S1PR2 participates in intestinal injury in severe acute pancreatitis by regulating macrophage pyroptosis.

Background: Severe acute pancreatitis (SAP) is an inflammatory disorder affecting the gastrointestinal system. Intestinal injury plays an important role in the treatment of severe acute pancreatitis. In this study, we mainly investigated the role of S1PR2 in regulating macrophage pyroptosis in the intestinal injury of severe acute pancreatitis. Methods: The SAP model was constructed using cerulein and lipopolysaccharide, and the expression of S1PR2 was inhibited by JTE-013 to detect the degree of pancreatitis and intestinal tissue damage in mice. Meanwhile, the level of pyroptosis-related protein was detected by western blot, the level of related mRNA was detected by PCR, and the level of serum inflammatory factors was detected by ELISA. In vitro experiments, LPS+ATP was used to construct the pyroptosis model of THP-1. After knockdown and overexpression of S1PR2, the pyroptosis proteins level was detected by western blot, the related mRNA level was detected by PCR, and the level of cell supernatant inflammatory factors were detected by ELISA. A rescue experiment was used to verify the sufficient necessity of the RhoA/ROCK pathway in S1PR2-induced pyroptosis. Meanwhile, THP-1 and FHC were co-cultured to verify that cytokines released by THP-1 after damage could regulate FHC damage. Results: Our results demonstrated that JTE-013 effectively attenuated intestinal injury and inflammation in mice with SAP. Furthermore, we observed a significant reduction in the expression of pyroptosis-related proteins within the intestinal tissue of SAP mice upon treatment with JTE-013. We confirmed the involvement of S1PR2 in THP-1 cell pyroptosis in vitro. Specifically, activation of S1PR2 triggered pyroptosis in THP-1 cells through the RhoA/ROCK signaling pathway. Moreover, it was observed that inflammatory factors released during THP-1 cell pyroptosis exerted an impact on cohesin expression in FHC cells. Conclusion: The involvement of S1PR2 in SAP-induced intestinal mucosal injury may be attributed to its regulation of macrophage pyroptosis.

Surface Activity, Wettability, and Aggregation Behavior of Ecofriendly Fluorocarbon Surfactant Based on Double Perfluorinated Branched Short Chains.

This article reports the synthesis of a novel sulfonated fluorocarbon surfactant (SFDC) containing double C6 perfluorinated branched short chains and compares its surface properties with a similar structured compound (SFDC-L) in solutions. The critical micelle concentration (CMC) and the corresponding surface tension (γCMC) of SFDC aqueous solution are 9.77 × 10-3 mmol/L and 22.15 mN/m, respectively, indicating that SFDC has excellent surface properties. Besides, the addition of n-hexyltrimethylammonium bromide (HTAB) could further enhance the surface properties of SFDC. Meanwhile, the micellization, aggregation behavior, wettability, and adsorption at the air-water interface of SFDC and SFDC/HTAB mixture aqueous solutions are systematically investigated. Both SFDC and SFDC/HTAB show excellent wettability at low concentrations. The aggregation of SFDC and SFDC/HTAB mixtures in aqueous solution could be clearly seen as vesicles and rod-like micelles on TEM micrographs.

Timing of endoscopy in patients with cirrhosis and acute variceal bleeding: a single-center retrospective study.

BACKGROUND: The optimal timing of endoscopy in liver cirrhosis with acute variceal bleeding (AVB) remains controversial in current guidelines and studies. METHODS: Consecutive patients with liver cirrhosis and AVB were screened. The timing of endoscopy was calculated from the last presentation of AVB or the admission to endoscopy. Early endoscopy was defined as the interval < 12 h, < 24 h, or < 48 h. A 1:1 propensity score matching (PSM) analysis was performed. Five-day failure to control bleeding and in-hospital mortality were evaluated. RESULTS: Overall, 534 patients were included. When the timing of endoscopy was calculated from the last presentation of AVB, PSM analysis demonstrated that the rate of 5-day failure to control bleeding was significantly higher in early endoscopy group defined as < 48 h (9.7% versus 2.4%, P = 0.009), but not < 12 h (8.7% versus 6.5%, P = 1.000) or < 24 h (13.4% versus 6.2%, P = 0.091), and that the in-hospital mortality was not significantly different between early and delayed endoscopy groups (< 12 h: 6.5% versus 4.3%, P = 1.000; <24 h: 4.1% versus 3.1%, P = 1.000; <48 h: 3.0% versus 2.4%, P = 1.000). When the timing of endoscopy was calculated from the admission, PSM analyses did not demonstrate any significant difference in the rate of 5-day failure to control bleeding (< 12 h: 4.8% versus 12.7%, P = 0.205; <24 h: 5.2% versus 7.7%, P = 0.355; <48 h: 4.5% versus 6.0%, P = 0.501) or in-hospital mortality (< 12 h: 4.8% versus 4.8%, P = 1.000; <24 h: 3.9% versus 2.6%, P = 0.750; <48 h: 2.0% versus 2.5%, P = 1.000) between early and delayed endoscopy groups. CONCLUSION: Our study could not support any significant association of timing of endoscopy with cirrhotic patients with AVB.

Synthesis and Characterization of a One-Dimensional Malleable Spin-Crossover Polymer Complex Modified by Methoxy Polyethylene Glycol.

A novel one-dimensional malleable spin-crossover (SCO) complex {[Fe(MPEG-trz)3](BF4)2} has been successfully synthesized by molecular self-assembly between 4-amino-1,2,4-triazoles (MPEG-trz) grafted with a long flexible chain methoxy polyethylene glycol (MPEG) and metallic complex Fe(BF4)2•6H2O. The detailed structure information was illustrated by using FT-IR and 1H NMR measurements, while the physical behaviors of the malleable SCO complexes were systematically investigated by using magnetic susceptibility measurements using superconductivity quantum interference device (SQUID) and differential scanning calorimetry (DSC). This new metallopolymer exhibits a remarkable spin crossover transition behavior, between two spin quantum states (Fe2+ ions): high spin (HS) state (quintet state) and low spin (LS) state (singlet state), at a specific critical temperature with a slender hysteresis loop of 1 K. DFT computations revealed the partial rules of HOMO-LUMO energy levels and spin density distributions of different four-position substituted [Fe(1,2,4-triazole)3]2+ derivatives with different length of repeat units in polymer complexes. This can go a step further to depict the spin and magnetic transition behaviors of SCO polymer complexes. Furthermore, the coordination polymers possess an excellent processability due to an outstanding malleability, which can be easily shaped into a polymer film with spin magnetic switching properties.

Identification of microRNA and analysis of target genes in Panax ginseng.

Objective: Ginsenosides, polysaccharides and phenols, the main active ingredients in Panax ginseng, are not different significantly in content between 3 and 5 years old of ginsengs called Yuan ginseng and more than ten years old ones called Shizhu ginseng. The responsible chemical compounds cannot fully explain difference in efficacy between them. According to reports in Lonicerae Japonicae Flos (Jinyinhua in Chinese) and Glycyrrhizae Radix et Rhizoma (Gancao in Chinese), microRNA may play a role in efficacy, so we identified microRNAs in P. ginseng at the different growth years and analyzed their target genes. Methods: Using high-throughput sequencing, the RNA-Seq, small RNA-Seq and degradome databases of P. ginseng were constructed. The differentially expressed microRNAs was identified by qRT-PCR. Results: A total of 63,875 unigenes and 24,154,579 small RNA clean reads were obtained from the roots of P. ginseng. From these small RNAs, 71 miRNA families were identified by bioinformatics target prediction software, including 34 conserved miRNAs, 37 non-conserved miRNA families, as well as 179 target genes of 17 known miRNAs. Through degradome sequencing and computation, we finally verified 13 targets of eight miRNAs involved in transcription, energy metabolism, biological stress and disease resistance, suggesting the significance of miRNAs in the development of P. ginseng. Consistently, major miRNA targets exhibited tissue specificity and complexity in expression patterns. Conclusion: Differential expression microRNAs were found in different growth years of ginsengs (Shizhu ginseng and Yuan ginseng), and the regulatory roles and functional annotations of miRNA targets in P. ginseng need further investigation.

Effects of postoperative use of proton pump inhibitors on gastrointestinal bleeding after endoscopic variceal treatment during hospitalization.

BACKGROUND: Endoscopic variceal treatment (EVT) is recommended as the mainstay choice for the management of high-risk gastroesophageal varices and acute variceal bleeding in liver cirrhosis. Proton pump inhibitors (PPIs) are widely used for various gastric acid-related diseases. However, the effects of PPIs on the development of post-EVT complications, especially gastrointestinal bleeding (GIB), remain controversial. AIM: To evaluate the effects of postoperative use of PPIs on post-EVT complications in patients with liver cirrhosis during hospitalization. METHODS: Patients with a diagnosis of liver cirrhosis who were admitted to the Department of Gastroenterology of the General Hospital of Northern Theater Command, treated by an attending physician between January 2016 and June 2020 and underwent EVT during their hospitalization were included. Logistic regression analyses were performed to explore the effects of postoperative use of PPIs on the development of post-EVT complications during hospitalization. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 143 patients were included. The incidence of post-EVT GIB and other post-EVT complications was 4.90% and 46.85%, respectively. In the overall analyses, postoperative use of PPIs did not significantly reduce the risk of post-EVT GIB (OR = 0.525, 95%CI = 0.113-2.438, P = 0.411) or other post-EVT complications (OR = 0.804, 95%CI = 0.413-1.565, P = 0.522). In the subgroup analyses according to the enrollment period, type and route of PPIs after the index EVT, use of PPIs before the index EVT, use of vasoactive drugs after the index EVT, indication of EVT (prophylactic and therapeutic), and presence of portal venous system thrombosis, ascites, and hepatocellular carcinoma, the effects of postoperative use of PPIs on the risk of post-EVT GIB or other post-EVT complications remain not statistically significant. CONCLUSION: Routine use of PPIs after EVT should not be recommended in patients with liver cirrhosis for the prevention of post-EVT complications during hospitalization.

Comparison of the effects of sufentanil-dominant anaesthesia/analgesia and epidural anaesthesia/analgesia on postoperative immunological alterations, stress responses and prognosis in open hepatectomy: a randomized trial.

Background: Both in vitro and in animal studies have shown immunosuppressive effects of opioids which might provoke tumour growth and metastasis, while no definite results were shown in previous clinical studies. To find out the effects between general anaesthesia combined with sufentanil target-controlled infusion (SGA) and general anaesthesia combined with epidural anaesthesia (EGA) on immunological alterations, stress responses and prognosis in patients undergoing open hepatectomy, a prospective, non-inferiority, randomized-controlled study was performed. Methods: Patients with liver neoplasms undergoing open hepatectomy were randomly assigned to either SGA (n=81) or EGA (n=81) group. The primary outcome was the ratio of interferon (IFN)-γ/interleukin (IL)-4 at 24 h after surgery (T3). The secondary outcomes included immune-related cytokines, circulating immune cells, stress-related cytokines, cortisol and blood glucose, visual analogue scale scores. Plasma was sampled at five-time points [baseline/before surgery (T0), 5 min after portal block release (T1), 1 h after surgery (T2), T3, and on a postoperative day (POD)5 (T4)]. Cancer-related outcomes, including recurrence, metastasis and survival, were followed up at 3 months and 1 year after surgery. Results: The IFN-γ/IL-4 ratios were comparable between both groups at T3 {median [interquartile range (IQR)]: 20.78 (12.73-29.18) vs. 19.52 (13.98-29.29), P=0.607}. At T3, the proportions of circulating T cells were decreased, while those of B and natural killer cells were increased. The plasma level of tumour necrosis factor (TNF)-α at T2 was significantly higher in the SGA group [median (IQR): 7.45 (6.20-9.80) vs. 5.95 (4.95-7.45) pg/mL, P<0.001]. Patient-controlled intravenous analgesia was less effective than epidural analgesia on POD0 and POD2. For hepatocellular carcinoma (HCC)-related outcomes, no significant differences were found in either short- or long-term follow-ups. Conclusions: Although the levels of TNF-α were higher in the SGA group, the tumour-related immunological alterations and follow-ups showed no difference between groups. SGA appears not to be inferior to EGA regarding tumour-related immunity and prognosis. Intravenous opioid use appears not to be inferior to epidural anaesthesia, and can be used safely in HCC patients without worsening patients' prognosis. Trial Registration: Chinese Clinical Trial Registry (No. ChiCTR2000035299).

Extracellular vesicles derived from astrocyte-treated with haFGF14-154 attenuate Alzheimer phenotype in AD mice.

Background: aFGF content in serum and cerebrospinal fluid is increased in Alzheimer's disease (AD) patients and attenuates the activation of astrocytes. Extracellular vesicles (EVs) are a major mediator in astrocyte-neuron communications. Since excessive or persistent reactive astrocytes lead to chronic inflammation and neuronal dysfunction, and the activation of astrocytes can be inhibited by aFGF, we proposed that the cargoes of astrocyte-derived EVs (AEVs) might be modified by aFGF stimulation, playing an important role in AD progression. However, the mechanisms underlying the role of aFGF remain unclear. Methods: AEVs were isolated from damaged astrocytes, treated with or without aFGF in Aß-loading condition, and were intranasally administered to AD mice. We determined the ability of AEVs to enter the brain, ameliorate cognitive behavior deficits, alleviate the Aß burden in the brain, and improve synapse ultrastructure. Subsequently, the miRNAs enriched in AEVs were sequenced to identify the key molecules specifically modified by aFGF. Finally, we explored the protective effects of miR-206-3p inhibition on cognitive deficiency and its regulatory mechanism and determined its role as a specific biomarker for potential AD diagnosis. Results: AEVs stimulated by aFGF (defined as AEVs-Aß+H) had favorable neuroprotection in AD pathology by enhancing neurite growth and reduction of Aß loading on neurons in vitro. Following intranasal administration, AEVs-Aß+H ameliorated cognitive behavior deficits, promoted synaptic plasticity, and alleviated brain Aß burden in the APP/PS1 and Aß brain-injected mice. AEVs-Aß+H showed beneficial effects on AD similar to AEVs produced in normal situations (AEVs-Ctrl). aFGF stimulation modified the cargoes in EVs derived from Aß damaged astrocytes, the most significant of which being the down-regulation of miR-206-3p. The miR-206-3p level was specifically high in the plasma of AD mice and patients, and miR-206-3p antagomir reversed the Alzheimer phenotype in AD mice. The brain-derived neurotrophic factor (BDNF) gene was negatively regulated by miR-206-3p and upregulated by AEVs-Aß+H and miR-206-3p antagomir in AD mice. AEVs-Aß+H inhibited δ-secretase (Asparagine endopeptidase, AEP) activation via the miR-206-3p/BDNF axis to alleviate Aß burden in the AD brain. Conclusion: Our findings highlight the role of aFGF in the modification of AEVs cargoes, especially miR-206-3p that can potentially serve as a biomarker for AD diagnosis and therapeutic target.

SIRT2 regulates proliferation and chemotherapy response of MLL-ENL-driven acute myeloid leukemia.

Both MLL-AF9 and MLL-ENL leukemia fusion proteins drive oncogenic transformation of hematopoietic cells through their N-terminal DNA/histone binding mixed-lineage leukemia 1 domain and C-terminal fragment of AF9 or ENL containing an unstructured linker region and the ANC1 homology domain, which recruits transcription factors. Despite of their structural similarity, acute myeloid leukemia (AML) patients bearing MLL-ENL show more adverse outcomes compared to those with MLL-AF9. We recapitulated the clinical patterns of these two MLL-fusions driven AMLs using murine models and found that MLL-ENL AML cells showed slower cell cycle progression and more resistance to standard chemotherapy than MLL-AF9 cells. These phenotypes were primarily controlled by the linker regions of ENL and a highly conserved lysine residue K469 within. Substitution of K469 with an acetylated mimic glutamine abolished the ability of MLL-ENL to suppress proliferation and promote chemo-resistance. We showed that deacetylase Sirt2 might act as an upstream regulator of MLL-ENL. Deletion of Sirt2 promoted proliferation of AML cells with either MLL fusions. Importantly, loss of Sirt2 greatly enhanced the sensitivity of the MLL-ENL AML cells to chemo-treatment. Taken together, our study uncovered a unique regulatory role of Sirt2 in leukemogenesis and suggested targeting SIRT2 as a new way to sensitize MLL-ENL AML patience for chemotherapy.

Phase separation of RNA-binding protein promotes polymerase binding and transcription.

An RNA-involved phase-separation model has been proposed for transcription control. However, the molecular links that connect RNA to the transcription machinery remain missing. Here we find that RNA-binding proteins (RBPs) constitute half of the chromatin proteome in embryonic stem cells (ESCs), some being colocalized with RNA polymerase (Pol) II at promoters and enhancers. Biochemical analyses of representative RBPs show that the paraspeckle protein PSPC1 inhibits the RNA-induced premature release of Pol II, and makes use of RNA as multivalent molecules to enhance the formation of transcription condensates and subsequent phosphorylation and release of Pol II. This synergistic interplay enhances polymerase engagement and activity via the RNA-binding and phase-separation activities of PSPC1. In ESCs, auxin-induced acute degradation of PSPC1 leads to genome-wide defects in Pol II binding and nascent transcription. We propose that promoter-associated RNAs and their binding proteins synergize the phase separation of polymerase condensates to promote active transcription.

Pharmacotherapy for the Treatment of Gastric Antral Vascular Ectasia: A Narrative Review.

Gastric antral vascular ectasia (GAVE) is an uncommon clinical entity leading to recurrent gastrointestinal bleeding. There is no consensus regarding treatment of GAVE. Endoscopic therapy is the preferred treatment option, but has a fairly high recurrence rate. Surgical resection can completely resolve GAVE, but is invasive with a relatively high risk of postoperative complications. Recently, the role of pharmacotherapy for GAVE has been recognized. However, the evidence is limited to scattered case reports or small case series. This review comprehensively summarizes the efficacy and side effects of drugs commonly used for the treatment of GAVE, including octreotide, cyproheptadine, cyclophosphamide, prednisolone, estrogen-progesterone, thalidomide, bevacizumab, and tranexamic acid.

Endoscopic treatment for gastric antral vascular ectasia.

Gastric antral vascular ectasia (GAVE) is one of the uncommon causes of upper gastrointestinal bleeding. Major treatment of GAVE includes pharmacotherapy, endoscopy, and surgery. The efficacy and safety of pharmacotherapy have not been sufficiently confirmed; and surgery is just considered when conservative treatment is ineffective. By comparison, endoscopy is a common treatment option for GAVE. This paper reviews the currently used endoscopic approaches for GAVE, mainly including argon plasma coagulation (APC), radiofrequency ablation (RFA), and endoscopic band ligation (EBL). It also summarizes their efficacy and procedure-related adverse events. The endoscopic success rate of APC is 40-100%; however, APC needs several treatment sessions, with a high recurrence rate of 10-78.9%. The endoscopic success rates of RFA and EBL are 90-100% and 77.8-100%, respectively; and their recurrence rates are 21.4-33.3% and 8.3-48.1%, respectively. Hyperplastic gastric polyps and sepsis are major adverse events of APC and RFA; and Mallory-Weiss syndrome is occasionally observed after APC. Adverse events of EBL are rare and mild, such as nausea, vomiting, esophageal or abdominal pain, and hyperplastic polyps. APC is often considered as the first-line choice of endoscopic treatment for GAVE. RFA and EBL have been increasingly used as alternatives in patients with refractory GAVE. A high recurrence of GAVE after endoscopic treatment should be fully recognized and cautiously managed by follow-up endoscopy. In future, a head-to-head comparison of different endoscopic approaches for GAVE is warranted.

Upregulation of GLT-1 via PI3K/Akt Pathway Contributes to Neuroprotection Induced by Dexmedetomidine.

Perioperative ischemic stroke usually leads to neurological dysfunction caused by neuron death. During the ischemic condition, excitotoxity due to extracellular glutamate accumulation is a main mechanism of neuron damage. The clearance of glutamate mainly depends on glutamate transporter-1 (GLT-1) which is expressed in astrocytes. Dexmedetomidine, an α2 adrenergic receptor agonist, is proved to induce neuroprotection. This study was set out to investigate the glutamate-related mechanism involved in the neuroprotective effect of dexmedetomidine. Middle cerebral artery occlusion (MCAO) was used as a model of ischemic stroke in our study. We determined Neurological deficit scores (NDS) and Magnetic resonance imaging (MRI) at three points (2, 6, and 24 h) after middle cerebral artery occlusion (MCAO) to evaluate the neuroprotective effect of dexmedetomidine. Besides, we performed western blot (6 and 24 h after MACO) and immunofluorescent staining (24 h after MCAO) to observe the expression of GLT-1. The effect and mechanism of dexmedetomidine on GLT-1 in primary cultured astrocytes were investigated using western blot and RT-PCR. Our results showed that pretreatment with dexmedetomidine improved NDS and reduced infarct volume as well as upregulating GLT-1 expression. Furthermore, using Atipamezole and LY294002, we found that dexmedetomidine significantly increased GLT-1 levels in astrocytes via activating α2 adrenergic receptor and PI3K/AKT pathway both in vitro and in vivo study. Overall, our present study indicated that dexmedetomidine had neuroprotective effects on ischemia stroke and upregulation of GLT-1 levels by PI3K/AKT dependent pathway might be the potential mechanism.

Analysis of Panax ginseng miRNAs and Their Target Prediction Based on High-Throughput Sequencing.

Panax ginseng has been widely and effectively used as medicine for thousands of years. However, only limited studies have been conducted to date on ginseng miRNAs. In the present study, we collected 3 ginseng samples from the Changbai Mountain in China. Small RNA libraries were constructed and sequenced on the Illumina HiSeq platform. Sequencing analyses identified 3798 miRNAs, including 298 known miRNAs and 3500 potentially novel miRNAs. The miR166, miR159, and miR396 families were among the most highly expressed miRNAs in all libraries. The results of miRNA expression analyses were validated by qRT-PCR. Target gene prediction through computational and pathway annotation analyses revealed that the primary pathways were related to plant development, including metabolic processes and single-organism processes. It has been reported that plant miRNAs might be one of the hidden bioactive ingredients in medicinal plants. Based on the combined use of RNAhybrid, Miranda, and TargetScan software, a total of 50,992 potential human genes were predicted as the putative targets of 2868 miRNAs. Interestingly, the enriched KEGG pathways were associated with some human diseases, especially cancer, immune system diseases, and neurological disorders, and this could support the clinical use of ginseng. However, the human targets of ginseng miRNAs should be confirmed by further experimental validation. Our results provided valuable insight into ginseng miRNAs and the putative roles of these miRNAs.

Verification of miRNAs in ginseng decoction by high-throughput sequencing and quantitative real-time PCR.

Panax ginseng C. A. Meyer is a precious traditional Chinese medicine that has been clinically used for over thousands of years. In general, ginseng needs to be prepared to ginseng decoction before taking it. MicroRNAs are a class of small (18-24 nt), single-stranded molecules that regulate gene expression at the post-transcriptional level. Considering that ginseng miRNAs may be bioactive compounds, we used Illumina high-throughput sequencing and quantitative real-time PCR (qRT-PCR) to validate the existence of miRNAs in fresh ginseng decoction which have been boiled at high temperature. Our previous studies have demonstrated that there are several miRNAs in fresh ginseng. The roots of fresh Panax ginseng were prepared according to routine methods, from which miRNAs were extracted and sequenced. A total of 43 miRNAs were identified from water decoction by Illumina high-throughput sequencing, belonging to 71 miRNA families. The target genes of these miRNAs were predicted by sequencing, and were annotated by GO, KEGG and Nr databases. The functions of these target genes mainly included plant hormone signal transduction, transcription regulation, macromolecular metabolism and auxin signaling. Nine highly expressed miRNAs (miR159, miR167, miR396, miR166, miR168, miR156, miR165, miR162 and miR394) were verified by qRT-PCR, and the results of Illumina high-throughput sequencing and qRT-PCR were consistent. Results from this study indicate that miRNAs remained stable in P. ginseng after high-temperature boiling. Additionally, Illumina high-throughput sequencing was superior in the acquisition of higher amount of small RNAs.

Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring.

Maternal sevoflurane exposure during pregnancy is associated with increased risk for behavioral deficits in offspring. Several studies indicated that neurogenesis abnormality may be responsible for the sevoflurane-induced neurotoxicity, but the concrete impact of sevoflurane on fetal brain development remains poorly understood. We aimed to investigate whether maternal sevoflurane exposure caused learning and memory impairment in offspring through inducing abnormal development of the fetal prefrontal cortex (PFC). Pregnant mice at gestational day 15.5 received 2.5% sevoflurane for 6 h. Learning function of the offspring was evaluated with the Morris water maze test at postnatal day 30. Brain tissues of fetal mice were subjected to immunofluorescence staining to assess differentiation, proliferation, and cell cycle dynamics of the fetal PFC. We found that maternal sevoflurane anesthesia impaired learning ability in offspring through inhibiting deep-layer immature neuron output and neuronal progenitor replication. With the assessment of cell cycle dynamics, we established that these effects were mediated through cell cycle arrest in neural progenitors. Our research has provided insights into the cell cycle-related mechanisms by which maternal sevoflurane exposure can induce neurodevelopmental abnormalities and learning dysfunction and appeals people to consider the neurotoxicity of anesthetics when considering the benefits and risks of nonobstetric surgical procedures.

Multiple sevoflurane anesthesia in pregnant mice inhibits neurogenesis of fetal hippocampus via repressing transcription factor Pax6.

Sevoflurane is widely used in non-obstetric surgeries of pregnant women, but its influences on fetal brain are still not fully known. We set out to assess the effects of multiple maternal sevoflurane exposure on neurogenesis and cognitive dysfunction in fetus and offspring. Pregnant mice (gestational day 15.5) and cultured mouse neural stem cells (NSCs) received daily sevoflurane exposure (2.5%×2h and 4.1%×2h respectively) for three consecutive days. Cognitive function of the offspring was determined with the Morris water maze. The expression of Ccnd1 and Pax6 in fetal brains and NSCs were analyzed by immunofluorescence, Western blot and qPCR. The neurogenesis was evaluated by BrdU staining. Results showed that multiple sevoflurane exposure in pregnant mice caused the decrease of Pax6 and Ccnd1 expression, the inhibition of NSCs proliferation and fetal hippocampus neurogenesis, which may contribute to the impaired learning and memory in offspring at P28. Moreover, lithium mitigated the sevoflurane-induced reduction in Pax6, Ccnd1 and neurogenesis. All these results suggest that multiple sevoflurane exposure may induce detrimental effects in the developing brains of fetus and offspring by the depression of neurogenesis through Pax6 pathway.