Epithelium-derived 6-nitrodopamine modulates noradrenaline-induced contractions in human seminal vesicles.

AIMS: To evaluate the basal release of 6-nitrodopamine (6-ND) from human isolated seminal vesicles (HISV) and to characterize its action and origin. MAIN METHODS: Left HISV obtained from patients undergoing prostatectomy surgery was suspended in a 3-mL organ bath containing warmed (37 °C) and gassed (95%O2:5%CO2) Krebs-Henseleit's solution (KHS) with ascorbic acid. An aliquot of 2 mL of the supernatant was used to quantify catecholamines by LC-MS/MS. For functional studies, concentration-responses curves to catecholamines were obtained, and pEC50 and Emax values were calculated. Detection of tyrosine hydroxylase and S100 protein were also carried out by both immunohistochemistry and fluorescence in-situ hybridization assays (FISH). KEY FINDINGS: Basal release of 6-ND was higher than the other catecholamines (14.76 ± 14.54, 4.99 ± 6.92, 3.72 ± 4.35 and 5.13 ± 5.76 nM for 6-ND, noradrenaline, adrenaline, and dopamine, respectively). In contrast to the other catecholamines, the basal release of 6-ND was not affected by the sodium current (Nav) channel inhibitor tetrodotoxin (1 µM; 10.4 ± 8.9 and 10.4 ± 7.9 nM, before and after tetrodotoxin, respectively). All the catecholamines produced concentration-dependent HISV contractions (pEC50 4.1 ± 0.2, 4.9 ± 0.3, 5.0 ± 0.3, and 3.9 ± 0.8 for 6-ND, noradrenaline, adrenaline, and dopamine, respectively), but 6-ND was 10-times less potent than noradrenaline and adrenaline. However, preincubation with very low concentration of 6-ND (10-8 M, 30 min) produced significant leftward shifts of the concentration-response curves to noradrenaline. Immunohistochemical and FISH assays identified tyrosine hydroxylase in tissue epithelium of HISV strips. SIGNIFICANCE: Epithelium-derived 6-ND is the major catecholamine released from human isolated seminal vesicles and that modulates smooth muscle contractility by potentiating noradrenaline-induced contractions.

Norepinephrine may promote the progression of Fusobacterium nucleatum related colorectal cancer via quorum sensing signalling.

Fusobacterium nucleatum (F. nucleatum) is closely correlated with tumorigenesis in colorectal cancer (CRC). We aimed to investigate the effects of host norepinephrine on the carcinogenicity of F. nucleatum in CRC and reveal the underlying mechanism. The results revealed that both norepinephrine and bacterial quorum sensing (QS) molecule auto-inducer-2 (AI-2) were positively associated with the progression of F. nucleatum related CRC (p < 0.01). In vitro studies, norepinephrine induced upregulation of QS-associated genes and promoted the virulence and proliferation of F. nucleatum. Moreover, chronic stress significantly increased the colon tumour burden of ApcMin/+ mice infected with F. nucleatum (p < 0.01), which was decreased by a catecholamine inhibitor (p < 0.001). Our findings suggest that stress-induced norepinephrine may promote the progression of F. nucleatum related CRC via bacterial QS signalling. These preliminary data provide a novel strategy for the management of pathogenic bacteria by targeting host hormones-bacterial QS inter-kingdom signalling.

Effects of noise exposure on stress hormone changes during task performance in young Korean men: quasi-experimental study.

Numerous studies have suggested that noise exposure might be associated with changes in stress hormone levels. However, quantitative evidence for these effects in humans is rare and remains controversial. This study aimed to investigate the acute effects of exposure to noise and its different levels on stress hormone changes in task performance. Quasi-experimental noise exposure environment was established for 90 male university student volunteers in their twenties, and each was exposed to different noise levels during task performance. The stress hormones tested included cortisol, adrenocorticotropic hormone (ACTH), adrenaline, and noradrenaline. A one-way ANOVA was performed to investigate differences in hormone levels measured in the three groups according to the noise exposure levels (35, 45, or 75 dB). Analysis of covariance (ANCOVA) was used to adjust for confounding factors that might affect hormone levels. After adjusting for confounders, significant exposure-dependent differences were found in hormone levels in salivary cortisol, serum cortisol, serum ACTH, and serum adrenaline. The amount of hormonal increase in 75 dB exposure group compared to 35 or 45 dB groups was detected. Similar results were also seen in the rate of change analysis. Our findings indicate that short-term noise exposure during task performance elevates stress hormone levels. Further, the extent of stress hormone alterations varies with noise exposure levels. Changes in hormone levels are an objective measure that may be used to identify health effects and stress responses in various noise environments.

Sleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes.

Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent type of cell death activated by the excessive accumulation of intracellular copper. Here, we showed that 16 weeks of sleep fragmentation (SF) resulted in elevated copper levels in the male mouse heart and exacerbated myocardial ischemia-reperfusion injury with increased myocardial cuproptosis and apoptosis. Mechanistically, we found that SF promotes sympathetic overactivity, increases the germination of myocardial sympathetic nerve terminals, and increases the level of norepinephrine in cardiac tissue, thereby inhibits VPS35 expression and leads to impaired ATP7A related copper transport and copper overload in cardiomyocytes. Copper overload further leads to exacerbated cuproptosis and apoptosis, and these effects can be rescued by excision of the sympathetic nerve or administration of copper chelating agent. Our study elucidates one of the molecular mechanisms by which sleep disorders aggravate myocardial injury and suggests possible targets for intervention.

Treatment of fibromyalgia among patients with mastalgia and fibromyalgia improved mastalgia.

OBJECTIVES: The aim of this study is to examine the effect of fibromyalgia (FM) treatment on mastalgia by performing fibromyalgia screening in patients who applied for mastalgia and whose underlying cause could not be found. METHODS: Patients who applied to Kocaeli University General Surgery Outpatient Clinic between November 2017 and November 2020 with breast pain were included (n=120). Patients without cancer, systemic disease, previous breast surgery, and breast mass larger than 3 cm (n=30) were referred to the Physical Therapy and Rehabilitation Outpatient Clinic. A total of 13 patients (43%) were diagnosed with FMS. Twelve of them were given selective serotonin-noradrenaline reuptake inhibitor (duloxetine) treatment for 3 months. Turkish version of the Short Form - 36 (SF-36) quality of life scores, Visual Analog Scale (VAS), Cardiff breast pain score before and after treatment were compared. The remaining 17 patients were followed as only mastalgia. RESULTS: Patients with fibromyalgia and mastalgia had similar demographic results. At the end of the 3rd month, the complaints of breast pain completely regressed in all of the patients. Statistically significant changes were detected in VAS score, the number of trigger points, and SF-36 quality of life scores, Cardiff breast pain score after duloxetine treatment. CONCLUSION: In the presence of unexplained mastalgia, fibromyalgia should be kept in mind. Duloxetine treatment improved the breast pain and quality of life in patients with mastalgia and fibromyalgia.

Effects of morphine on conditioned place preference and pain are independent of uptake­2.

Morphine changes neurotransmitter release, including norepinephrine, dopamine, and serotonin. Decynium­22 (D22) inhibits an alternative neurotransmitter removal pathway, namely uptake­2. Uptake­2 includes plasma membrane monoamine transporter (PMAT) and organic cation transporters that have a low affinity, but high capacity for uptake of various monoamines such as norepinephrine, dopamine, and serotonin. This study was done to assess the effect of uptake­2 inhibition on morphine­induced conditioned place preference (CPP) and analgesia. In this study, the effects of morphine and/or D22 on CPP were evaluated following intraperitoneal injection in mice. Afterward, changes in motor activity were evaluated by the open field test. Using the tail­flick model, the effects of D22 and/or morphine were evaluated on the pain threshold. The results showed that 20 mg/kg of morphine induced a place preference response. D22, at the dose of 0.03 mg/kg, caused place avoidance, while at the dose of 0.3 mg/kg, it produced a notable place preference response. Co­administration of D22 and morphine showed that morphine reversed the CPP aversion induced by D22 at the lowest dose. Motor activity did not alter. In the tail­flick test, morphine, at the dose of 3 mg/kg but not 1 mg/kg, increased the pain threshold. D22 induced significant analgesic responses. Co­administration of D22 and morphine caused considerable analgesic effects. The findings revealed that D22 induced both conditioned aversion and preference depending on the dose while morphine induced CPP. Both drugs produced analgesia.

High-dose vitamin C improves norepinephrine level in patients with septic shock: A single-center, prospective, randomized controlled trial.

BACKGROUND: The effects of vitamin C supplementation on patients with septic shock remain controversial. We aimed to evaluate the effects of different vitamin C dosages on norepinephrine (NE) synthesis in adult patients with septic shock. METHODS: A total of 58 patients with septic shock admitted to our intensive care unit (ICU) between July 2021 and December 2022 were included. Patients were randomly divided into 3 groups: high-dose vitamin C (150 mg/kg/d, group A), low-dose vitamin C (50 mg/kg/d, group B), and placebo (group C). NE synthesis-related indicators (dopamine-ß-hydroxylase [DßH], tyrosine hydroxylase [TH], tetrahydrobiopterin [BH4], and dopamine [DA]), plasma NE, and vitamin C levels were measured every 24 hours and analyzed. All-cause mortality within 28 days and other clinical outcomes (including Acute Physiology and Chronic Health Evaluation [APACHE], Sequential Organ Failure Assessment [SOFA], and Multiple-Organ Dysfunction Syndrome [MODS] scores) were compared. RESULTS: Changes in TH, BH4, and DßH levels at 96 hours in groups A and B were greater than those in group C. These differences became more pronounced over the course of the intravenous vitamin C administration. Significant differences between groups A and C were detected at 96-hours TH, 72-hours BH4, 96-hours BH4, 96-hours DA, and DßH levels every 24 hours. The 96-hours TH, 96-hours BH4, and 48-hours DßH in group B were significantly higher than those in group C. The NE levels every 24 hours in groups A and B were higher than those in group C, group A and group C had a statistically significant difference. The 96-hours exogenous NE dosage in groups A and B was significantly lower than that in group C. No significant reductions in APACHE, SOFA, or MODS scores were observed in the vitamin C group, including the duration of ICU stay and mechanical ventilation. The 28-days mortality was lower in groups A and B than in group C (0%, 10%, and 16.67%, P = .187), but the difference was not significant. CONCLUSION: For patients with septic shock, treatment with vitamin C significantly increased TH, BH4, and DßH levels and reduced the exogenous NE dosage, but did not significantly improve clinical outcomes.

Phasic locus coeruleus activity enhances trace fear conditioning by increasing dopamine release in the hippocampus.

Locus coeruleus (LC) projections to the hippocampus play a critical role in learning and memory. However, the precise timing of LC-hippocampus communication during learning and which LC-derived neurotransmitters are important for memory formation in the hippocampus are currently unknown. Although the LC is typically thought to modulate neural activity via the release of norepinephrine, several recent studies have suggested that it may also release dopamine into the hippocampus and other cortical regions. In some cases, it appears that dopamine release from LC into the hippocampus may be more important for memory than norepinephrine. Here, we extend these data by characterizing the phasic responses of the LC and its projections to the dorsal hippocampus during trace fear conditioning in mice. We find that the LC and its projections to the hippocampus respond to task-relevant stimuli and that amplifying these responses with optogenetic stimulation can enhance long-term memory formation. We also demonstrate that LC activity increases both norepinephrine and dopamine content in the dorsal hippocampus and that the timing of hippocampal dopamine release during trace fear conditioning is similar to the timing of LC activity. Finally, we show that hippocampal dopamine is important for trace fear memory formation, while norepinephrine is not.

Our brains are more likely to remember activities or incidents that stand out from typical day-to-day experiences. For instance, if your phone is stolen on the way to work, you will have a stronger memory of this experience compared to other uneventful commutes. These are known as salient events and can be emotional, surprising, or even just out of the ordinary. During salient events, an area of the brain known as the hippocampus receives chemicals called neuromodulators from other parts of the brain. These neuromodulators enhance the formation of the memory by modifying how neurons connect together in the hippocampus. One of the regions that signals to the hippocampus ­ called the locus coeruleus ­ was thought to enhance memory by releasing the neuromodulator norepinephrine. Recent studies indicate that the locus coeruleus also releases a second neuromodulator called dopamine. However, it remained unclear what causes the locus coeruleus to release dopamine, and what effect this neuromodulator has on the hippocampus. To investigate these questions, Wilmot et al. recorded and manipulated the activity of the locus coeruleus in the brains of mice experiencing salient, fearful events. The mice were exposed to a sound and, a few seconds later, a shock to the foot to illicit the formation of an aversive salient memory. If the next day, the mice responded to just the sound as if they were expecting a shock, this indicated they had remembered the aversive experience. Wilmot et al. observed that neurons in the locus coeruleus were active during the salient event, resulting in increased dopamine in the hippocampus. When the activity of these neurons was forcefully increased during relatively non-salient events, such as a quiet tone and a very mild shock, the animals still showed strong memory formation. Finally, blocking the action of dopamine in the hippocampus substantially affected memory formation, whereas blocking the action of norepinephrine did not have the same effect. These findings suggest that the locus coeruleus enhances the memory of salient events by increasing the levels of dopamine in the hippocampus not norepinephrine, as was previously thought. Developing a better understanding of how the locus coeruleus regulates memory may lead to improved treatments for various neurological disorders, like Alzheimer's disease, which are associated with neuromodulators taking on different roles in the hippocampus.

Understanding How Clinicians Personalize Fluid and Vasopressor Decisions in Early Sepsis Management.

Importance: Recent sepsis trials suggest that fluid-liberal vs fluid-restrictive resuscitation has similar outcomes. These trials used generalized approaches to resuscitation, and little is known about how clinicians personalize fluid and vasopressor administration in practice. Objective: To understand how clinicians personalize decisions about resuscitation in practice. Design, Setting, and Participants: This survey study of US clinicians in the Society of Critical Care Medicine membership roster was conducted from November 2022 to January 2023. Surveys contained 10 vignettes of patients with sepsis where pertinent clinical factors (eg, fluid received and volume status) were randomized. Respondents selected the next steps in management. Data analysis was conducted from February to September 2023. Exposure: Online Qualtrics clinical vignette survey. Main Outcomes and Measures: Using multivariable logistic regression, the associations of clinical factors with decisions about fluid administration, vasopressor initiation, and vasopressor route were tested. Results are presented as adjusted proportions with 95% CIs. Results: Among 11 203 invited clinicians, 550 (4.9%; 261 men [47.5%] and 192 women [34.9%]; 173 with >15 years of practice [31.5%]) completed at least 1 vignette and were included. A majority were physicians (337 respondents [61.3%]) and critical care trained (369 respondents [67.1%]). Fluid volume already received by a patient was associated with resuscitation decisions. After 1 L of fluid, an adjusted 82.5% (95% CI, 80.2%-84.8%) of respondents prescribed additional fluid and an adjusted 55.0% (95% CI, 51.9%-58.1%) initiated vasopressors. After 5 L of fluid, an adjusted 17.5% (95% CI, 15.1%-19.9%) of respondents prescribed more fluid while an adjusted 92.7% (95% CI, 91.1%-94.3%) initiated vasopressors. More respondents prescribed fluid when the patient examination found dry vs wet (ie, overloaded) volume status (adjusted proportion, 66.9% [95% CI, 62.5%-71.2%] vs adjusted proportion, 26.5% [95% CI, 22.3%-30.6%]). Medical history, respiratory status, lactate trend, and acute kidney injury had small associations with fluid and vasopressor decisions. In 1023 of 1127 vignettes (90.8%) where the patient did not have central access, respondents were willing to start vasopressors through a peripheral intravenous catheter. In cases where patients were already receiving peripheral norepinephrine, respondents were more likely to place a central line at higher norepinephrine doses of 0.5 µg/kg/min (adjusted proportion, 78.0%; 95% CI, 74.7%-81.2%) vs 0.08 µg/kg/min (adjusted proportion, 25.2%; 95% CI, 21.8%-28.5%) and after 24 hours (adjusted proportion, 59.5%; 95% CI, 56.6%-62.5%) vs 8 hours (adjusted proportion, 47.1%; 95% CI, 44.0%-50.1%). Conclusions and Relevance: These findings suggest that fluid volume received is the predominant factor associated with ongoing fluid and vasopressor decisions, outweighing many other clinical factors. Peripheral vasopressor use is common. Future studies aimed at personalizing resuscitation must account for fluid volumes and should incorporate specific tools to help clinicians personalize resuscitation.

Evaluation of the early use of norepinephrine in major abdominal surgery on medical and surgical postoperative complications: study protocol for a randomised controlled trial (EPON STUDY).

BACKGROUND: Post-induction anaesthesia often promotes intraoperative hypotension (IOH) that can worsen postoperative outcomes. This study aims to assess the benefit of norepinephrine versus ephedrine at the induction of anaesthesia to prevent postoperative complications following major abdominal surgery by preventing IOH. METHODS AND ANALYSIS: The EPON STUDY is a prospective single-centre randomised controlled trial with the planned inclusion of 500 patients scheduled for major abdominal surgery at the Amiens University Hospital. The inclusion criteria are patients aged over 50 years weighing more than 50 kg with an American Society of Anesthesiologists physical status score of ≥2 undergoing major abdominal surgery under general anaesthesia. Patients are allocated either to the intervention group (n=250) or the standard group (n=250). In the intervention group, the prevention of post-induction IOH is performed with norepinephrine (dilution to 0.016 mg/mL) using an electric syringe pump at a rate of 0.48 mg/h (30 mL/h) from the start of anaesthesia and then titrated to achieve the haemodynamic target. In the control group, the prevention of post-induction IOH is performed with manual titration of ephedrine, with a maximal dose of 30 mg, followed by perfusion with norepinephrine. In both groups, the haemodynamic target to maintain is a mean arterial pressure (MAP) of 65 mm Hg or 70 mm Hg for patients with a medical history of hypertension. An intention-to-treat analysis will be performed. The primary outcome is the Clavien-Dindo score assessed up to 30 days postoperatively. The secondary endpoints are the length of hospital stay and length of stay in an intensive care unit/postoperative care unit; postoperative renal function; postoperative cardiovascular, respiratory, neurological, haematological and infectious complications at 1 month; and volume of intraoperative vascular filling and mortality at 1 month. ETHICS AND DISSEMINATION: Ethical approval was obtained from the committee of protection of the persons of Ile de France in May 2021 (number 21 05 41). The authors will be involved in disseminating the research findings (through attending conferences and co-authoring papers). The results of the study will be disseminated via peer-reviewed publications and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT05276596.

A retrospective, multi-agency 'target trial emulation' for the comparison of post-resuscitation epinephrine to norepinephrine.

INTRODUCTION: Epinephrine and norepinephrine are the two most commonly used prehospital vasopressors in the United States. Prior studies have suggested that use of a post-ROSC epinephrine infusion may be associated with increased rearrest and mortality in comparison to use of norepinephrine. We used target trial emulation methodology to compare the rates of rearrest and mortality between the groups of OHCA patients receiving these vasopressors in the prehospital setting. METHODS: Adult (18-80 years of age) non-traumatic OHCA patients in the 2018-2022 ESO Data Collaborative datasets with a documented post-ROSC norepinephrine or epinephrine infusion were included in this study. Logistic regression modeling was used to evaluate the association between vasopressor agent and outcome using two sets of covariables. The first set of covariables included standard Utstein factors, the dispatch to ROSC interval, the ROSC to vasopressor interval, and the follow-up interval. The second set added prehospital systolic blood pressure and SpO2 values. Kaplan-Meier time-to-event analysis was also conducted and the vasopressor groups were compared using a multivariable Cox regression model. RESULTS: Overall, 1,893 patients treated by 309 EMS agencies were eligible for analysis. 1,010 (53.4%) received an epinephrine infusion and 883 (46.7%) received a norepinephrine infusion as their initial vasopressor. Adjusted analyses did not discover an association between vasopressor agent and rearrest (aOR: 0.93 [0.72, 1.21]) or mortality (aOR: 1.00 [0.59, 1.69]). CONCLUSIONS: In this multi-agency target trial emulation, the use of a post-resuscitation epinephrine infusion was not associated with increased odds of rearrest in comparison to the use of a norepinephrine infusion.

Impact of Serotonergic 5HT1A and 5HT2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson's Disease.

In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.

1-(Phenylselanyl)-2-(p-tolyl)indolizine: A selenoindolizine with potential antidepressant-like activity in mice mediated by the modulation of dopaminergic and noradrenergic systems.

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective ß receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and ß1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.

Trimethylamine-N-oxide aggravated the sympathetic excitation in D-galactose induced aging rats by down-regulating P2Y12 receptor in microglia.

This study aimed to determine whether trimethylamine N-oxide (TMAO) was involved in sympathetic activation in aging and the underlying mechanisms. Our hypothesis is TMAO reduces P2Y12 receptor (P2Y12R) and induces microglia-mediated inflammation in the paraventricular nucleus (PVN), then leading to sympathetic activation in aging. This study involved 18 young adults and 16 old adults. Aging rats were established by injecting D-galactose (D-gal, 200 mg/kg/d) subcutaneously for 12 weeks. TMAO (120 mg/kg/d) or 1% 3, 3-dimethyl-l-butanol (DMB) was administrated via drinking water for 12 weeks to investigate their effects on neuroinflammation and sympathetic activation in aging rats. Plasma TMAO, NE and IL-1ß levels were higher in old adults than in young adults. In addition, standard deviation of all normal to normal intervals (SDNN) and standard deviation of the average of normal to normal intervals (SDANN) were lower in old adults and negatively correlated with TMAO, indicating sympathetic activation in old adults, which is associated with an increase in TMAO levels. Treatment of rats with D-gal showed increased senescence-associated protein levels and microglia-mediated inflammation, as well as decreased P2Y12R protein levels in PVN. Plasma TMAO, NE and IL-1ß levels were increased, accompanied by enhanced renal sympathetic nerve activity (RSNA). While TMAO treatment exacerbated the above phenomenon, DMB mitigated it. These findings suggest that TMAO contributes to sympathetic hyperactivity in aging by downregulating P2Y12R in microglia and increasing inflammation in the PVN. These results may provide promising new target for the prevention and treatment of aging and aging-related diseases.

Increased ß2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the ß2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Management of hepatorenal syndrome and associated outcomes: a systematic reviews.

BACKGROUND: Hepatorenal syndrome (HRS), a multiorgan condition of acute kidney injury, is seen in advanced liver disease. This study aims to evaluate the current treatment for HRS. METHODS: The authors searched PubMed, Scopus and Google Scholar literature. After quality assessment, 31 studies were included in this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology and the population, intervention, comparison and outcome scheme were used. We included human-controlled trials that evaluate the current treatment for HRS. Two authors independently screened articles for inclusion, extracted data and assessed the quality of included studies. RESULTS: This study investigated the studies conducted on the effects of different treatments on follow-up of HRS patients. We gathered 440 articles, so 31 articles remained in our study. Of which 24 articles were conducted on terlipressin versus placebo or other treatments (midodrine/octreotide, norepinephrine, etc) that showed the higher rate of HRS reversal was detected for terlipressin in 17 studies (10 of them were significant), 2 studies achieved an insignificant lower rate of the model for end-stage liver disease score for terlipressin, 15 studies showed a decreased mortality rate in the terlipressin group (4 of them were significant). CONCLUSION: This review showed that terlipressin has a significantly higher reversal rate of HRS than the other treatments. Even the results showed that terlipressin is more efficient than midodrine/octreotide and norepinephrine as a previous medication, in reverse HRS, increasing patient survival.

A dual-response fluorescent probe for norepinephrine and viscosity and its application in depression research.

Depression is a serious mental disease that causes grievous harm to human health and quality of life. The vesicular exocytosis of noradrenaline (NE), rather than its intrinsic intracellular concentration, is more associated with depression. Based on the reports on exocytosis of NE, it is reasonable to assume that the viscosity of cells has an important effect on the release of NE. Herein, a dual-response fluorescent probe (RHO-DCO-NE) for detecting NE and viscosity was designed and synthesized. The probe can simultaneously detect NE concentration and viscosity level with negligible crosstalk between the two channels. We utilized the probe to study the effect of viscosity changes on the NE release of PC12 and the corticosterone-induced PC12 cells. The experiment data revealed that the decrease in viscosity level can accelerate the release of NE of depression cell models. The finding provides new insight into the study of the pathological mechanisms of depression.

Neural crest origin of sympathetic neurons at the dawn of vertebrates.

The neural crest is an embryonic stem cell population unique to vertebrates1 whose expansion and diversification are thought to have promoted vertebrate evolution by enabling emergence of new cell types and structures such as jaws and peripheral ganglia2. Although jawless vertebrates have sensory ganglia, convention has it that trunk sympathetic chain ganglia arose only in jawed vertebrates3-8. Here, by contrast, we report the presence of trunk sympathetic neurons in the sea lamprey, Petromyzon marinus, an extant jawless vertebrate. These neurons arise from sympathoblasts near the dorsal aorta that undergo noradrenergic specification through a transcriptional program homologous to that described in gnathostomes. Lamprey sympathoblasts populate the extracardiac space and extend along the length of the trunk in bilateral streams, expressing the catecholamine biosynthetic pathway enzymes tyrosine hydroxylase and dopamine ß-hydroxylase. CM-DiI lineage tracing analysis further confirmed that these cells derive from the trunk neural crest. RNA sequencing of isolated ammocoete trunk sympathoblasts revealed gene profiles characteristic of sympathetic neuron function. Our findings challenge the prevailing dogma that posits that sympathetic ganglia are a gnathostome innovation, instead suggesting that a late-developing rudimentary sympathetic nervous system may have been characteristic of the earliest vertebrates.

Locus Ceruleus Dynamics Are Suppressed during Licking and Enhanced Postlicking Independent of Taste Novelty.

Attending to salient sensory attributes of food, such as tastes that are new, displeasing, or unexpected, allows the procurement of nutrients without food poisoning. Exposure to new tastes is known to increase norepinephrine (NE) release in taste processing forebrain areas, yet the central source for this release is unknown. Locus ceruleus norepinephrine neurons (LC-NE) emerge as a candidate in signaling salient information about taste, as other salient sensory stimuli (e.g., visual, auditory, somatosensation) are known to activate LC neurons. To determine if LC neurons are sensitive to features of taste novelty, we used fiber photometry to record LC-NE activity in water-restricted mice that voluntarily licked either novel or familiar substances of differential palatability (saccharine, citric acid). We observed that LC-NE activity was suppressed during lick bursts and transiently activated upon the termination of licking and that these dynamics were independent of the familiarity of the substance consumed. We next recorded LC dynamics during brief and unexpected consumption of tastants and found no increase in LC-NE activity, despite their responsiveness to visual and auditory stimuli, revealing selectivity in LC's responses to salient sensory information. Our findings suggest that LC activity during licking is not influenced by taste novelty, implicating a possible role for non-LC noradrenergic nuclei in signaling critical information about taste.