Injection Of Dex Research Articles

Dexmedetomidine-mediated improvement of perioperative neurocognitive disorders by miR-184-3p-mediated NLRP3

BackgroundPerioperative neurocognitive disorders (PND) is a neurological complication in the perioperative period, which may lead to severe poor prognosis. Dexmedetomidine (Dex) is a commonly used sedative in the perioperative period. However, the effect of intraoperative anesthetic Dex on PND remains complicated and confusing. MethodsPND model was established using aged male mice, treated with Dex, and subjected to behavioral tests. The effect of Dex on pyroptosis was assessed by western blot, enzyme-linked immunosorbent assay and immunofluorescence. In addition, the miRNA expression profile of PND mice was identified by small RNA sequencing and performed PCR to detect miRNAs. Finally, the effect of miRNA on mice neuron pyroptosis was verified in vitro. ResultsWe found postoperative cognitive was declined in PND mice compared with control group, while preoperative injection of Dex improved short-term working memory and anxious exploration behavior, alleviated the cognitive impairment. Intriguingly, Dex ameliorated hippocampal inflammation and neuron pyroptosis in PND mice as evidenced by the reduced GSDMD, NLRP3, IL-1β and IL-18. The miRNA expression profile of PND mice hippocampus was disordered, including 5 miRNAs up-regulated and 17 miRNAs down-regulated, compared to the sham group. Dysregulated miRNAs were mainly enriched in biological functions related to neuronal development and signaling pathways related to pyroptosis. MiR-184-3p was the key miRNA, overexpression of miR-184-3p blocked the inhibitory effect of Dex on neuron pyroptosis, which was manifested as increased expression of GSDMD and NLRP3, increased inflammatory factors IL-1β and IL-18. ConclusionsThis study revealed that miR-184-3p may mediate NLRP3 to prevent the alleviating effect of Dex on PND, which provides a new potential way to improve the therapeutic intervention of PND.

Dexmedetomidine attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora

Dexmedetomidine (Dex) has been used in surgery to improve patients' postoperative cognitive function. However, the role of Dex in stress-induced anxiety-like behaviors and cognitive impairment is still unclear. In this study, we tested the role of Dex in anxiety-like behavior and cognitive impairment induced by acute restrictive stress and analyzed the alterations of the intestinal flora to explore the possible mechanism. Behavioral and cognitive tests, including open field test, elevated plus-maze test, novel object recognition test, and Barnes maze test, were performed. Intestinal gut Microbe 16S rRNA sequencing was analyzed. We found that intraperitoneal injection of Dex significantly improved acute restrictive stress-induced anxiety-like behavior, recognition, and memory impairment. After habituation in the environment, mice (male, 8 weeks, 18–23 g) were randomly divided into a control group (control, N = 10), dexmedetomidine group (Dex, N = 10), AS with normal saline group (AS + NS, N = 10) and AS with dexmedetomidine group (AS + Dex, N = 10). By the analysis of intestinal flora, we found that acute stress caused intestinal flora disorder in mice. Dex intervention changed the composition of the intestinal flora of acute stress mice, stabilized the ecology of the intestinal flora, and significantly increased the levels of Blautia (A genus of anaerobic bacteria) and Coprobacillus. These findings suggest that Dex attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

The Effects of Nebulized Inhaled Triptolide on Airway Inflammation in a Mouse Model of Asthma.

Inhalation of nebulized TP has received little attention in the past. Here, we intend to investigate the effect of nebulized inhaled TP on airway inflammation in a mouse model of asthma. 29 SPF BALB/c mice were divided into four groups: blank control (Blk, n = 5), normal saline (NS, n = 8), dexamethasone (Dex, n = 8), and TP (n = 8). During the process of sensitization, mice in the three intervention groups were treated with nebulized NS, an injection of Dex, and nebulized triptolide, respectively. Then bronchoalveolar lavage fluid (BALF), peripheral blood, and lung tissue were collected. Relevant cytokines, transcriptional factors, and CD4+Th17+ T cell proportions were assessed and compared. IL-6, IL-17, IL-23, and TGF-β1 demonstrated a significant difference between groups in the following order: Dex < TP < NS (P ≤ 0.001), while IL-10 changed in the opposite direction (P < 0.001). At the transcriptional level in lung tissue, the Ct value of IL-17 in the Dex group was significantly higher than in the NS and TP groups (P < 0.001). Meanwhile, it was higher in the TP group than in the NS group (P < 0.001). The Ct value of RORγt demonstrated a significant difference among three groups in the following order: Dex > TP > NS (P < 0.001). An opposite trend of FoxP3 Ct value was revealed in the order: NS > TP > Dex. The proportion of CD4+Th17+ cells was 9.53 ± 2.74% in the NS group, 4.23 ± 2.26% in the Dex group, and 6.76 ± 2.99% in the TP group, which shows significant differences between the NS and Dex (P < 0.001) or NS and TP groups (P < 0.05). Inhalation of nebulized triptolide can play a role in suppressing airway inflammation with inflammatory cytokines and transcriptional factors reduced and CD4+Th17+ T cells dampened, also in a manner less than injected dexamethasone.

Change of dexmedetomidine and midazolam concentrations by simultaneous injection in an in vitro extracorporeal circuit.

Patient sedation and analgesia are vital for safety and comfort during extracorporeal membrane oxygenation (ECMO). However, adsorption by the circuit may alter drug pharmaco-kinetics and remains poorly characterized. This study is the first to examine the concentrations of DEX and MDZ in the presence of drug-drug interactions using an in vitro extracorporeal circuit system that incorporates a polymer-coated polyvinyl chloride tube, but not a membrane oxygenator. Nine in vitro extracorporeal circuits were prepared using polymer-coated PVC tubing. Once the circuits were primed and running, either a single drug or two drugs were injected as boluses into the circuit with three circuits per drug. Drug samples were drawn following injection at 2, 5, 15, 30, 60, and 120min and at 4, 12, and 24h. They were then analyzed using high-performance liquid chromatography with mass spectrometry. When compared with an injection of DEX alone, the combination of DEX and MDZ is highly changed, with DEX and MDZ affecting the availability of free drugs in the circuit. The change of DEX and MDZ concentrations was confirmed by a combination of both drugs as compared with either single-infusion DEX or MDZ in an in vitro extracorporeal circuit. Drug-drug interactions developed between DEX and MDZ through albumin in an extracorporeal circuit; as a result, the unbounded drugs might change in the circuit.

Dexamethasone effects on the expression and content of glycosylated components of mouse brain tissue

Introduction. Glucocorticoids are actively used in the treatment of various diseases, however their long-term use leads to numerous negative side-effects, the molecular mechanisms of which remain poorly understood.Aim. Study of the short-term (1–10 days) effects of various doses of dexamethasone (Dex) (0,1–10 mg/kg) on the expression of the glucocorticoid receptor (GR, Nr3c1), core proteins of main proteoglycans and heparan sulfate metabolism-involved genes, as well as the content of carbohydrate macromolecules of glycosaminoglycans in the brain tissue of experimental animals.Materials and methods. In the study, C57Bl/6 mice were used. The expression of GR, proteoglycan core proteins and heparan sulfate metabolism-involved genes was determined by real-time polymerase chain reaction with reverse transcription. The content and localization of GR protein molecule were studied by Western blot and immunohistochemical analysis, and the glycosaminoglycan content was determined by dot-blot analysis and Alcian Blue staining.Results. It was shown that a single Dex administration leads to fast (1–3 days) short-term activation of GR expression (+1.5 times, p &lt;0.05), proteoglycan’s genes (syndecan-3, Sdc3; perlecan, Hspg2; phosphacan, Ptprz1; neurocan, Ncan; +2–3-fold; p &lt;0.05) and heparan sulfate-metabolism-involved genes (Ndst1, Glce, Hs2st1, Hs6st1, Sulf1 / 2; +1.5–2-fold; p &lt;0.05) in the mouse brain, with a return to control values by 7–10 days after Dex administration. At the same time, the effect of Dex on carbohydrate macromolecules of glycosaminoglycans was more delayed and stable, increasing the content of low-sulfated glycosaminoglycans in the brain tissue in a dose-dependent manner starting from day 1 after Dex administration. Highly-sulfated glycosaminoglycans showed more delayed response to Dex administration, and an increase in their content was observed only at higher doses (2.5 and 10 mg/kg) and only on 7–10 days after its administration, apparently, mainly due to an increase in heparan sulfate content.Conclusion. In general, the effect of a single injection of Dex on the transcriptional activity of GR, proteoglycan core proteins and heparan sulfate metabolism-involved genes were short-termed, and the genes expression quickly returned to the normal levels. However, even a single use of Dex significantly increased the content of total as well as highly sulfated glycosaminoglycans in the mouse brain tissue, which can lead to the changes in the composition and structure of the brain tissue, as well as its functional characteristics.

Effect of dexamethasone implant on intraocular cytokines in diabetic macular edema.

Our primary aim was to evaluate intraocular cytokines (IC) before and after dexamethasone in diabetic macular edema (DME). Our secondary aim was to study the early and late effects of single dexamethasone implant in DME. This before and after comparative study was conducted at the Department of Ophthalmology and Centre for Nanosciences at a quaternary referral center in Kerala, India, from September 2016 to September 2018. Patients underwent complete ophthalmological examination and cytokine analysis before and after dexamethasone implant. Levels of cytokines at baseline and repeat sample were studied. Twenty-seven eyes (21 patients) were divided into two groups depending on time from baseline to second injection. Group 1 included patients with <3 months between the two samples - 12 (44.4%). Group 2 included patients with >3 months between the two samples -15 (55.6%). Best corrected visual acuity (BCVA) and central macular thickness (CMT) improved significantly post-dexamethasone in group 1, but not in group 2. Interleukin (IL)-4, IL-6, IL-10, vascular endothelial growth factor (VEGF), IL-1β, interferon-gamma inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), and IL-2 decreased post-injection in group 1. But cytokines increased post-dexamethasone in group 2, except IL-10. When compared to baseline, IL-6 reduced to half in group 1 (P-value 0.814) and it tripled in group 2 ( P-value 0.009). The level of VEGF in the first and second samples was not different in either group. Our study suggests that dexamethasone acts more on IC than VEGF in DME. This is significant in the first 3 months with a rebound effect on IL-6 after 3 months. Our study also suggests that repeat injection of DEX in DME should be done at 3 months to prevent deterioration of visual acuity (VA) and worsening of CMT.

KLF2 reduces dexamethasone-induced injury to growth plate chondrocytes by inhibiting the Runx2-mediated PI3K/AKT and ERK signalling pathways

Dexamethasone (Dex) is a type of glucocorticoid drug. Long term use can induce growth plate chondrocytes (GPCs) apoptosis, impair differentiation, and inhibit cell proliferation and bone growth. It has been reported that Krüppel-like factor 2 (KLF2) inhibits osteoblast damage induced by Dex, but the role in Dex-induced GPCs remains unclear. Dex was used to construct a model of growth plate injury in vitro. CCK-8 and TUNEL kits were used to determine cell viability and apoptosis. A model of growth plate injury was established by intraperitoneal injection of Dex. Immunohistochemistry was used to investigate the expression of KLF2 in rats. The results showed that KLF2 expression of rat tibial GPCs was down-regulated after Dex stimulation. Overexpression of KLF2 promoted cell viability and cell cycle, while inhibited apoptosis of growth plate Dex-induced chondrocytes. Moreover, KLF2 inhibited Runx2-mediated PI3K/AKT and ERK signalling pathways. And PI3K/AKT and ERK signalling pathways, which were involved in the regulation of KLF2 on GPCs. Further studies showed that KLF2 alleviated growth plate injury in vivo. In conclusion, our study found that KLF2 promoted proliferation and inhibited apoptosis of Dex-induced GPCs by targeting the Runx2-mediated PI3K/AKT and ERK signalling pathways.

Dexmedetomidine inhibits abnormal muscle hypertrophy of myofascial trigger points via TNF-α/ NF-κB signaling pathway in rats.

Myofascial pain syndrome (MPS) is a chronic pain disorder with inflammation-related primarily characterized by the presence of myofascial trigger points (MTrPs). Myocyte enhancer factor 2C (MEF2C) is involved in the occurrence of a variety of skeletal muscle diseases. However, it is not yet clear if MEF2C is involved in MTrPs. The purpose of this study was to investigate whether MEF2C was involved in the inflammatory pathogenesis of MTrPs. In the present study, we used RNA sequencing (RNA-seq) to compare the differential expression of myocyte enhancer factor 2C (MEF2C) in healthy participants and MTrPs participants. The widely used rat MTrPs model was established to research the upstream and downstream regulatory mechanism of MEF2C and found that MEF2C was significantly increased in patients with MTrPs. Dexmedetomidine (Dex) was injected intramuscularly in the MTrPs animal to assess its effects on MEF2C. The expression of MEF2C protein and mRNA in skeletal muscle of rats in the MTrPs group were up-regulated. In addition, the expression of TNF- α, p-P65, MLCK, and Myocilin (MyoC) was up-regulated and the mechanical pain threshold was decreased. Peripheral TNF- α injection significantly decreased the mechanical pain threshold and increased the expression of p-P65, MLCK, MEF2C, and MyoC in healthy rats. Maslinic acid increased the mechanical pain threshold and inhibited the expression of p-P65, MLCK, MEF2C, and MyoC. In addition, peripheral injection of DEX in MTrPs rats also inhibited the expression of TNF- α, p-P65, MLCK, MEF2C, and MyoC. These results suggest that MEF2C is involved in the inflammatory pathogenesis of MTrPs and DEX serves as a potential therapeutic strategy for the treatment of MPS.

Effects of electroacupuncture with dexmedetomidine on myocardial ischemia/reperfusion injury in rats.

To investigate the protective effect of electroacupuncture combined with dexmedetomidine (EA + Dex) on oxidative stress injury in myocardial ischemia/reperfusion (I/R) rats. A total of 50 male Sprague-Dawley (SD) rats were randomly divided into 5 groups: sham operation (sham group); I/R group; dexmedetomidine group (Dex group); electroacupuncture group (EA group); and EA + Dex group. The myocardial I/R model was established. The EA group received EA at the Neiguan acupoint [pericardium 6 (PC6)] every day for 1 week before modeling. Rats in the EA + Dex group received EA at PC6 every day for 1 week before modeling, and intraperitoneal injection of Dex was performed 15 minutes before modeling. Dex was injected intraperitoneally in the Dex group 15 minutes before modeling. The rats were sacrificed 1 hour after reperfusion, and myocardial tissue was obtained to measure the myocardial infarction area. The myocardial tissue pathologic changes were shown by hematoxylin and eosin (HE) staining, and the superoxide dismutase (SOD), malondialdehyde (MDA), adenosine triphosphate (ATP), and reactive oxygen species (ROS) content in serum was determined. Compared with the sham group, the myocardial infarction area was significantly increased (P<0.01), SOD and ATP content was significantly decreased (P<0.01), and MDA and ROS content was significantly increased (P<0.01) in the I/R group; this change was significantly reduced in the Dex, EA, and EA + Dex groups (P<0.01). The indicators in the EA + Dex group were better than those in the EA and Dex groups (P<0.05). There was no significant change in the above indices in the Dex group compared with the EA group (P>0.05). EA + Dex pretreatment improved the damage of myocardial I/R by increasing SOD and ATP content and reducing the generation of MDA and ROS in an oxygen-free radical system.

Dexamethasone and MicroRNA-204 Inhibit Corneal Neovascularization.

This was an in vivo animal study designed to investigate the interaction between dexamethasone (Dex) and microRNA-204 (miR-204) in a mouse alkali burn-induced corneal neovascularization (CNV) model. The function of miR-204 was then investigated in human mammary epithelial cells (HMECs) in vitro. The CNV model was induced by corneal alkali burn in BLAB/c mice. The mice were randomly divided into five groups: normal control (Ctrl), alkali burn-induced corneal injury (Alkali), alkali burn + Dex (Dex), alkali burn + negative control (NTC), and alkali burn + miR-204 agomir (miR-204). Subconjunctival injection of NTC, Dex, or miR-204 agomir was conducted at 0, 3, and 6 days, respectively, after alkali burn. The corneas were collected at day 7 after injury, and the CNV area was observed using immunofluorescence staining. The expression of miR-204 was analyzed with quantitative real time (qRT)-PCR. In HMECs, exogenous miR-204 agomir or antagomir was used to strengthen or inhibit the expression of miR-204. Migration assays and tube formation studies were conducted to evaluate the function of miR-204 on HMECs. At 7 days post-alkali burn, CNV grew aggressively into the cornea. MicroRNA-204 expression was reduced in the Alkali group in contrast with the Ctrl group (P = .003). However, miR-204 was upregulated in the Dex group (vs. alkali group, P = .008). The CNV areas in the NTC and miR-204 groups were 59.30 ± 8.32% and 25.60 ± 2.30%, respectively (P = .002). In vitro, miR-204 agomir showed obvious inhibition on HMEC migration in contrast with NTC (P = .033) and miR-204 antagomir (P = .017). Compared with NTC, miR-204 agomir attenuated tube formation, while miR-204 antagomir accelerated HMEC tube formation (P < .05). The role of Dex in attenuating CNV may be partly attributed to miR-204. MiR-204 may be a potential therapeutic target in alkali burn-induced CNV.

Dex modulates the balance of water-electrolyte metabolism by depressing the expression of AVP in PVN.

Dexmedetomidine (Dex) is a highly selective α2 adrenergic agonist used in clinical anesthesia. Studies have shown that Dex can act on the collecting duct and reduce the body’s water reabsorption, thereby increasing water discharge. However, the specific mechanism of Dex on water homeostasis remains unclear. The hypothalamus is the regulatory center of water and salt balance and secretes related neurochemical hormones, such as arginine vasopressin (AVP), to regulate the discharge of water and salt. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) in the hypothalamus are also considered to be the key targets of the thirst loop. They are responsible for the secretion of AVP. The suprachiasmatic nucleus (SCN) is also one of the brain regions where AVP neurons are densely distributed in the hypothalamus. This study used C57BL/6J mice for behavior, immunofluorescence, and blood analysis experiments. Our results showed that Dex could not only depress the expression of AVP in the PVN but also reduce serum AVP concentration. The animal water intake was decreased without impairing the difference in food consumption and the urine excretion was enhanced after the intraperitoneal injection of Dex, while AVP supplementation restored the water intake and inhibited the urine excretion of mice in the Dex group. In addition, the renin-angiotensin-aldosterone system is vital to maintaining serum sodium concentration and extracellular volume. We found that serum sodium, serum chloride, serum aldosterone (ALD) concentration, and plasma osmolality were decreased in the Dex group, which inhibited water reabsorption, and the plasma osmolarity of mice in the Dex group supplemented with AVP was significantly higher than that in Dex group. We also found that Dex significantly increased the concentration of blood urea nitrogen and decreased the concentration of creatinine within the normal range of clinical indicators, indicating that there was no substantive lesion in the renal parenchyma. These results showed that Dex could modulate the balance of water-electrolyte metabolism by depressing the expression of AVP in PVN without impairing renal function.

Adoption of Dexmedetomidine in Different Doses at Different Timing in Perioperative Patients.

Dexmedetomidine (Dex) is an alpha-2 agonist used for sedation during various procedures. Dex activates 2-adrenoceptors, and causes the decrease of sympathetic tone, with attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery; it reduces anesthetic and opioid requirements; and causes sedation and analgesia. Objective: it was to compare the perioperative effects of different doses of Dex at different timing in patients using Dex during the perioperative period adopting a medical data classification algorithm based on optimized semi-supervised collaborative training (Tri-training). Methods: 495 patients requiring surgical treatment in Xingtai People's Hospital were randomly selected as the study subjects. The patients were divided into group A (used before induction), group B (used during induction), and group C (used after induction) according to different induction timing, with 165 cases in each group. Then, groups A, B, and C were divided into groups A1, B1, and C1 (0.4 μg/(kg·h) rate), groups A2, B2, and C2 (0.6 μg/(kg·h) rate), and groups A3, B3, and C3 (0.8 μg/(kg·h) rate) according to the dose used, with 55 cases in each group. Intraoperative anesthesia and postoperative adverse reactions were compared among the 9 groups. Results: the similarity between the Tri-training algorithm optimized by Naive Bayes (NB) classification algorithm and the actual classification (93.49%) was clearly higher than that by decision tree (DT) and K-nearest neighbor (kNN) classification algorithm (76.21%, 74.31%); heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) values decreased obviously after Dex used in groups B1, C1, B2, C2, B3, and C3 (P <0.05), but did not change significantly in groups A1, A2, and A3 (P >0.05); the proportion of patients with satisfactory Ramsay score in group A3 was distinctly superior than that in groups A1, A2, B1, B2, B3, C1, C2, and C3 (P <0.05); the incidence of adverse reactions in group A3 was significantly inferior than that in groups A1, A2, B1, B2, B3, C1, C2, and C3 (P <0.05). Conclusion: the optimization effect of NB classification algorithm was the best, and the injection of Dex at the injection rate of 0.8 μg/(kg·h) before induction of anesthesia could apparently improve the fluctuation of HR, SBP, and DBP during perioperative period, and effectively reduce the occurrence of adverse reactions in patients, with better sedative effect on patients.

Dexmedetomidine preconditioning alleviates acute lung injury induced by intestinal ischemia-reperfusion in rats by inhibiting NLRP3 inflammasome activation

To investigate the protective effect of dexmedetomidine (Dex) against acute lung injury induced by intestinal ischemia-reperfusion (II/R) in rats and its effect on NLRP3 inflammasome activity. Thirty-two normal male SD rats were randomly divided into 4 groups (n=8): the sham operation group, where the superior mesenteric artery (SMA) was exposed only; II/R group, where the SMA was occluded for 1 h followed by reperfusion for 2 h; Dex+II/R group, where the rats were subjected to II/R and received intraperitoneal injection of Dex before reperfusion; and Dex group, where the rats received Dex pretreatment and sham operation. The rats in sham operation group and II/R group received intraperitoneal injection of normal saline. The wet/dry weight ratio (W/D) and myeloperoxidase (MPO) activity in the lung tissues were measured, and HE staining was used to evaluate lung pathologies and determine lung injury score of the rats. The levels of inflammatory cytokines (TNF-α, IL-18, and IL-1β) in the lung tissue were detected using ELISA, and the expressions of NLRP3, ASC, caspase-1 and p-AMPK proteins were determined with Western blotting. Compared with the sham-operated rats, the rats with II/R injury showed obvious lung pathologies and significantly increased W/D value, MPO activity and expression of TNF-α, IL-18 and IL-1β in the lung tissue (P < 0.05) with also significantly increased expressions of NLRP3, ASC, and caspase-1 proteins (P < 0.05) but obviously lowered expression of p-AMPK protein (P < 0.05) in the lung tissues. Compared with those in II/R group, the rats in Dex+II/R group showed milder lung pathologies, significantly reduced W/D value, MPO activity and expressions of TNF-α, IL-18 and IL-1β in the lung tissue (P < 0.05), and significant lower expressions of NLRP3, ASC, and caspase-1 (P < 0.05) but higher expression of p-AMPK protein (P < 0.05). Dex treatment reduces II/R-induced inflammatory response by inhibiting the activation of NLRP3 inflammasomes, thereby improving acute lung injury caused by II/R in rats.

Hepatocyte Nuclear Factor 4-α (HNF4α) controls the insulin resistance-induced pancreatic β-cell mass expansion

BackgroundRegardless of the etiology, any type of DM presents a reduction of insulin-secreting cell mass, so it is important to investigate pathways that induce the increase of this cell mass. AimBased on the fact that (1) HNF4α is crucial for β-cell proliferation, (2) DEX-induced IR promotes β-cell mass expansion, and (3) the stimulation of β-cell mass expansion may be an important target for DM therapies, we aimed to investigate whether DEX-induced proliferation of β pancreatic cells is dependent on HNF4α. MethodsWe used WildType (WT) and Knockout (KO) mice for HNF4-α, treated or not with 100 mg/Kg/day of DEX, for 5 consecutive days. One day after the last injection of DEX the IR was confirmed by ipITT and the mice were euthanized for pancreas removal. ResultsIn comparison to WT, KO mice presented increased glucose tolerance, lower fasting glucose and increased glucose-stimulates insulin secretion (GSIS). DEX induced IR in both KO and WT mice. In addition, DEX-induced β-cell mass expansion and an increase in the Ki67 immunostaining were observed only in WT mice, evidencing that IR-induced β-cell mass expansion is dependent on HNF4α. Also, we observed that DEX-treatment, in an HNF4α-dependent way, promoted an increase in PDX1, PAX4 and NGN3 gene expression. ConclusionsOur results strongly suggest that DEX-induced IR promotes β-cell mass expansion through processes of proliferation and neogenesis that depend on the HNF4α activity, pointing to HNF4α as a possible therapeutic target in DM treatment.

The Influence of Anesthesia on the Cardiovascular Effects of Centrally Administered Clonidine

The α2 adrenergic receptor (α2AR) agonists are known to induce hypotensive responses when administered via intracerebroventricular (icv) route in normotensive rats anesthetized with either pentobarbital or urethane. However, the icv injection of α2AR agonists such as clonidine (CLO) produces hypertensive responses in normotensive conscious rats. To date, the effects icv administration of CLO in normotensive rats under ketamine/xylazine anesthesia, a commonly used anesthetic combination in experimental studies, is still unknown. We hypothesized that anesthetic drugs differentially modulate cardiovascular responses to centrally administered CLO. To evaluate this hypothesis, we assessed blood pressure (BP) and heart rate (HR) of normotensive male rats anesthetized with pentobarbital or ketamine/xylazine, both under mechanical ventilation. These animals received CLO (10 μg/5 μL) or dexmedetomidine (DEX; 0.6 μg/5 μL) by icv route. In additional experiments, yohimbine (5 μg/5 μL), a selective α2AR antagonist, was given by icv route 15 min before a second injection of CLO or DEX in ketamine/xylazine anesthetized rats. As widely described, the icv microinjection of CLO decreased the mean arterial pressure (MAP) and HR by 40.73 ± 6.3 mmHg and 134 ± 15 bpm in pentobarbital anesthetized rats (n = 5). On the other hand, in ketamine/xylazine anesthetized rats (n = 6) CLO increased MAP by 29.4 ± 5.1 mmHg and decreased HR by 34 ± 5 bpm, a less pronounced effect when compared with the pentobarbital group (p < 0.0001). Similarly, the icv microinjection of DEX in ketamine/xylazine anesthetized rats (n = 6) increased MAP by 20.8 ± 3.2 mmHg and decreased HR by 51 ± 16 bpm. Notably, yohimbine generated a pattern of hypotensive responses comparable to CLO and DEX. Additionally, after yohimbine administration, both CLO- and DEX-increased MAP were reduced to 9.9 ± 2.3 mmHg and 6.7 ± 1.1 mmHg, respectively (n = 6, p < 0.05), despite the lack of influence of yohimbine in the bradycardia induced by these α2AR agonists in ketamine/xylazine anesthetized rats. This study discloses that in normotensive rats under ketamine/xylazine anesthesia, central administration of CLO produces a hypertensive effect, opposing the findings obtained in pentobarbital-anesthetized rats and resembling the vascular responses described in conscious animals. This data was reproduced by DEX and reduced by yohimbine, suggesting that stimulation of central α2AR takes a preponderant role in this effect. Our results reinforce the relevance regarding the influence of anesthetic choice for studies involving cardiovascular parameters.

1. Modeling ovarian cancer for dendritic cells‐derived exosomes treatment

Ovarian cancer (OC) is the fifth leading cause of death from cancer among women in the United States and high‐grade serous carcinoma (HGSC) is the most common subtype. Patients often present metastatic disease with ascites buildup, which further complicates the treatment landscape. Although immunotherapy is a promising cancer treatment method, it fails to have an impact on HGSC patients due to the immunosuppressive and heterogeneous micro‐environment and impaired lymphatic drainage created by cancer cells within the peritoneal cavity. We are interested in boosting the anti‐tumor immunity by employing exosomes derived from dendritic cells (DC)‐based vaccines (Dex) for their capacity of overcoming the transport barriers, bypassing the immunosuppressive environment, prompting T cell infiltration in target organs, and activating them. Dex were collected and characterized in terms of yield, size distribution, and their biomolecular features as compared to parental cells, proving the expression of MHC‐II and co‐stimulatory markers (CD80 and CD86). When DC were pulsed with tumor antigen lysates from an ovalbumin‐overexpressing cancer cell line (ID8‐OVA), Dex presented OVA on their surface and activated the proliferation of OVA‐specific T cells (OT‐I). Intra‐peritoneal injection of Dex into a metastatic OC mouse model revealed a preferential accumulation within the peritoneal metastatic nodules, in tumors and in the liver. Preliminary data suggest Dex as a potential complement to the standard of care treatments for metastatic OC. We are currently testing their ability to induce an anti‐tumor immune response and increase survival when coupled with standard chemotherapeutics, with the potential of being effective in several metastatic diseases with peritoneal invasion.

Dexmedetomidine Promotes Hippocampal Neurogenesis and Improves Spatial Learning and Memory in Neonatal Rats.

BackgroundDexmedetomidine (Dex) is a highly selective α2-adrenoceptor agonist used as an off-label medication for pediatric sedation and analgesia. Recently, Dex was reported to exhibit neuroprotective efficacy in several brain injury models. Here we investigate whether neonatal Dex administration promotes hippocampal neurogenesis and enhances hippocampus-dependent spatial learning and memory under physiological conditions.MethodsPostnatal day 7 (P7) pups were administered saline (vehicle control) or Dex (10, 20, or 40 µg/kg) by intraperitoneal injection. Neurogenesis and astrogenesis were examined in brain slices by BrdU immunostaining on P8 and changes in the expression levels of GDNF, NCAM, CREB, PSD95, and GAP43 were assessed by Western blotting on P35, respectively. Open field and Morris water maze (MWM) tests were conducted from P28 to P36 in order to assess effects on general motor activity and spatial learning, respectively.ResultsDexmedetomidine at 20 µg/kg significantly enhanced neurogenesis and astrogenesis in hippocampus and upregulated GDNF, NCAM, CREB, PSD95, and GAP43 compared to vehicle and other Dex doses. Moreover, 20 µg/kg Dex-injected rats showed no changes in motor or anxiety-like behavior but performed better in the MWM test compared to all other groups.ConclusionNeonatal injection of Dex (20 µg/kg) enhances spatial learning and memory in rat pups, potentially by promoting hippocampal neurogenesis and synaptic plasticity via activation of GDNF/NCAM/CREB signaling.

Effects of dexmedetomidine on the memory and pain threshold in rats with sleep deprivation

Objective To investigate the effects of intraperitoneal injection of dexmedetomidine (Dex) on the memory and pain threshold in rats with sleep deprivation. Methods Ninety adult SD rats were randomly divided into three groups (n=30): a control group (group C), a group of sleep deprivation (group SD) and a group of sleep deprivation with Dex (group SD+D). The rats in groups SD and SD+D were placed on a glass platform within a tank filled with water, 10 h per day for 8 consecutive days. Meanwhile, those in group C were placed on a glass platform within a tank without water. Rats in group SD+D was intraperitoneally injected with 50 μg/kg Dex once a day, while those in groups C and SD were given the same amount of normal saline. Morris water maze positioning navigation behavior test was performed to measure escape latency every day. Then, paw mechanical withdrawal threshold (PMWT) and paw withdraw thermal latency (PWTL) were measured. Results Compared with group C, group SD showed obviously prolonged escape latency from day 3 to day 8(P 0.05). Compared with group SD, group SD+D presented obviously shortened escape latency from day 3 to day 8 (P 0.05). Compared with group SD, groups C and SD+D presented obviously increased PMWT and PWTL from day 2 to day 8 (P<0.05). Conclusions Intraperitoneal injection of Dex can improve the memory of rats with sleep deprivation, and reduce the pain in those rats. Key words: Dexmedetomidine; Sleep deprivation; Pain threshold; Rat

Dexmedetomidine hydrochloride up-regulates expression of hypoxia inducible factor-1α to alleviate renal ischemiareperfusion injury in diabetic rats

To verify whether dexmedetomidine hydrochloride (Dex) alleviates renal ischemia-reperfusion (IR) injury in diabetic rats by increasing the expression of hypoxia inducible factor-1α (HIF-1α). A rat model of type 2 diabetes mellitus was established by high-fat diet and streptozotocin injection. The rats were subjected to daily intragastric administration of 0.05 mg/kg digoxin for 7 consecutive days and intraperitoneal injection of Dex 2 h before renal IR injury induced by ligation of the bilateral renal arteries for 60 min followed by reperfusion for 120 min. After reperfusion, blood samples were taken for detection of serum creatinine (Scr) and urea nitrogen (BUN) levels. Western blotting was used to detect the expression of HIF-1α, cleaved caspase-3, Bcl-2, and Bax in the renal tissues; the expression of the HIF-1α, p-eNOS, and eNOS were detected using ELISA. The percentage of apoptotic glomerular cells was assessed using TUNEL assay. The levels of Scr, BUN, HIF-1α, p-eNOS, and eNOS and the percentage of apoptotic cells in both normal and diabetic rats increased significantly after renal IR injury (P &lt; 0.05). The expressions of Scr, BUN, p-eNOS, and eNOS decreased while HIF-1α expression increased significantly in Dex-treated rats with renal IR injury (P &lt; 0.05). Compared with the non-diabetic rats, the diabetic rats showed more obvious increase in the expressions of Scr, BUN, p-eNOS, and eNOS following renal IR injury. In the diabetic rats with renal IR injury, Dex treatment prior to the injury significantly lowered the expressions of Scr, BUN, p-eNOS, eNOS, cleaved caspase-3, and Bax, decreased the percentage of apoptotic cells, and increased the levels of HIF-1a and Bcl-2 (P &lt; 0.05). Digoxin treatment significantly antagonized the effects of Dex in the diabetic rats with renal IR injury by increasing the expressions of cleaved caspase-3 and Bax, promoting glomerular cell apoptosis, and decreasing renal expressions of HIF-1 and Bcl-2 (P &lt; 0.05). Dex alleviates renal IR injury in diabetic rats probably by inhibiting renal expression of HIF-1α and glomerular cell apoptosis.

Dexmedetomidine inhibits the NF-κB pathway and NLRP3 inflammasome to attenuate papain-induced osteoarthritis in rats

Context: Dexmedetomidine (Dex) has been reported to have an anti-inflammatory effect. However, its role on osteoarthritis (OA) has not been explored.Objective: This study investigates the effect of Dex on OA rat model induced by papain.Materials and methods: The OA Wistar rat model was induced by intraluminal injection of 20 mL of papain mixed solution (4% papain 0.2 mL mixed with 0.03 mol L−1 l-cysteine 0.1 mL) into the right knee joint. Two weeks after papain injection, OA rats were treated by intra-articular injection of Dex (5, 10, or 20 μg kg−1) into the right knee (once a day, continuously for 4 weeks). Articular cartilage tissue was obtained after Dex treatment was completed.Results: The gait behavior scores (2.83 ± 0.49), PWMT (15.2 ± 1.78) and PTWL (14.81 ± 0.92) in H-DEX group were higher than that of OA group, while Mankin score (5.5 ± 0.81) was decreased (p < 0.05). Compared with the OA group, the IL-1β (153.11 ± 16.05 pg mg−1), IL-18 (3.71 ± 0.7 pg mg−1), IL-6 (14.15 ± 1.94 pg/mg) and TNF-α (40.45 ± 10.28 pg mg−1) levels in H-DEX group were decreased (p < 0.05). MMP-13, NLRP3, and caspase-1 p10 expression in Dex groups were significantly lower than that of OA group (p < 0.05), while collagen II was increased (p < 0.05). p65 in the nucleus of Dex groups was significantly down-regulated than that of OA group (p < 0.05).Discussion and Conclusions: Dex can improve pain symptoms and cartilage tissue damage of OA rats, which may be related to its inhibition of the activation of NF-κB and NLRP3 inflammasome.