancer therapy. Much of these positive effects of β-blockade are mediated by improved immunosurveillance. The present trial watch summarizes current knowledge from preclinical and clinical studies investigating the anticancer effects of β-blockers either as standalone agents or in combination with conventional antineoplastic treatments or immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: In medical facilities all throughout the world, many specialists adopt the radial method for coronary angioplasty. In comparison to conventional femoral access, using radial access is linked to less vascular problems and the same success rate. Spasm of the radial artery is one of the key issues with this approach. The radial artery's short size and high density of alpha-1 adrenergic receptors in this artery can cause the spasm to progress more quickly. The purpose of this study was to determine whether radial artery dilation and decreased patient pain and sympathetic response may occur during radial puncture using a topical gel formulation of lidocaine, verapamil, and nitroglycerin. Methods: In a single-center, double-blind research, patients receiving elective trans-radial angioplasty were randomly assigned to the placebo or therapeutic gel groups. 1 cm near the radial styloid process, a placebo or therapeutic gel is placed. Ultrasound was used to gauge the size of the radial artery. Visual analogue scale (VAS) was used to measure radial pain, and changes in systolic (SBP), diastolic (DBP), and heart rate were used to measure the sympathetic response (HR). The radial artery spasm score was used to determine the incidence of spasm. Results: This study involved 60 patients, with 30 patients in each group. When compared to the placebo group, the group receiving the therapeutic gel showed a substantial increase in radial artery size (mean diameter, mm: 2.95 ± 0.48 vs. 2.54 ± 0.43, p = 0.001; area, cm2: 0.07 vs. 0.05, p = 0.001). Patients receiving therapeutic gel experienced considerably less radial discomfort during radial puncture (4 (1-5) vs. 2 (1-2), p = 0.003. There were no radial artery spasms in any of the groups. Conclusion: According to our findings, giving patients having trans-radial angioplasty a topical gel combination of verapamil, nitroglycerin, and lidocaine before to the procedure greatly expands the size of the radial artery and significantly lessens radial pain during radial puncture. [ABSTRACT FROM AUTHOR]