NE Levels Research Articles

THE GREAT PRETENDER: COULD A PHEOCHROMOCYTOMA MANIFEST ITSELF AS A SEIZURE?

Objective: Seizures are defined as transient occurrence of signs or symptoms due to the abnormally excessive or synchronous neuronal activity in the cerebral cortex. Pheochromocytomas and paragangliomas (PPGL) are chromaffin cell tumors arising from the adrenal medulla in 80–85% of patients and from extra-adrenal sympathetic tissue in 10–20% of patients. PPGL has been referred to as ‘‘the great mimic’’ disease. We present a patient with pheochromocytoma possibly disguised as seizures. Design and method: A 44 years old woman was referred to University Clinic of Endocrinology by radiologist. Two years earlier she had syncopal crises . She complained of headache, heart palpitation and malaise, heart palpitations and fatigue during exertion and sense of panic. The maximal self-measured blood pressure was 160/100 mmHg, the pulse is 90-100 beats per min. Abdominal US: a hyperechoic change, 76x65mm was seen, then described in the right lobe of the liver. The following year she had two commotional crises of consciousness and spasms of the extremities . She had a non-specific slowing of FC on EEG on the right for 1-2 seconds. MSCT abdomenal : in the right adrenal gland, a mass 144 x 90mm, with clear borders, pressing into the liver and pushing the right kidney,. The 24h urine was collected, which confirmed a norepinephrine secreting pheochromocytoma. We administered long acting alpha blocking agent preoperatively. The complete surgical excision of the right adrenal mass was done, pathohistological diagnosis: Pheochromocytoma. The last EEG after sleep deprivation performed 2 months postoperatively was described as normal. The patient had no headache or seizure. Results: PPGLs have a notable ability of boosting NE levels systemically and hypertension, the most common sign of PPGL could facilitate the permeability of blood brain barrier to NE. Studies showed NE could play its anticonvulsant property at an appropriate concentration but has a proconvulsant effect in either too high or too low concentrations . Conclusions: The definite pathogenetic mechanisms explaining how PPGL can cause seizures are far from being clearly understood, though “the great pretender” should be considered as a possible etiological factor of seizures.

Impact of dietary analyzed calcium to phosphorus ratios and standardized total tract digestible phosphorus to net energy ratios on growth performance, bone, and carcass characteristics of pigs.

A total of 2,184 pigs (337 × 1,050, PIC; initially 12.4 ± 0.17 kg) were used in a 143-d study to evaluate the effects of feeding varying analyzed calcium to phosphorus ratios (Ca:P) at two standardized total tract digestible (STTD) phosphorus to net energy ratios (STTD P:NE). Pens of pigs (26 pigs per pen) were assigned to 1 of the 6 dietary treatments in a 2 × 3 factorial with main effects of STTD P:NE and Ca:P ratio. Diets consisted of two levels of STTD P:NE; High (1.80, 1.62, 1.43, 1.25, 1.10, and 0.99 g STTD P/Mcal NE from 11 to 22, 22 to 40, 40 to 58, 58 to 81, 81 to 104, and 104 to 129 kg, respectively); or Low (75% of the High levels), and three analyzed Ca:P ratios (0.90:1, 1.30:1, and 1.75:1). There were 14 pens per treatment. Diets were corn-soybean meal-based and contained a constant phytase concentration within each dietary phase with levels decreasing throughout the trial (phases 1 through 3, 500 FTU/kg, assumed release of 0.13% STTD P; phase 4, 400 FTU/kg, assumed release of 0.11% STTD P; phase 5, 290 FTU/kg, assumed release of 0.09% STTD P; and phase 6, 210 FTU/kg, assumed release of 0.07% STTD P). Overall, there was a Ca:P × STTD P:NE interaction (P < 0.05) observed for average daily gain (ADG), feed efficiency (G:F), final body weight (BW), hot carcass weight (HCW), bone mineral density, bone mineral content, and bone-breaking strength. When feeding Low STTD P:NE levels, increasing the analyzed Ca:P ratio decreased (linear, P < 0.001) ADG final BW, HCW, and tended to worsen G:F, bone mineral density, and bone mineral content (linear, P < 0.10). However, when feeding High STTD P:NE levels, increasing the analyzed Ca:P ratio significantly improved bone mineral content and bone mineral density (linear, P < 0.05), and tended to improve ADG and final BW (linear, P < 0.10) and G:F (quadratic P < 0.10). Additionally, increasing the analyzed Ca:P ratio worsened ADG, G:F, and bone mineralization with Low STTD P:NE but had marginal impacts when adequate STTD P:NE was fed.

Short-term arecoline exposure affected the systemic health state of mice, in which gut microbes played an important role

Arecoline is a critical bioactive component in areca nuts with toxicity and pharmacological activities. However, its effects on body health remain unclear. Here, we investigated the effects of arecoline on physiologic and biochemical parameters in mouse serum, liver, brain, and intestine. The effect of arecoline on gut microbiota was investigated based on shotgun metagenomic sequencing. The results showed that arecoline promoted lipid metabolism in mice, manifested as significantly reduced serum TC and TG and liver TC levels and a reduction in abdominal fat accumulation. Arecoline intake significantly modulated the neurotransmitters 5-HT and NE levels in the brain. Notably, arecoline intervention significantly increased serum IL-6 and LPS levels, leading to inflammation in the body. High-dose arecoline significantly reduced liver GSH levels and increased MDA levels, which led to oxidative stress in the liver. Arecoline intake promoted the release of intestinal IL-6 and IL-1β, causing intestinal injury. In addition, we observed a significant response of gut microbiota to arecoline intake, reflecting significant changes in diversity and function of the gut microbes. Further mechanistic exploration suggested that arecoline intake can regulate gut microbes and ultimately affect the host's health. This study provided technical help for the pharmacochemical application and toxicity control of arecoline.

Shiwei Qingwen decoction regulates TLR4/NF-κB signaling pathway and NLRP3 inflammasome to reduce inflammatory response in lipopolysaccharide-induced acute lung injury

Ethnopharmacological relevanceShiwei Qingwen decoction (SWQ), a Chinese herbal formula based on the classic traditional Chinese medicine prescription Yu Ping Feng San, has shown efficacy in preventing and treating early pneumonia with good clinical outcomes. However, its underlying mechanism is yet unclear. Aim of the studyTo clarify the preventive and therapeutic effects of SWQ on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore the underlying mechanism by which SWQ influences pneumonia. Materials and methodsFirst, the chemical composition of SWQ was preliminarily determined by high performance liquid chromatography (HPLC), and the impact of SWQ (3.27, 6.55, and 13.1 g/kg) was assessed in the LPS-induced ALI rat model. Next, its inflammatory pathway was determined via network pharmacology. Finally, the molecular mechanism of SWQ was validated using a rat ALI model and a THP-1 cell inflammation model. ResultsHPLC identified chlorogenic acid, prime-O-glucosylcimifugin, calycosin, and 5-O-methylaminoside in the chemical profile of SWQ. In the ALI model, SWQ alleviated ALI by reducing lung wet/dry weight ratio (W/D) and preventing histopathological damage to the lungs. At the same time, SWQ decreased penetration of inflammatory mediators by upregulating AQP1 and AQP5 and endothelial nitric oxide synthase (eNOS). Pretreatment with SWQ downregulated white blood cells and neutrophils count in BALF and suppressed LPS-induced expression levels of MPO, NE, and pro-inflammatory factors (TNF-α, IL-1β, IL-6, and iNOS). Network pharmacology showed that SWQ was associated with TLR4/NF-κB inflammation pathway. Moreover, pretreatment with SWQ reduced the expression level of TLR4/NF-κB signaling pathway-associated proteins (TLR4, Myd88, p-IκB, and p-p65) and NLRP3 inflammasome (NLRP3, ASC, caspase-1, and cleaved-IL-1β) in vivo and vitro. ConclusionsThe present study demonstrates that SWQ can reduce inflammation in ALI by inhibiting TLR4/NF-κB and NLRP3 inflammasome activation.

Screening the effective components of Suanzaoren decoction on the treatment of chronic restraint stress induced anxiety-like mice by integrated chinmedomics and network pharmacology

BackgroundSuanzaoren decoction (SZRD) is a classical traditional Chinese prescription. It is widely used to treat mental disorders, including insomnia, anxiety, and depression, in China and other Asian countries. However, the effective components and mechanisms underlying SZRD remained unclear. PurposeWe aimed to develop a new strategy to discover the effects and potential mechanisms of SZRD against anxiety and to further reveal the effective components of SZRD in treating anxiety. Study design and methodsFirst, the chronic restraint stress (CRS)-induced mouse model of anxiety was orally administered SZRD, and behavioral indicators and biochemical parameters were applied to assess efficacy. A chinmedomics strategy based on UHPLC-Q-TOF-MS technology and network pharmacology were then used to screen and explore potentially effective components and therapeutic mechanisms. Finally, molecular docking was applied to further confirm the effective components of SZRD, and a multivariate network for anxiolytic effects was constructed. ResultsSZRD exerted anxiolytic effects by increasing the percentage of entries into open arms and the time spent in open arms; improving hippocampal 5-HT, GABA, and NE levels; and increasing serum corticosterone (CORT) and corticotropin-releasing hormone (CRH) levels caused by CRS challenge. Beside, SZRD exerted a sedative effect by decreasing sleep time and prolonging sleep latency with no muscle relaxation effect in CRS mice. A total of 110 components were identified in SZRD, 20 of which were absorbed in the blood. Twenty-one serum biomarkers involved in arachidonic acid, tryptophan, sphingolipid, and linoleic acid metabolism were identified after SZRD intervention. Finally, a multivariate network including prescription-effective components-targets-pathway of SZRD treating anxiety, including 11 effective components, 4 targets and 2 pathway was constructed. ConclusionThe current study demonstrated that integrating chinmedomics and network pharmacology was a powerful approach to investigating the effective components and therapeutic mechanisms of SZRD and provided a solid basis for the quality marker (Q-marker) of SZRD.

A combination of umbilical cord mesenchymal stem cells and monosialotetrahexosy 1 ganglioside alleviates neuroinflammation in traumatic brain injury.

Neuro-inflammation and activated microglia play important roles in neuron damage in the traumatic brain injury (TBI). In this study, we determined the effect of neural network reconstruction after human umbilical cord mesenchymal stem cells (UMSCs) combined with monosialotetrahexosy 1 ganglioside (GM1) transplantation and the effect on the neuro-inflammation and polarization of microglia in a rat model of TBI, which was established in male rats using a fluid percussion brain injury device. Rats survived until day 7 after TBI were randomly treated with normal control (NC), saline (NS), GM1, UMSCs, and GM1 plus UMSCs. Modified neurological severity score (mNSS) was assessed on days 7 and 14, and the brain tissue of the injured region was collected. Immunofluorescence, RT-PCR, and western blot analysis found that inhibitory neuro-inflammatory cytokines TGF-β and CD163 protein expression levels in injured brain tissues were significantly increased in rats treated with GM1 + UMSCs, GM1, or UMSCs and were up-regulated compared to saline-treated rats. Neuro-inflammatory cytokines IL-6, COX-2 and iNOS protein expressions were down-regulated compared to rats treated with saline. The protein expression levels of NE, NF-200, MAP-2 and β-tubulin III were increased in the injured brain tissues from rats treated with GM1 + UMSCs, or GM1 and UMSCs alone compared to those in the rats treated with NS. The protein expression levels in rats treated with GM1 plus UMSCs were most significant on day 7 following UMSC transplantation. The rats treated with GM1 plus UMSCs had the lowest mNSS compared with that in the other groups. These data suggest that UMSCs and GM1 promote neural network reconstruction and reduce the neuro-inflammation and neurodegeneration through coordinating injury local immune inflammatory microenvironment to promote the recovery of neurological functions in the TBI.

Norepinephrine inhibits CD8+ T-cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma

BackgroundMental stress-induced neurotransmitters can affect the immune system in various ways. Therefore, a better understanding of the role of neurotransmitters in the tumour immune microenvironment is expected to promote the development of novel anti-tumour therapies.MethodsIn this study, we analysed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments and experiments in vitro were used to reveal the specific mechanism of norepinephrine’s (NE) effect on immunotherapy.ResultsThe plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of C-X-C Motif Chemokine Ligand 9 (CXCL9) and adenosine (ADO) in tumour cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/β-catenin signalling pathway plays a crucial role in this progression.ConclusionNE can affect the secretion of CXCL9 and ADO in tumour cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD).

The Effect of Chinese Agarwood Essential Oil with Cyclodextrin Inclusion against PCPA-Induced Insomnia Rats.

To study the extraction process of agarwood active ingredients (AA) and investigate the safety and effectiveness of AA in the treatment of insomnia rats by nasal administration. A β-cyclodextrin (β-CD) inclusion compound (a-β-CD) was prepared from agarwood essential oil (AEO), and the preparation process was optimized and characterized. The safety of AA in nasal mucosa was evaluated through Bufo gargarizans maxillary mucosa and rat nasal mucosa models. Insomnia animal models were replicated by injecting p-chlorophenylalanine (PCPA), conducting behavioral tests, and detecting the expression levels of monoamine neurotransmitters (NE and 5-HT) and amino acids (GABA/Glu) in the rat hypothalamus. The optimum inclusion process conditions of β-CD were as follows: the feeding ratio was 0.35:1.40 (g:g), the inclusion temperature was 45 °C, the inclusion time was 2 h, and the ICY% and IEO% were 53.78 ± 2.33% and 62.51 ± 3.21%, respectively. The inclusion ratio, temperature, and time are the three factors that have significant effects on the ICY% and IEO% of a-β-CD. AA presented little damage to the nasal mucosa. AA increased the sleep rate, shortened the sleep latency, and prolonged the sleep time of the rats. The behavioral test results showed that AA could ameliorate depression in insomnia rats to a certain extent. The effect on the expression of monoamine neurotransmitters and amino acids in the hypothalamus of rats showed that AA could significantly reduce NE levels and increase the 5-HT level and GABA/Glu ratio in the hypothalamus of insomnia rats. The preparation of a-β-CD from AEO can reduce its irritation, improve its stability, increase its curative effect, and facilitate its storage and transport. AA have certain therapeutic effects on insomnia. The mechanism of their effect on rat sleep may involve regulating the expression levels of monoamine neurotransmitters and amino acids in the hypothalamus.

Dose-dependent biological toxicity of green synthesized silver nanoparticles in rat’s brain

Metal nanoparticles, in general, and silver nanoparticles (AgNPs), in particular, have been the focus of numerous studies over the last two decades. Recently, the green synthesis of metal nanoparticles has been favored over chemical synthesis due to its low toxicity and easy preparation. The present study aims to investigate the dose-dependent toxicity of green synthesized AgNPs on rats’ brains. Thirty-four Wistar male rats were divided into four groups. The first, second, and third groups were administered for 14 days with three different doses (0.5, 5, and 10 mg/kg) of AgNPs, respectively. The fourth group, which served as a control group, was given normal saline for the same period. The toxicity of the green synthesized AgNPs on the cortical and hippocampal levels of the oxidative stress markers (MDA, NO, and GSH) as well as the activity of acetylcholinesterase (AchE) and the monoamine neurotransmitters (DA, NE, and 5H-T) were investigated. AgNPs showed minimal oxidative stress in the cortex and hippocampus for the administered doses. However, AgNPs showed an inhibitory effect on AchE activity in a dose-dependent manner and a decrease in the 5H-T and NE levels. The green synthesized AgNPs showed an ultrastructural change in the cellular membranes of the neurons. The green synthesis of AgNPs has reduced their cytotoxic oxidative effects due to their capping with biologically compatible and boosting molecules such as flavonoids. However, another neurotoxicity was observed in a dose-dependent manner.

Potential Therapeutic Effects of NAMPT-Mediated NAD Biosynthesis in Depression In Vivo.

This study aimed to investigate the potential therapeutic effects of nicotinamide phosphoribosyltransferase (NAMPT)-mediated adenine dinucleotide (NAD) biosynthesis in depression models in vivo. Namptflox/flox mice were used to evaluate the role of NAMPT in depression. NAMPT and NAD levels in the prefrontal cortex (PFC) were measured, and depression-associated behavior, cognitive function, and social interaction were evaluated. The expression levels of BDNF, pCREB, CREB, monoamine neurotransmitters, and corticosterone (CORT) were also detected in the PFC. The contents of NAMPT and NAD decreased in the PFC in Namptflox/flox mice. Namptflox/flox mice showed depression-like behaviors, cognitive function deterioration, decreased social ability, and decreased dominance. Meanwhile, there were decreased expression levels of the pCREB/CREB ratio, but not BDNF, in the PFC. Levels of DA, 5-HT, and NE were decreased, and CORT was activated in the PFC of Namptflox/flox mice. Additionally, the role of NAMPT-NAD was examined in rats treated with nicotinamide riboside (NR) after being exposed to chronic unexpected mild stress (CUMS). NR reversed the decreased NAMPT expression in the PFC and HIP, and the NAD content in the PFC, but not HIP in rats with CUMS-induced depression. NR also improved depressive- and anxiolytic-like behaviors, locomotor activity, and cognitive function. BDNF expression and the pCREB/CREB ratio were significantly increased in both the PFC and HIP after NR treatment. The activation of CORT and decreased content of DA were reversed after NR treatment in the PFC. There was no difference in the 5-HT content among groups in both the PFC and HIP. Taken together, NAD synthesis induced by NAMPT could be associated with depression-like behaviors in mice, and the elevated NAD level by NR improved depression in rats.

Quinazolinealkylthio derivative targets norepinephrine and calcitonin gene-related peptide to improve behavior and radiographic score in the rat model of cervical vertigo.

The present study investigated the effect of quinazolinealkylthio derivative(QAD) on cervical vertigo in the rat model and explored the underlying mechanism. Treatment of the cervical vertigo rats with QAD led to a significant (P<0.05) improvement in balance beam score compared to the model group. Cervical vertigo-mediated reduction in CGRP level in rat plasma samples was effectively inhibited on treatment with QAD. Treatment with QAD led to a significant (P<0.05) reduction in cervical vertigo-induced increase in ET-1 and NE levels in rats. An increase in NO production by cervical vertigo induction showed a significant (P<0.05) decrease in rats by QAD treatment. The QAD treatment of the rats significantly (P<0.05) inhibited cervical vertigo-induced increase in radiographic score on day 56. The radiographic score in cervical vertigo rats was decreased to 0.42 on treatment with QAD compared to 8.2 in the model group. Therefore, QAD treatment of the cervical vertigo rats improves behavioral score and inhibits radiographic score. It upregulates CGRP expression and suppresses ET-1, NE and NO levels in a rat model of cervical vertigo. Thus, QAD can be used for the treatment of cervical vertigo however, further investigations are required to study the mechanism in detail.

Phenoxazine-based red-emitting fluorescence probe for specific detection and imaging of endogenous neutrophil elastase in vitro and in vivo

Neutrophil elastase is a crucial serine protease, which can be acted as a biomarker of inflammatory-related diseases. Therefore, visual monitoring of NE level is of great significance for studying the occurrence and development of NE-related disease. As far as we know, up till now only five red-emitting fluorescence probes for NE detection with low fluorescent enhancement have been reported. In order to improve the development of NE detection, we developed a novel NE fluorescent probe BP-NE by using a rarely used red-emitting fluorophore BP, which shows extremely high quantum yield. As expected, BP-NE can successfully detect NE activity with low limit of detection, high fluorescence signal-to-noise ratio and high affinity compare with those previous reported red-emitting NE fluorescent probes. More importantly, BP-NE is able to realize quantitative analysis of endogenous NE levels in three different living cell lines (SKOV3, HepG2 and HeLa) and in zebrafish. The results indicate that BP-NE will promisingly facilitate the NE disease research in vitro and in vivo.

Abstract 11977: Dapagliflozin Downregulates Adrenal G Protein-Coupled Receptor-Kinase-2 to Exert Sympatholysis in Heart Failure

Introduction: Dapagliflozin is a sodium-glucose co-transporter (SGLT)-2 inhibitor exerting several cardiorenal protective effects independently of blood glucose regulation. Adrenal G protein-coupled receptor kinase (GRK)-2 upregulation is a major driver of circulating catecholamine (CA) elevation and sympathetic nervous system (SNS) hyperactivity, especially in heart failure (HF). GRK2 severely dysregulates adrenal sympatho-inhibitory α 2 -adrenergic receptors (ARs), leading to unchecked, chronically elevated CA secretion. Hypothesis: SGLT2 inhibition with dapagliflozin lowers SNS hyperactivity in part by opposing adrenal GRK2 actions. Methods: We used the rat pheochromocytoma PC12 cell line expressing human α 2A AR, as well as freshly isolated adrenal glands from rats treated with dapagliflozin in vivo. Results: Dapagliflozin treatment for 7 consecutive days (20 mg/kg/d in drinking water) led to a significant reduction in blood circulating NE levels (217+67 pg/ml, n=6), compared to control, vehicle-treated rats (363+77 pg/ml, n=6, p&lt;.05), suggesting reduced SNS activity. This was accompanied by reduced GRK2 and tyrosine hydroxylase (TH) mRNA and protein levels in dapagliflozin-treated rat adrenals vs. vehicle-treated animal-derived glands, indicating reduced adrenal CA synthesis and secretion. Finally, adrenal α 2 AR density was higher in dapagliflozin- vs. vehicle-treated rats(51.3+7.3 vs. 26.1+8.1 fmol/mg of protein, respectively; n=12 glands from 6 animals per group, p&lt;.05). GRK2 and TH downregulation were also observed in PC12 cells treated with 5 μM dapagliflozin for 24 hours. Importantly, α 2 AR-dependent inhibition of CA secretion was markedly enhanced 24 hrs post-dapagliflozin application. This was due to reduced GRK2-dependent receptor desensitization induced by dapagliflozin, since this effect was abolished in PC12 cells overexpressing GRK2. Conclusions: Dapagliflozin exerts a sympatholytic action in the adrenal medulla via downregulation of both TH, thus reducing CA biosynthesis, and GRK2, thus reducing α 2 AR desensitization to lower CA secretion. This adrenal-mediated sympatholysis may be part of the increasingly apparent cardiovascular benefits of SGLT2 inhibitors in human HF irrespective of diabetic status.

PSXIII-10 Association of Fatty Acids, Prebiotics and Zinc Proteinate to Support Weaned Piglet Growth in Antibiotic Growth Promoter Free Diets

Abstract To evaluate the association of fatty acids, prebiotics and zinc proteinate (Viligen NE) in weaned piglet diets without AGP, 80 piglets averaging 6.69±0.19 kg (21-days old) were distributed in randomized blocks design. Eight replicates of one male and one female were used for each of five treatments: positive control (an antibiotic growth promoter; 0.02% Halquinol 60%), negative control (no additive) and 3 levels of Viligen NE (0.10, 0.14 and 0.18%). Daily feed intake (DFI), average daily gain (ADG) and feed conversion (FC) were determined from 21 to 35 and 36 to 49 days of age. At the end of the experiment, jejunum content was collected to evaluate Lactobacillus sp and Enterobacteria sp counts, and cecum content for Bifidobacterium sp and Clostridium perfringens counts. The negative control had the worst ADG (P=0.0004) and FC (P=0.0357) from 21 to 35 days and ADG (P=0.0196) from 21 to 49 days. All levels of Viligen NE showed the same performance as 0.02% Halquinol, for both portions of the feeding period. The optimal Viligen NE levels for ADG, estimated by quadratic and broken line models, were 0.137 and 0.100%, respectively. Significant linear relationships were found between Viligen NE and FC (negative from 21 to 35 days) and ADG (positive from 21 to 46 days). Jejunal Lactobacillus count was least for Halquinol (P=0.0001). Cecal Bifidobacterium count was greater (P=0.0063) for the negative control and 0.18% Viligen NE, while Clostridium count was less (P=0.0008) for 0.10 and 0.18% Viligen NE. Quadratic and broken line models estimated less jejunal Enterobacteria sp count with 0.110 and 0.070% of Viligen NE, respectively, less cecal Clostridium count was estimated at 0,096 and 0,079% of Viligen NE, respectively. Under the conditions of this experiment, Viligen NE in weaned piglet diets at 0.10% or greater supported growth without detrimental effects on intestinal microbiota populations.

Epidural Anesthesia versus General Anesthesia for Total Knee Arthroplasty: Influences on Perioperative Cognitive Function and Deep Vein Thrombosis.

Purpose This research mainly discussed the impacts of epidural anesthesia (EA) and general anesthesia (GA) on perioperative cognitive function (CF) and deep vein thrombosis (DVT) in patients undergoing total knee arthroplasty (TKA). Methods One hundred and twenty-four patients undergoing TKA in our hospital between July 2015 and October 2021 were selected, of which 74 patients received EA (research group) and the other 50 patients received GA (control group). Perioperative CF, DVT, stress response indicators (norepinephrine, NE; cortisol, Cor), and heart rate (HR) levels were observed and compared. Risk factors affecting DVT of TKA patients were analyzed by logistic regression. Results The research group had statistically better CF than the control group, with notably lower NE, Cor, and HR levels and incidence of DVT. Logistic regression analysis showed that the type of anesthesia and MoCA were risk factors for DVT in TKA patients. Conclusion EA is more feasible for patients undergoing TKA, which is conducive to improving their CF, relieving stress responses, and reducing the incidence of DVT, with a certain sedative effect.

The protective effect of gamma aminobutyric acid B receptor activation on sympathetic nerve remodeling via the regulation of M2 macrophage polarization after myocardial infarction

Introduction & objectivesAcute myocardial infarction (AMI) in coronary heart disease is a leading cause of sudden death primarily due to malignant ventricular arrhythmias (VAs). Inflammatory cell infiltration and inflammation-induced overactivation of sympathetic nerves are the major cause of VAs in AMI pathophysiological processes. Type 2 macrophages play an anti-inflammatory role in AMI. Targeting macrophages may be a therapeutic strategy to prevent VAs post AMI. We found that gamma aminobutyric acid (GABA) promotes macrophages polarized to M2 and hypothesized that GABA might exert anti-inflammatory effects by promoting type 2 macrophage polarization in AMI. We aim to characterized GABAB receptor distribution, function, and mechanisms in M2 macrophage polarization and explored the functional aspect of GABAB receptor activation in sympathetic remodeling. ResultsGamma aminobutyric acid B receptors were expressed on macrophage surface both in vitro and in vivo. GABAB receptor agonist baclofen, GABA promoted macrophage switch to M2. While GABAB receptor antagonist CGP52432 blocked a baclofen induced switch to M2 polarization. GABA and baclofen increased M2 macrophage percentage and CGP52432 blocked this process in vivo. Also, IL-10 and TGF-β1 released by M2 were increased in both AMI and baclofen/AMI group; Serum NE levels were decreased by baclofen. All the above effects were reversed by CGP52432 treatment. Baclofen decreased TH and GAP-43 staining while CGP52432 enhanced their expression post AMI indicating GABAB receptor activation inhibited sympathetic nerve sprouting and activity by reducing NE release. ConclusionsGamma aminobutyric acid B receptor activation promoted M2 polarization and protested AMI heart by regulating sympathetic nerve remodeling.

Cocaine increases quantal norepinephrine secretion through NET-dependent PKC activation in locus coeruleus neurons.

The norepinephrine neurons in locus coeruleus (LC-NE neurons) are essential for sleep arousal, pain sensation, and cocaine addiction. According to previous studies, cocaine increases NE overflow (the profile of extracellular NE level in response to stimulation) by blocking the NE reuptake. NE overflow is determined by NE release via exocytosis and reuptake through NE transporter (NET). However, whether cocaine directly affects vesicular NE release has not been directly tested. By recording quantal NE release from LC-NE neurons, we report that cocaine directly increases the frequency of quantal NE release through regulation of NET and downstream protein kinase C (PKC) signaling, and this facilitation of NE release modulates the activity of LC-NE neurons and cocaine-induced stimulant behavior. Thus, these findings expand the repertoire of mechanisms underlying the effects of cocaine on NE (pro-release and anti-reuptake), demonstrate NET as a release enhancer in LC-NE neurons, and provide potential sites for treatment of cocaine addiction.

Xiaoyao Pill Improves the Affective Dysregulation of Sleep-deprived Female Mice by Inhibiting Brain Injury and Regulating the Content of Monoamine Neurotransmitter.

Sleep curtailment is a serious problem in many societies. Clinical evidence has shown that sleep deprivation is associated with mood dysregulation, formation of false memory, cardio-metabolic risk factors and outcomes, inflammatory disease risk, and all-cause mortality. The affective disorder dysregulation caused by insufficient sleep has become an increasingly serious health problem. However, to date, not much attention has been paid to the mild affective dysregulation caused by insufficient sleep, and there is no clear and standard therapeutic method to treat it. The Xiaoyao Pill is a classic Chinese medicinal formula, with the effect of dispersing stagnated hepatoqi, invigorating the spleen, and nourishing the blood. Therefore, it is most commonly used to treat gynecological diseases in China. In the present study, the effects of the Xiaoyao Pill on affective dysregulation of sleep-deprived mice and its underlying molecular mechanisms were investigated. Forty adult female mice were used in the present study. The sleep deprivation model was established by improving the multi-platform water environment method. After 7 consecutive days of sleep deprivation, the mice were administrated low (LXYP, 0.32mg/kg) and high (HXYP, 0.64 mg/kg) doses of the Xiaoyao Pill for two weeks. Then, the body weight, behavioral deficits, and histopathology were evaluated. Meanwhile, the expression of c-fos protein and the concentrations of monoamine neurotransmitters in the hippocampus and prefrontal cortex were determined after two weeks of treatment. Xiaoyao Pill treatment significantly increased body weight and sucrose consumption and decreased the irritability scores of the sleep-deprived mice. Meanwhile, Xiaoyao Pill treatment prevented brain injury and inhibited the expression of c-fos protein in the hippocampus and prefrontal cortex. In addition, HXYP treatment significantly upregulated the levels of NE in the hippocampus and prefrontal cortex (p < 0.01). LXYP treatment significantly up-regulated the levels of 5-HT in the prefrontal cortex. Meanwhile, both HXYP and LXYP treatment significantly upregulated the levels of DA in the prefrontal cortex (p < 0.05 or p < 0.01) of sleep-deprived mice. The present study demonstrates that Xiaoyao Pill treatment prevented the behavioral deficits of mice induced by sleep deprivation by promoting the recovery of brain tissue injury and up-regulating the levels of NE, 5-HT, and DA in the brain tissue.

Electroacupuncture promotes apoptosis and inhibits axonogenesis by activating p75 neurotrophin receptor for triple-negative breast xenograft in mice

PurposeThe aim of this study was to investigate the anti-tumor effect of electroacupuncture (EA) on mice bearing breast tumors by regulating p75 neurotrophin receptor (p75NTR) and remodelling intratumoral innervation. Methods: Female BALB/c mice were implanted with 4T1 breast tumor cells to establish a murine mammary cancer model. Tumor volume and weight were measured to evaluate tumor growth. Cell apoptosis was assessed by TUNEL assay. The relative expression of p75NTR, TrkA, TrkB, NGF and proNGF were detected by immunohistochemistry. Neurotransmitter and neurotrophin were detected by enzyme-linked immunosorbent assay. Intratumoral innervation was confirmed by β3-tubulin and TH labeling immunohistochemistry. The antagonist TAT-Pep5 was employed to determine if the effects of EA on tumor growth and cell apoptosis were mediated by p75NTR. Results: Peritumoral EA alleviated tumor growth especially after 14 days of intervention. Apoptosis index in the tumor tissue was obviously decreased after EA. Meanwhile, EA intervention significantly upregulated the expression of p75NTR and proNGF, along with a decline in the tumor growth and an increase in the cell apoptosis. Besides, EA reduced local sympathetic innervation and downregulated sympathetic neurotransmitter NE level in the local tumor. Furthermore, p75NTR antagonist alleviated EA-mediated cell apoptosis and intratumoral innervation. Conclusions: One mechanism of EA intervention for alleviating tumor progression is mediated by p75NTR to promote apoptosis and decrease intratumoral axonogenesis in the tumor microenvironment.

Evaluation of Scrophularia striata Hydroalcoholic Extract's Hematomodulatory Effects: An Approach to Traditional Ethnomedicine

Background: Silver nanoparticles (AgNPs) have broad biomedical applications and may result in a high risk of human and environmental toxicity. Scrophularia striata possesses a strong antioxidant capacity. Objectives: This study seeks to examine the modulatory influence of S. striata hydroalcoholic extract on the toxicity of silver nanoparticles on blood granulocytes, agranulocytes, and general parameters in male Wistar rats. Methods: Thirty male rats weighing an average of 200 ± 20 were divided into five experimental groups of six. In 30 days, rats were given 2 mL of distilled water in group 1 (negative control), 200 ppm AgNPs (hepatotoxicity dosage) in group 2, as well as 20, 60, and 180 mg/kg S. striata extract and 200 ppm AgNPs in groups 3, 4, and 5. Rats’ blood samples were taken 24 hours following their last partial anesthesia treatment. One-way ANOVA was used to evaluate the data, followed by Tukey's post hoc test. Results: When compared to the control groups, oral treatment of AgNPs resulted in substantial changes in WBC, NE, LY, MO, EO, BA, RBC, Hb, HCT, MCV, MCH, MCHC, PLT, and MPV levels. In comparison to the positive and negative groups, the extract's modulatory effects on hematological parameters demonstrated substantial variations, especially in groups 4 and 5 (60 and 180 mg/kg). Conclusions: Due to the presence of some unique components, such as flavonoids, the extract of the S. striata plant was discovered to be an efficient hematomodulatory, compensating to some extent for the cytotoxic side effects of AgNPs within the body.