Dexmedetomidine enables copper homeostasis in cerebral ischemia/reperfusion via ferredoxin 1.

Excessive oxygen free radicals and toxic substances are generated in cerebral ischemia-reperfusion (I/R) process. Dexmedetomidine (DEX), a common anesthetic and sedative drug, can considerably boost glutathione (GSH), which has anti-copper influx effects. Focusing on cuproptosis, the mechanism of DEX in the I/R was revealed. Using the I/R rat model, the effects of DEX and the copper chelator D-penicillamine on cerebral infarct volume, copper levels, mitochondrial respiration and membrane potential, GSH content, and enrichment of cuproptosis functional proteins were examined. The involvement of ferredoxin 1 (FDX1) in the DEX regulatory pathway was verified by overexpressing FDX1 in vitro. DEX could significantly reduce cerebral infarction in rats, reduce copper levels, maintain mitochondrial functions, increase GSH, and reduce the content of key proteins related to cuproptosis. These aspects were replicated in vitro and revealed that FDX1 overexpression partially reversed the impacts of DEX. Together, cuproptosis occurs in the brain I/R process and DEX can enhance cell survival by blocking the primary pathway mediated by FDX1.KEY MESSAGESDexmedetomidine reduces cerebral infarction in the I/R rat models.Dexmedetomidine reduces cuproptosis in the I/R rat models.FDX1, an upstream of protein fatty acylation, mediates regulation of Dexmedetomidine.

Alarm Calling in Plateau Pika (Ochotona curzoniae): Evidence from Field Observations and Simulated Predator and Playback Experiments.

Acoustic communication plays a vital role in passing or sharing information between individuals. Identifying the biological meaning of vocal signals is crucial in understanding the survival strategies of animals. However, there are many challenges in identifying the true meaning of such signals. The plateau pika (Ochotona curzoniae) is a call-producing mammal endemic to the Qinghai-Tibet plateau (QTP) and considered a keystone species owing to its multiple benefits in alpine rangeland ecosystems. Previous studies have shown that plateau pikas emit alarm calls as part of their daily activities. However, only field observations have been used to identify these alarm calls of the plateau pika, with no attempts at using playback experiments. Here, we report the alarm calling of plateau pikas through field observations as well as simulated predator and playback experiments in the Eastern QTP from 2021 to 2022. We found that both female and male adults emitted alarm calls, the signals of which comprised only one syllable, with a duration of 0.1-0.3 s. There were no differences in the characteristics between the observed alarm calls and those made in response to the simulated predator. The duration of the alarm call response varied with altitude, with plateau pikas living at higher altitudes responding at shorter durations than those at lower altitudes.

Aurantimonas marianensis sp. nov., isolated from deep-sea sediment of the Mariana Trench.

A novel strain, designated as LRZ36T, was isolated from deep-sea sediment (from a depth of 5400 m) from the Mariana Trench. Cells of this strain are rod-shaped, Gram-stain-negative, strictly aerobic and non-motile. Phylogenetic analysis of LRZ36T based on 16S rRNA gene sequences revealed a lineage in the family Aurantimonadaceae but distinct from the most closely related species Aurantimonas marina CGMCC 1.17725T, 'Aurantimonas litoralis' KCTC 12094 and Aurantimonas coralicida DSM 14790T with sequence identities of 99.4 %, 98.0 and 97.9 %, respectively. The genome of LRZ36T was 3.8 Mbp in size with a DNA G+C content of 64.8 %, containing 3623 predicted coding genes. LRZ36T showed average nucleotide identity values of 89.8 %, 78.7 and 78.5 % and digital DNA-DNA hybridization values of 38.9 %, 21.7 and 21.6 % with A. marina CGMCC 1.17725T, 'A. litoralis' KCTC 12094 and A. coralicida DSM 14790T, respectively. The major respiratory quinone was ubiquinone-10 (Q-10), and the predominant fatty acids were C18 : 1ω7c (74.4 %) and C16 : 0 (12.1 %). The polar lipids in LRZ36T are diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylcholine, phosphatidylinositol mannoside, an unidentified aminophospholipid, three unidentified lipids, three unidentified phospholipids and two unidentified aminolipids. On the basis of genotypic and phenotypic evidence, LRZ36T represents a novel species of the genus Aurantimonas, for which the name Aurantimonas marianensis sp. nov. is proposed. The type strain is LRZ36T (= KCTC 92065T = GDMCC 1.2985T=MCCC 1K07227T).

Mirtazapine prevents cell activation, inflammation, and oxidative stress against isoflurane exposure in microglia.

Mirtazapine is an antidepressant drug that has been proven to possess a cognitive enhancer efficiency. In this study, we evaluated the potential protective effects of mirtazapine on BV2 microglia in response to isoflurane exposure. Our results show that mirtazapine attenuated isoflurane-induced expression of microglia-specific protein Iba1 in BV2 microglia. Mirtazapine prevented isoflurane-induced production of the pro-inflammatory factors interleukin (IL)-1ß and IL-18 by inhibiting the activation of the nod-like receptor family protein 3 (NLRP3) inflammasome in BV2 microglia. The increased reactive oxygen species (ROS) production and elevated expression level of NADPH oxidase 4 (NOX4) in isoflurane-induced BV2 microglia were mitigated by mirtazapine. Isoflurane exposure reduced triggering receptor expressed on myeloid cells 2 (TREM2) expression in BV2 microglia, which was restored by mirtazapine. Moreover, silencing of TREM2 abolished the inhibitory effects of mirtazapine on ionized calcium-binding adapter molecule 1 (Iba1) expression and inflammation in BV2 microglia. From these results, we could infer that mirtazapine exerted a protective effect on BV2 microglia against isoflurane exposure-caused microglia activation, neuroinflammation, and oxidative stress via inducing TREM2 activation. Hence, mirtazapine might be a potential intervention strategy to prevent isoflurane exposure-caused cognitive dysfunction in clinical practice.

Effects of different sedatives/analgesics on stress responses in patients undergoing craniotomy and bone flap decompression.

OBJECTIVE: To explore the effects of sedation and analgesia with dexmedetomidine and other drugs on the stress response in patients with cerebral hemorrhage after craniotomy hematoma removal and bone flap decompression and insertion of an indwelling endotracheal catheter. METHODS: A total of 180 patients with cerebral hemorrhage with consciousness disturbance who underwent emergency surgery were included in this study. They were divided into six groups treated with propofol, dexmedetomidine, lidocaine, sufentanil, dezocine, and remifentanil, respectively. Intravenous medication was given after recovery of spontaneous respiration, and stress responses were compared among the group. RESULTS: Serum concentrations of norepinephrine, epinephrine, and cortisol and systolic blood pressure were significantly correlated with drug treatment. Serum norepinephrine concentrations differed significantly among the groups, except between the sufentanil and propofol groups. There were significant differences in serum epinephrine concentrations among all groups, and significant differences in serum cortisol concentrations among all groups, except the propofol, dexmedetomidine, and lidocaine groups. CONCLUSION: Dexmedetomidine can reduce the stress response in patients with intracerebral hemorrhage undergoing emergency craniotomy and bone flap decompression, and can reduce adverse events from an indwelling endotracheal catheter 3 hours post-operation.

Sevoflurane preconditioning inhibits cardiomyocyte injury induced by oxygen­glucose deprivation by modulating TXNIP.

The thioredoxin interaction protein (TXNIP) has been reported to be closely related to cell oxidative stress, apoptosis and inflammation. TXNIP is involved in the regulation of oxidative stress in lung and renal injury. However, it is unclear as to whether it participates in the protective effects of sevoflurane preconditioning in cardiomyocyte injury caused by oxidative stress in ischemia. In the present study, H9c2 cardiomyocytes were cultured with 0, 1.5, 2, 3.5, 5 or 6% sevoflurane for 3 h, followed by exposure to oxygen and glucose deprivation. The results demonstrated that oxygen and glucose deprivation induced an increase in TXNIP expression, lactate dehydrogenase (LDH) release, caspase­3 activity, reactive oxygen species and malondialdehyde production. Preconditioning of the H9c2 cells with 3.5% sevoflurane suppressed TXNIP expression, LDH leakage, caspase­3 activity, reactive oxygen species and malondialdehyde production, and it promoted cell viability. TXNIP overexpression reversed the effects of 3.5% sevoflurane preconditioning on caspase­3 activity, reactive oxygen production and cell viability. Furthermore, TXNIP modulated p27 expression via PKB (protein kinase B/AKT) phosphorylation following preconditioning with 3.5% sevoflurane, and oxygen and glucose deprivation. On the whole these findings indicated that sevoflurane preconditioning protected the H9c2 cells against injury induced by oxygen and glucose deprivation by modulating TXNIP, AKT activation and p27 signaling.

Propofol suppresses proliferation, invasion, and migration of human melanoma cells via regulating microRNA-137 and fibroblast growth factor 9.

Propofol is an intravenous anesthetic widely used in clinical surgeries, such as tumor resection. Propofol affects the growth of many cancers, though its effect on melanoma is unknown. Our study aimed to explore how propofol affects melanoma cells. Melanoma cells A2058 and WM793B were cultured with propofol for 24 hr. Propofol significantly suppressed proliferation, migration, and invasion of A2058 and WM793B cells. Lower miR-137 level was observed in A2058 and WM793B cells, compared with normal human epidermal melanocyte HEMa-LP cells. Propofol-induced miR-137 upregulation and decreased proliferation, invasive ability, and migrated ability of A2058 and WM793B cells. Transfection with the miR-137 inhibitor reversed these effects. Additionally, miR-137 was verified to target and negatively regulate fibroblast growth factor 9 (FGF9) expression. Propofol efficiently downregulated FGF9 protein expression by upregulating miR-137. Furthermore, FGF9 overexpression abrogated propofol's repressive effects on the malignant potential of A2058 and WM793B cells. These findings indicate that propofol suppressed melanoma cell proliferation, invasion, and migration by regulating miR-137 and FGF9.

Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation.

AIM: Substance P (SP) causes vasodilation and blood pressure (BP) reduction. However, the involvement of tachykinin receptors (NKRs) within baroreflex afferent pathway in SP-mediated BP regulation is largely unknown. METHODS: Under control and hypertensive condition, NKRs' expressions were evaluated in nodose (NG) and nucleus of tractus solitary (NTS) of male, female, and ovariectomized (OVX) rats; BP was recorded after microinjection of SP and NKRs agonists into NG; Baroreceptor sensitivity (BRS) was tested as well. RESULTS: Immunostaining and immunoblotting data showed that NK1R and NK2R were estrogen-dependently expressed on myelinated and unmyelinated afferents in NG. A functional study showed that BP was reduced dose-dependently by SP microinjection, which was more dramatic in males and can be mimicked by NK1R and NK2R agonists. Notably, further BP elevation and BRS dysfunction were confirmed in desoxycorticosterone acetate (DOCA)-salt model in OVX compared with DOCA-salt model in intact female rats. Additionally, similar changes in NKRs' expression in NG were also detected using DOCA-salt and SHR. Compared with NG, inversed expression profiles of NKRs were also found in NTS with either gender. CONCLUSION: The estrogen-dependent NKRs' expression in baroreflex afferent pathway participates at least partially in sexual-dimorphic and SP-mediated BP regulation under physiological and hypertensive conditions.

miR­223­3p/TIAL1 interaction is involved in the mechanisms associated with the neuroprotective effects of dexmedetomidine on hippocampal neuronal cells in vitro.

Dexmedetomidine (DEX), an α2 adrenoceptor agonist, is a commonly used anesthetic drug in surgical procedures. Previous studies have indicated that DEX exerts neuroprotective effects. However, the molecular mechanism underlying this process remains to be elucidated. The present study investigated a potential implication of microRNA (miR)­223­3p in the DEX­induced anti­oxidative effect on neuronal cells. The results indicated that following hydrogen peroxide (H2O2)­mediated induction of oxidative stress, the viability of human hippocampal neuronal cells was markedly decreased, as determined by an MTT assay. In addition, treatment with H2O2 induced cell apoptosis, the release of lactate dehydrogenase, accumulation of intracellular calcium, phosphorylation of calmodulin­2, and production of malondialdehyde and reactive oxygen species. Furthermore, treatment with H2O2 inhibited the expression of mir­223­3p and enhanced the expression of its target cytotoxic granule associated RNA binding protein like 1 (TIAL1), and these effects were reversed by treatment with DEX. Mechanistic studies demonstrated that the 3'­untranslated region of TIAL1 is a direct target of mir­223­3p. The results of the present study demonstrated that DEX may induce its neuroprotective effects by regulating the interaction between miR­223­3p and TIAL1. Therefore, the manipulation of miR­223­3p/TIAL1 interaction may be involved in the neuroprotective effects of DEX.

Inhibition of lncRNA X inactivate-specific transcript ameliorates inflammatory pain by suppressing satellite glial cell activation and inflammation by acting as a sponge of miR-146a to inhibit Nav 1.7.

Long noncoding RNAs (lncRNA) has been validated to participate in nociception in inflammatory pain, presenting as a potential target against anesthesia. Previous research work confirmed the correlation between lncRNA X inactivate-specific transcript (XIST) and inflammation. However, its role in inflammatory pain is undefined. In animal pain models, voltage-gated sodium channels (VGSCs) reportedly participate in neural excitation. In this study, we observed the high expression of XIST and VGSC 1.7 (Nav 1.7) in the dorsal root ganglion (DRG) of the complete Freund's adjuvant (CFA)-induced rat inflammatory pain model. Furthermore, XIST inhibition alleviated pain behavior and the activation of DRG satellite glial cells by suppressing glial fibrillary acidic protein (GFAP) expression, as well as inflammatory cytokine levels of interleukin-6 and tumor necrosis factor-α. XIST downregulation increased the mechanical pain threshold in an inflammatory pain model. Moreover, the expression of miR-146a was decreased in CFA rats. In vitro, XIST acted as a sponge of miR-146a, which targeted Nav 1.7 via bioinformatic prediction, luciferase reporter, and pull-down assay. More importantly, activation of the Nav 1.7 pathway or miR-146 depression both reversed XIST knockdown-inhibited satellite glial cell activation and inflammatory pain in CFA rats. These results suggest that cessation of XIST may ameliorate inflammatory pain by acting as a sponge of miR-146a to inhibit Nav1.7, implying a promising strategy against inflammatory pain.

Neuropeptide Y-mediated sex- and afferent-specific neurotransmissions contribute to sexual dimorphism of baroreflex afferent function.

BACKGROUND: Molecular and cellular mechanisms of neuropeptide-Y (NPY)-mediated gender-difference in blood pressure (BP) regulation are largely unknown. METHODS: Baroreceptor sensitivity (BRS) was evaluated by measuring the response of BP to phenylephrine/nitroprusside. Serum NPY concentration was determined using ELISA. The mRNA and protein expression of NPY receptors were assessed in tissue and single-cell by RT-PCR, immunoblot, and immunohistochemistry. NPY was injected into the nodose while arterial pressure was monitored. Electrophysiological recordings were performed on nodose neurons from rats by patch-clamp technique. RESULTS: The BRS was higher in female than male and ovariectomized rats, while serum NPY concentration was similar among groups. The sex-difference was detected in Y1R, not Y2R protein expression, however, both were upregulated upon ovariectomy and canceled by estrogen replacement. Immunostaining confirmed Y1R and Y2R expression in myelinated and unmyelinated afferents. Single-cell PCR demonstrated that Y1R expression/distribution was identical between A- and C-types, whereas, expressed level of Y2R was ~15 and ~7 folds higher in Ah- and C-types than A-types despite similar distribution. Activation of Y1R in nodose elevated BP, while activation of Y2R did the opposite. Activation of Y1R did not alter action potential duration (APD) of A-types, but activation of Y2R- and Y1R/Y2R in Ah- and C-types frequency-dependently prolonged APD. N-type ICa was reduced in A-, Ah- and C-types when either Y1R, Y2R, or both were activated. The sex-difference in Y1R expression was also observed in NTS. CONCLUSIONS: Sex- and afferent-specific expression of Neuropeptide-Y receptors in baroreflex afferent pathway may contribute to sexual-dimorphic neurocontrol of BP regulation.