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American Journal of Cancer Research 2023Acute lung injury (ALI) is an acute infectious diseases caused by a variety of factors. The function of TTC4 in sepsis-induced lung injury remains largely unknown. This...
Acute lung injury (ALI) is an acute infectious diseases caused by a variety of factors. The function of TTC4 in sepsis-induced lung injury remains largely unknown. This study aimed to explore the critical role of TTC4 in sepsis-induced lung injury. Mice anaesthetized using pentobarbital sodium and subjected to cecal ligation and puncture (CLP) surgery. TTC4 expression levels in patients with sepsis-induced lung injury were down-regulated. The inhibition of TTC4 gene promoted lung injury in mice model of sepsis. TTC4 gene improved inflammation in vitro model and mice model. TTC4 gene reduced pyroptosis in macrophages of sepsis-induced lung injury by the inhibition of mitochondrial damage. TTC4 gene induced HSP70 expression to reduce NLRP3-induced pyroptosis in macrophages. TTC4 protein interlinked HSP70 protein. The activation of HSP70 reduced the effects of sh-TTC4 in model of sepsis-induced lung injury through mitochondrial damage. m6A-forming enzyme METTL3 reduced TTC4 stability. Our study suggests the m6A forming enzyme METTL3 control TTC4 reduced inflammation and pyroptosis in model of sepsis-induced lung injury through inhibition of mitochondrial damage by HSP70/ROS/NLRP3 signaling pathway, TTC4 gene as an represents a potential therapeutic strategy for the treatment of sepsis-induced lung injury.
PubMed: 38058818
DOI: No ID Found -
Pediatric Critical Care Medicine : a... Jan 2023To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status...
OBJECTIVES
To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status epilepticus (RSE).
DESIGN
One- and two-compartment in silico pharmacokinetic models of midazolam and pentobarbital.
SETTING
Not applicable.
SUBJECTS
Not applicable.
INTERVENTIONS
We compared the model variables used in midazolam and pentobarbital protocols for standard RSE.
MEASUREMENTS AND MAIN RESULTS
Standard RSE treatment protocols result in steady-state serum concentrations that are 6.2-9.0-fold higher for the one-compartment model and 2.3-4.7-fold higher for the two-compartment model. In the model, not including bolus doses delays the achievement of serum steady-state concentration by 0.5 and 2.7 hours for midazolam and pentobarbital, respectively. Abrupt discontinuation of these medications reduces modeled medication exposure by 1.1 and 6.4 hours, respectively.
CONCLUSIONS
Our in silico pharmacokinetic modeling of standard midazolam and pentobarbital dosing protocols for RSE suggests potential variables to optimize in future clinical studies.
Topics: Humans; Pentobarbital; Midazolam; Anticonvulsants; Status Epilepticus; Clinical Protocols
PubMed: 36394369
DOI: 10.1097/PCC.0000000000003106 -
Translational Neuroscience Jan 2021During the prodromal phase of schizophrenia with its complex and insidious clinical picture, electroencephalographic recordings detect widespread oscillation...
During the prodromal phase of schizophrenia with its complex and insidious clinical picture, electroencephalographic recordings detect widespread oscillation disturbances (or oscillopathies) during the wake-sleep cycle. Neural oscillations are electrobiomarkers of the connectivity state within systems. A single-systemic administration of ketamine, a non-competitive NMDA glutamate receptor antagonist, transiently reproduces the oscillopathies with a clinical picture reminiscent of the psychosis prodrome. This acute pharmacological model may help the research and development of innovative treatments against psychotic transition. Transcranial electrical stimulation is recognized as an appropriate non-invasive therapeutic modality since it can increase cognitive performance and modulate neural oscillations with little or no side effects. Therefore, our objective was to set up, in the sedated adult rat, a stimulation method that is able to normalize ketamine-induced increase in gamma-frequency (30-80 Hz) oscillations and decrease in sigma-frequency (10-17 Hz) oscillations. Unilateral and bipolar frontoparietal (FP), transcranial anodal stimulation by direct current (<+1 mA) was applied in ketamine-treated rats. A concomitant bilateral electroencephalographic recording of the parietal cortex measured the stimulation effects on its spontaneously occurring oscillations. A 5 min FP anodal tDCS immediately and quickly reduced, significantly with an intensity-effect relationship, the ketamine-induced gamma hyperactivity, and sigma hypoactivity at least in the bilateral parietal cortex. A duration effect was also recorded. The tDCS also tended to diminish the ketamine-induced delta hypoactivity. These preliminary neurophysiological findings are promising for developing a therapeutic proof-of-concept against neuropsychiatric disorders.
PubMed: 34239718
DOI: 10.1515/tnsci-2020-0157 -
Journal of the American Association For... May 2020Euthanasia is one of the most commonly performed procedures in biomedical research, involving tens of millions of animals in North America and Europe every year. The use... (Review)
Review
Euthanasia is one of the most commonly performed procedures in biomedical research, involving tens of millions of animals in North America and Europe every year. The use of sodium pentobarbital, injected intraperitoneally, for killing rodents is described as an acceptable technique by the AVMA and CCAC euthanasia guidelines. This drug and route are recommended over inhalant anesthetics, carbon dioxide, and physical methods for ethical and aesthetic reasons as well as efficiency. However, a growing body of evidence challenges the efficacy and utility of intraperitoneal pentobarbital. This methodology has been described as inconsistent and may induce pain and stress. With these considerations in mind, a review of the literature is needed to assess the evidence surrounding this killing method, the associated welfare implications, and potential for refinement.
Topics: Anesthetics, Inhalation; Animal Welfare; Animals; Animals, Laboratory; Biomedical Research; Euthanasia, Animal; Guidelines as Topic; Injections, Intraperitoneal; Pain; Pentobarbital; Rodentia
PubMed: 32156325
DOI: 10.30802/AALAS-JAALAS-19-000081 -
Pharmacological Research Feb 2021Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been...
Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been identified as baroreceptors. However, the underlying molecular mechanism for regulating these baroreceptors in hypertension remains unknown. In this study, we used spontaneously hypertensive rats (SHR) and NG-Nitro-l-Arginine (L-NNA)- and Angiotensin II (Ang II)-induced hypertensive model rats to determine the role and mechanism of Piezo1 and Piezo2 in hypertension. We found that Piezo2 was dominantly expressed in baroreceptor nodose ganglia (NG) neurons and aortic nerve endings in Wistar-Kyoto (WKY) rats. The expression of Piezo2 not Piezo1 was significantly downregulated in these regions in SHR and hypertensive model rats. Electrophysiological results showed that the rapidly adapting mechanically-activated (RA-MA) currents and the responsive neuron numbers were significantly reduced in baroreceptor NG neurons in SHR. In WKY rats, the arterial BP was elevated by knocking down the expression of Piezo2 or inhibiting MA channel activity by GsMTx4 in NG. Knockdown of Piezo2 in NG also attenuated the baroreflex and increased serum norepinephrine (NE) concentration in WKY rats. Co-immunoprecipitation experiment suggested that Piezo2 interacted with Neural precursor cell-expressed developmentally downregulated gene 4 type 2 (Nedd4-2, also known as Nedd4L); Electrophysiological results showed that Nedd4-2 inhibited Piezo2 MA currents in co-expressed HEK293T cells. Additionally, Nedd4-2 was upregulated in NG baroreceptor neurons in SHR. Collectively, our results demonstrate that Piezo2 not Piezo1 may act as baroreceptor to regulate arterial BP in rats. Nedd4-2 induced downregulation of Piezo2 in baroreceptor NG neurons leads to hypertension in rats. Our findings provide a novel insight into the molecular mechanism for the regulation of baroreceptor Piezo2 and its critical role in the pathogenesis of hypertension.
Topics: Animals; Aorta, Thoracic; Baroreflex; Cells, Cultured; Humans; Hypertension; Ion Channels; Male; Nedd4 Ubiquitin Protein Ligases; Neurons; Nodose Ganglion; Pressoreceptors; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Rats
PubMed: 33352230
DOI: 10.1016/j.phrs.2020.105391 -
Biomedicine Hub 2022The aim of this study was to investigate the effects of different anesthetic agents on electroretinograms (ERGs) in Spontaneously Diabetic Torii fatty rats (SDT fatty...
Differences in the Effects of Pentobarbital Anesthetic and Combination of Medetomidine Hydrochloride, Midazolam, and Butorphanol Tartrate Anesthetic on Electroretinogram in Spontaneously Diabetic Torii Fatty Rats.
PURPOSE
The aim of this study was to investigate the effects of different anesthetic agents on electroretinograms (ERGs) in Spontaneously Diabetic Torii fatty rats (SDT fatty rats).
METHODS
The ERG recordings were measured under general anesthesia using pentobarbital or a combination of medetomidine hydrochloride, midazolam, and butorphanol (MMB) tartrate anesthesia in 12 9-week-old normal Sprague-Dawley rats (Jcl:SD rats) and 16 SDT fatty rats. Each animal model was divided into 2 groups, the pentobarbital group and MMB group. The amplitudes and peak times of the a- and b-waves and oscillatory potentials (OPs) were measured from 0.0001 candela per square meter (cd.s/m) to 10.0 cd.s/m.
RESULTS
The amplitude of the a-wave was significantly higher in the MMB group of Jcl:SD rats, but there was no significant difference in amplitude between the two groups of SDT fatty rats. There was no significant difference in the OP1 amplitude between both groups of Jcl:SD rats, but the OP1 amplitude was significantly higher in the MMB group of SDT fatty rats. The OP2 amplitude was significantly higher in the pentobarbital group in both the Jcl:SD rats and SDT fatty rats. There was no significant difference in the OP3 amplitude between the Jcl:SD and SDT fatty rat groups. The amplitude of the OP4 waves was significantly higher in the MMB group for both Jcl:SD and SDT fatty rats. There was no significant difference in the sums of the OP1 to OP4 (ΣOPs) amplitudes between the Jcl:SD and SDT fatty rat groups. There was no significant difference in the b-wave amplitude between the Jcl:SD rat groups, but the b-wave amplitude was significantly higher in the SDT fatty rats that received pentobarbital. The peak times for a-wave, OP1, OP2, OP3, OP4, and ΣOPs were significantly longer in the pentobarbital group of SD rats. The peak time of the b-wave was significantly longer in the MMB group of Jcl:SD rats, but the same result was obtained in the SDT fatty rats except that there was no significant difference in the a-wave.
CONCLUSION
The overall ERG results vary depending on the anesthetic agent used. The OPs can be observed in detail when using MMB. Since the SDT fatty rat is a diabetic model animal, we recommend MMB as the anesthesia of choice when studying the OP waves in detail.
PubMed: 36262406
DOI: 10.1159/000526189 -
Naunyn-Schmiedeberg's Archives of... Feb 2023General anesthetic drugs have been associated with various unwanted effects including an interference with mitochondrial function. We had previously observed increases...
General anesthetic drugs have been associated with various unwanted effects including an interference with mitochondrial function. We had previously observed increases of lactate formation in the mouse brain during anesthesia with volatile anesthetic agents. In the present work, we used mitochondria that were freshly isolated from mouse brain to test mitochondrial respiration and ATP synthesis in the presence of six common anesthetic drugs. The volatile anesthetics isoflurane, halothane, and (to a lesser extent) sevoflurane caused an inhibition of complex I of the electron transport chain in a dose-dependent manner. Significant effects were seen at concentrations that are reached under clinical conditions (< 0.5 mM). Pentobarbital and propofol also inhibited complex I but at concentrations that were two-fold higher than clinical EC values. Only propofol caused an inhibition of complex II. Complex IV respiration was not affected by either agent. Ketamine did not affect mitochondrial respiration. Similarly, all anesthetic agents except ketamine suppressed ATP production at high concentrations. Only halothane increased cytochrome c release indicating damage of the mitochondrial membrane. In summary, volatile general anesthetic agents as well as pentobarbital and propofol dose-dependently inhibit mitochondrial respiration. This action may contribute to depressive actions of the drugs in the brain.
Topics: Mice; Animals; Halothane; Ketamine; Propofol; Pentobarbital; Anesthetics, General; Isoflurane; Mitochondria; Electron Transport Complex I; Adenosine Triphosphate
PubMed: 36385685
DOI: 10.1007/s00210-022-02338-9 -
BMC Anesthesiology Dec 2021To determine the hypnotic and analgesic effects of brimonidine, and evaluate its efficacy and safety for general anesthesia. Potentiation of pentobarbital sleeping time...
BACKGROUND
To determine the hypnotic and analgesic effects of brimonidine, and evaluate its efficacy and safety for general anesthesia. Potentiation of pentobarbital sleeping time following brimonidine administration was observed in mice, as was the analgesic activity of brimonidine.
METHODS
The median effective dose (ED) and lethal dose (LD) of intraperitoneally injected brimonidine were determined in hypnotized mice. In addition, the LD of intravenously injected brimonidine, and ED of intravenously, intramuscularly, and intrarectally injected brimonidine in hypnotized rabbits were determined. Finally, the synergistic anesthetic effect of brimonidine and chloral hydrate was evaluated in rabbits.
RESULTS
Intraperitoneal injection of 10 mg/kg brimonidine enhanced the hypnotic effect of a threshold dose of pentobarbital. Intraperitoneally injected brimonidine produced dose-related analgesic effects in mice. The ED of intraperitoneally administered brimonidine in hypnotized mice was 75.7 mg/kg and the LD was 379 mg/kg. ED values of intravenous, intramuscular, and intrarectal brimonidine for hypnosis in rabbits were 5.2 mg/kg, 8.8 mg/kg, and 8.7 mg/kg, respectively; the LD of intravenous brimonidine was 146 mg/kg. Combined intravenous administration of 0.6 mg/kg brimonidine and 0.03 g/kg chloral hydrate had a synergistic anesthetic effect.
CONCLUSIONS
Brimonidine elicited hypnotic and analgesic effects after systemic administration and exhibited safety. Moreover, brimonidine enhanced the effects of other types of narcotics when combined.
Topics: Adrenergic alpha-2 Receptor Agonists; Anesthesia, General; Animals; Brimonidine Tartrate; Dose-Response Relationship, Drug; Mice; Rabbits
PubMed: 34861822
DOI: 10.1186/s12871-021-01516-1 -
Computers in Biology and Medicine Jun 2022Anesthetics inhibit the respiratory muscles and even cause upper airway to collapse. Diaphragm electromyography (EMGdi) and airflow signals are usually extracted to...
Anesthetics inhibit the respiratory muscles and even cause upper airway to collapse. Diaphragm electromyography (EMGdi) and airflow signals are usually extracted to assess the degree of respiration inhibition by anesthetics. However, the ECG interference in EMGdi affects the accuracy of its time domain and frequency domain information extraction. We studied the changes in EMGdi (left EMGdi and right EMGdi) and airflow characteristics under two pentobarbital anesthetic doses. First, we filtered out the ECG in EMGdi based on the combination of stationary wavelet transform and the positioning of ECG to obtain EMGdi without ECG interference (EMGdi). The effectiveness of filtering algorithm was verified by calculating the power spectrum before and after noise reduction. Second, root mean square (RMS), average rectified value (ARV), and fixed sample entropy (fSampEn) were used to quantify EMGdi (left EMGdi, left EMGdi and right EMGdi). Median frequency (MF) and centroid frequency (f) of EMGdi were calculated. Tidal volume, respiratory cycle duration and peak airflow were calculated from airflow. Finally, the average and standard deviation of these parameters for all rabbits (n = 10) were compared and analyzed under two anesthesia states. Our results indicate that anesthesia induced by an increase in pentobarbital dose leads to decrease in ventilation and EMGdi amplitude. There was no significant change in diaphragm power spectrum (MF and f) with the increase of anesthesia dose.
Topics: Anesthetics; Animals; Diaphragm; Electromyography; Pentobarbital; Rabbits; Respiratory Rate
PubMed: 35417816
DOI: 10.1016/j.compbiomed.2022.105501 -
Journal of Ethnopharmacology Feb 2022Flowers from Styrax japonicus sieb. et Zucc. have been used as a Chinese folk medicine to alleviate pain such as toothache and sore throat.
ETHNOPHARMACOLOGICAL RELEVANCE
Flowers from Styrax japonicus sieb. et Zucc. have been used as a Chinese folk medicine to alleviate pain such as toothache and sore throat.
AIM OF THE STUDY
To testify the analgesic effect of flowers from Styrax japonicus, analyze components of the active fraction, and investigate the mechanism of analgesia.
MATERIALS AND METHODS
Flower extracts were obtained by ethanol, petroleum ether and hydrodistillation extraction. Different fractions of ethanol extracts (EE) were isolated by silica gel column chromatography and preparative liquid chromatography. Analgesic effects of EE, petroleum ether extracts (PEE), hydrodistillation extracts (HDE), and fractions of EE were evaluated using hot plate, acetic acid-induced writhing and formalin tests on mice. Components of the active fraction 1 (F1) were determined by the ultrahigh-performance liquid chromatography Q extractive mass spectrometry (UHPLC-QE-MS). Anti-inflammatory and sedative effects involving analgesic mechanisms were evaluated by carrageenan induced hind paw oedema and pentobarbital sodium sleep tests, respectively. In addition, antagonists including naloxone hydrochloride (NXH), flumazenil (FM), SCH23390 (SCH) and WAY100635 (WAY) were used to investigate the possible mechanism of analgesia. Contents of neurotransmitters and relevant metabolites in different brain regions of mice were also quantified by the ultraperformance liquid chromatography with a fluorescence detector (UPLC-FLD).
RESULTS
EE rather than PEE and HDE at medium and high doses (150 mg/kg and 300 mg/kg) significantly prolonged the latency time of the response of mice to the thermal stimulation in the hot plate test. Moreover, EE significantly decreased number of writhes in the acetic acid-induced writhing test, and reduced licking time in both two phases of the formalin test in a dose-dependent manner. The F1 (50 mg/kg) showed effective antinociceptive responses in all mice models. However, fraction 2 (F2) and fraction 3 (F3) at 50 mg/kg performed no analgesic action. Kaempferol-3-O-rutinoside, isorhamnetin-3-O-rutinoside, pinoresinol-4-O-glucoside, forsythin and arctiin were identified from components of the F1. Furthermore, F1 (50 mg/kg) did not significantly affect hind paw oedema of mice induced by carrageenan but significantly shortened sleep latency and increased sleep duration in the pentobarbital sodium sleep test. In addition, the antinociceptive response of F1 was not affected by NXH in two mice models, but significantly blocked by FM and WAY in the hot plate test. In the formalin test, FM avoided the effect of F1 only in the first phase, while the analgesic activity of F1 was totally suppressed by WAY in both two phases. Otherwise, contents of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) increased significantly in hippocampus and striatum of mice in the F1 group.
CONCLUSION
EE from flowers of Styrax japonicus, and F1, the active part isolated from EE, showed significant antinociceptive activities. The analgesic effect of F1 appeared to be related to the sedative effect, partially mediated by the GABAergic system, and highly involved in the serotonergic system. This was the first study confirming the analgesic effect of Styrax japonicus flower, which provided a candidate for the development of non-opioid analgesics.
Topics: Analgesics; Animals; Brain; Carrageenan; Edema; Flowers; Formaldehyde; Hot Temperature; Hypnotics and Sedatives; Male; Mice; Mice, Inbred ICR; Neurotransmitter Agents; Pain; Phytotherapy; Plant Extracts; Styrax
PubMed: 34715297
DOI: 10.1016/j.jep.2021.114779