Effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section

BACKGROUND Following cesarean section,a significant number of women encounter moderate to severe pain.Inadequate management of acute pain post-cesarean section can have far-reaching implications,adversely impacting maternal emotional wellbeing,daily activities,breastfeeding,and neonatal care.It may also impede maternal organ function recovery,leading to escalated opioid usage,heightened risk of postpartum depression,and the development of chronic postoperative pain.Both the Chinese Enhanced Recovery After Surgery(ERAS)guidelines and the American ERAS Society guidelines consistently advocate for the adoption of multimodal analgesia protocols in post-cesarean section pain management.Esketamine,functioning as an antagonist of the N-Methyl-D-Aspartate receptor,has been validated for pain management in surgical patients and has exhibited effectiveness in depression treatment.Research has suggested that incorporating esketamine into postoperative pain management via pain pumps can lead to improvements in short-term depression and pain outcomes.This study aims to assess the efficacy and safety of administering a single dose of esketamine during cesarean section.AIM To investigate the effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section.METHODS A total of 315 women undergoing elective cesarean section under combined spinal-epidural anesthesia were randomized into three groups:low-dose esketamine(0.15 mg/kg),high-dose esketamine(0.25 mg/kg),and control(saline).Postoperative Visual Analog Scale(VAS)scores were recorded at 6 hours,12 hours,24 hours,and 48 hours.Edinburgh Postnatal Depression Scale(EPDS)scores were noted on 2 days,7 days and 42 days.Ramsay sedation scores were assessed at specified intervals post-injection.Postoperative adverse reactions were also recorded.RESULTS Low-dose group and high-dose group compared to control group,had significantly lower postoperative VAS pain scores at 6 hours 12 hours,and 24 hours(P<0.05),with reduced analgesic usage(P<0.05).EPDS scores and postpartum depression rates were significantly lower on 2 days and 7 days(P<0.05).No significant differences in first exhaust and defecation times were observed(P>0.05),but ambulation times were shorter(P<0.05).Ramsay scores were higher at 5 minutes,15 minutes,and upon room exit(P<0.05).Low-dose group and high-dose group had higher incidences of hallucination,lethargy,and diplopia within 2 hours(P<0.05),and with low-dose group had lower incidences of hallucination,lethargy,and diplopia than high-dose group(P<0.05).CONCLUSION Esketamine enhances analgesia and postpartum recovery;a 0.15 mg/kg dose is optimal for cesarean sections,balancing efficacy with minimized adverse effects.

Cone-rod homeobox transcriptionally activates TCF7 to promote the proliferation of retinal pigment epithelial and retinoblastoma cells in vitro

AIM:To investigate the proliferation regulatory effect of cone-rod homeobox(CRX)in retinal pigment epithelium(RPE)and retinoblastoma(RB)cells to explore the potential application and side effect(oncogenic potential)of CRXbased gene therapy in RPE-based retinopathies.METHODS:Adult human retinal pigment epithelial(ARPE)-19 and human retinal pigment epithelial(RPE)-1 cells and Y79 RB cell were used in the study.Genetic manipulation was performed by lentivirus-based technology.The cell proliferation was determined by a CellTiter-Glo Reagent.The mRNA and protein levels were determined by quantitative real-time polymerase chain reaction(qPCR)and Western blot assay.The transcriptional activity of the promoter was determined by luciferase reporter gene assay.The bindings between CRX and transcription factor 7(TCF7)promoter as well as TCF7 and the promoters of TCF7 target genes were examined by chromatin immunoprecipitation(ChIP)assay.The transcription of the TCF7 was determined by a modified nuclear run-on assay.RESULTS:CRX overexpression and knockdown significantly increased(n=3,P<0.05 in all the cells)and decreased(n=3,P<0.01 in all the cells)the proliferation of RPE and RB cells.CRX overexpression and knockdown significantly increased and deceased the mRNA levels of Wnt signaling target genes[including MYC proto-oncogene(MYC),JUN,FOS like 1(FOSL1),CCND1,cyclin D2(CCND2),cyclin D3(CCND3),cellular communication network factor 4(CCN4),peroxisome proliferator activated receptor delta(PPARD),and matrix metallopeptidase 7(MMP7)]and the luciferase activity driven by the Wnt signaling transcription factor(TCF7).TCF7 overexpression and knockdown significantly increased and decreased the proliferation of RPE and RB cells and depletion of TCF7 significantly abolished the stimulatory effect of CRX on the proliferation of RPE and RB cells.CRX overexpression and knockdown significantly increased and decreased the mRNA level of TCF7 and the promoter of TCF7 was significantly immunoprecipitated by CRX antibody.CONCLUSION:CRX transcriptionally activates TCF7 to promote the proliferation of RPE and RB cells in vitro.CRX is a potential target for RPE-based regenerative medicine.The potential risk of this strategy,tumorigenic potential,should be considered.

A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells(BMSCs)

Receptor tyrosine kinase-like orphan receptor 2(ROR2)has a vital role in osteogenesis.However,the mechanism underlying the regulation of ROR2 in osteogenic differentiation is still poorly comprehended.A previous study by our research group showed that a novel compound heterozygous ROR2 variation accounted for the autosomal recessive Robinow syndrome(ARRS).This study attempted to explore the impact of the ROR2:c.904C>T variant specifically on the osteogenic differentiation of BMSCs.Methods:Coimmunoprecipitation(CoIP)-western blotting was carried out to identify the interaction between ROR2 and Wnt5a.Double-immunofluorescence staining was used for determining the expressions and co-localization of ROR2 and Wnt5a in bone marrow mesenchymal stem cells(BMSCs).Western blot(WB)analysis and quantitative reverse transcription polymerase chain reaction(RT-qPCR)were conducted to identify the expression levels of ROR2 in the BMSCs transfected with LV-shROR2 or LV-ROR2-c.904C>T.The alkaline phosphatase(ALP)activity was detected,and Alizarin Red S staining was done for evaluating the osteogenic differentiation of BMSCs.RT-qPCR was employed to identify the expression of the sphingomyelin synthase 1(SMS1)mRNA in the BMSCs transfected with LV-shROR2 or LV-ROR2-c.904C>T and the mRNA expression levels of Runt-related transcription factor 2(RUNX2),osteocalcin(OCN),and osteopontin(OPN).WB was performed to confirm the protein expressions of extracellular regulated protein kinases1(ERK),P-ERK,Smad family member1/5/8(Smad1/5/8),P-Smad1/5/8,P-P38,P38,RUNX2,OCN,and OPN in the BMSCs transfected with LV-shROR2/LV-ROR2-c.904C>T and sphingomyelin(SM).Results:The ROR2:c.904C>T mutant altered the subcellular localization of the ROR2 protein,which caused an impaired interaction between ROR2 and Wnt5a.The depletion of ROR2 restricted the osteogenic differentiation capability of BMSCs and downregulated the expression of SMS1.SM treatment could reverse the inhibition of osteoblastic differentiation in ROR2-depleted BMSCs.Conclusion:The findings of this work revealed that the ROR2:c.904C>T variant led to the loss of function of ROR2,which impaired the interaction between ROR2 and Wnt5a and also controlled the osteogenic differentiation capability of BMSCs.Furthermore,SM was revealed to be engaged in the osteoblastic differentiation of BMSCs regulated by ROR2,which renders SM a potential target in the therapy for ARRS.

Coiled-coil domain-containing 38 is required for acrosome biogenesis and fibrous sheath assembly in mice

During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful fertilization.Severe deformities in flagella cause a male infertility syndrome,multiple morphological abnormalities of the flagella(MMAF),while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential.However,evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited.Here,we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38(Ccdc38)via inducing a nonsense mutation and find that the males are infertile.The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes.We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm.Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3,a protein associated with acrosome biogenesis,in testes and an aberrant distribution of TEKT3 in sperm.We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility.Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.

New therapeutic target NCF1-directed multi-bioactive conjugate therapies prevent preterm birth and adverse pregnancy outcomes

Preterm birth(PTB)is a leading cause of neonatal morbidity and mortality worldwide,yet the cellular and molecular mechanisms driving this condition remain undeciphered,thus limiting discovery of new therapies.In-depth analyses of human and mouse tissues associated with PTB,in combination with cellular studies,indicated that aberrantly high-expressed neutrophil cytoplasmic factor(NCF)1 leads to oxidative distress,recruitment,and pro-inflammatory activation of neutrophils and macrophages,while sequentially overexpressed pro-inflammatory mediators induce contractions of uterine smooth muscle cells(USMCs)as well as apoptosis of USMCs and amniotic epithelial cells,thereby causing PTB.According to these new findings,we rationally engineered an amphiphilic macromolecular conjugate LPA by covalently integrating low-molecular-weight heparin,a reactive oxygen species-responsive/scavenging component,and an anti-inflammatory peptide.This bioengineered macromolecular conjugate can selfassemble into multi-bioactive nanoparticles(LPA NP).In a mouse model of PTB,LPA NP effectively delayed PTB and inhibited adverse pregnancy outcomes,by regulating NCF1-mediated oxidativeinflammatory cascades,i.e.,attenuating oxidative stress,inhibiting inflammatory cell activation,reducing local inflammation,and decreasing contraction/apoptosis of myometrial cells.Packaging LPA NP into temperature-responsive,self-healing,and bioadhesive hydrogel further potentiated its in vivo efficacies after intravaginal delivery,by prolonging retention time,sustaining nanotherapy release,and increasing bioavailability in the placenta/uterus.Importantly,both the conjugate/nanotherapy and hydrogel formulations exhibited excellent safety profiles in pregnant mice,with negligible side effects on the mother and offspring.

Predicting the Risk of Preterm Birth Throughout Pregnancy Based on a Novel Transcriptomic Signature

Objective::This study focused on the prediction of preterm birth(PTB).It aimed to identify the transcriptomic signature essential for the occurrence of PTB and evaluate its predictive value in early,mid,and late pregnancy and in women with threatened preterm labor(TPTL).Methods::Blood transcriptome data of pregnant women were obtained from the Gene Expression Omnibus database.The activity of biological signatures was assessed using gene set enrichment analysis and single-sample gene set enrichment analysis.The correlation among molecules in the interleukin 6(IL6)signature and between IL6 signaling activity and the gestational week of delivery and latent period were evaluated by Pearson correlation analysis.The effects of molecules associated with the IL6 signature were fitted using logistic regression analysis;the predictive value of both the IL6 signature and IL6 alone were evaluated using receiver operating characteristic curves and pregnancy maintenance probability was assessed using Kaplan-Meier analysis.Differential analysis was performed using the DEseq2 and limma algorithms.Results::Circulatory IL6 signaling activity increased significantly in cases with preterm labor than in those with term pregnancies(normalized enrichment score(NES)=1.857,P=0.001).The IL6 signature(on which IL6 signaling is based)was subsequently considered as the candidate biomarker for PTB.The area under the curve(AUC)values for PTB prediction(using the IL6 signature)in early,mid,and late pregnancy were 0.810,0.695,and 0.779,respectively;these values were considerably higher than those for IL6 alone.In addition,the pregnancy curves of women with abnormal IL6 signature differed significantly from those with normal signature.In pregnant women who eventually had preterm deliveries,circulatory IL6 signaling activity was lower in early pregnancy(NES=-1.420,P=0.031)and higher than normal in mid(NES=1.671,P=0.002)and late pregnancy(NES=2.350,P<0.001).In women with TPTL,the AUC values for PTB prediction(or PTB within 7 days and 48 hours)using the IL6 signature were 0.761,0.829,and 0.836,respectively;the up-regulation of IL6 signaling activity and its correlation with the gestational week of delivery(r=-0.260,P=0.001)and latency period(r=-0.203,P=0.012)were more significant than in other women.Conclusion::Our findings suggest that the IL6 signature may predict PTB,even in early pregnancy(although the predictive power is relatively weak in mid pregnancy)and is particularly effective in symptomatic women.These findings may contribute to the development of an effective predictive and monitoring system for PTB,thereby reducing maternal and fetal risk.

CircRNA expression profiles in decidual tissue of patients with early recurrent miscarriage

Circular RNAs(circRNAs)are a novel class of endogenous noncoding RNAs that play important roles in gene expression regulation.This study aimed to evaluate the potential role of circRNAs in decidual tissue of patients with early recurrent miscarriage(RM).We constructed circRNA expression profiles in decidual tissue using microarray data.A total of 123 differentially expressed circRNAs,including 78 upregulated and 45 downregulated circRNAs were detected in the early RM group compared with the control group(P<0.05).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis also revealed the enrichment of specific circRNAs.The verified circRNA-targeted miRNA-mRNA network was constructed,most of the circRNAs harbored miRNA binding sites.The network involved 3 circRNAs,27 microRNAs and 82 mRNAs.Hsa_circRNA_103092-miR-224-PRLR network was selected to verify by qRT-PCR.These results showed that circRNAs are aberrantly expressed in the decidual tissue in early RM patients and play potential roles in the development of early RM.It gives new insights into the mechanism of recurrent miscarriage.

The metabolic role of LncZBTB39-1:2 in the trophoblast mobility of preeclampsia

Preeclampsia is characterized by new onset of hypertension and proteinuria after 20 weeks’gestation and is a leading cause of maternal and neonatal morbidity and mortality.The pathogenesis of preeclampsia is often associated with aberrant trophoblast function that leads to shallow placental implantation.However,the exact underlying mechanisms remain unclear.Placental LncZBTB39-1:2 expression level was investigated in 20 healthy placentae and 20 placentae with preeclampsia using qRT-PCR,and the metabolic profile of trophoblasts overexpressing LncZBTB39-1:2 in vitro was analysed using gas chromatography-mass spectrometry(GCeMS).In this study,we found that the expression of LncZBTB39-1:2 was significantly higher in preeclamptic placentae than in healthy placentae.Our metabolomics results have shown that tricarboxylic acid cycle intermediates and metabolites related to carbohydrate metabolism were decreased with the overexpression of LncZBTB39-1:2 in HTR8/SVneo cells.These findings were validated by detecting a lower level of intracellular ATP in HTR8/Vneo cells.Furthermore,the migration of HTR8/SVneo cells was compromised when cells were transfected with a plasmid encompassing LncZBTB39-1:2 overexpression.From these results,we conclude that abnormal levels of LncZBTB39-1:2 expression might lead to aberrant conditions in HTR-8/SVneo trophoblast cells.Aberrant conditions might be associated with dysregulated trophoblast migration and subsequent failure of uterine spiral artery remodelling,a pathogenesis recognised as a contributing factor in the aetiology of preeclampsia.

CMHX008,a PPAR γ partial agonist,enhances insulin sensitivity with minor influences on bone loss

Traditional thiazolidinediones(TZDs),such as rosiglitazone,are peroxisome proliferator-activated receptor g(PPARg)potent agonists that can be used to treat type 2 diabetes but carry unwanted effects,including increased risk for fracture.The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008,a novel TZDs-like PPARg partial agonist,with those of rosiglitazone.A TR-FRET PPARg competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone.Mice were administered vehicle,CMHX008 or rosiglitazone for 16 weeks.Mesenchymal stem cells(MSCs)were used to examine differences in differentiation into osteoblasts after compounds treatment.TR-FRET showed lower affinity to PPARg by CMHX008 compared with rosiglitazone.Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone,which was related to the significant inhibition of PPARg Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues.Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone,as evidenced by consistent changes in BV/TV,Tb.N,Tb.Th,Tb.Sp,and the mineral apposition rate.MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test.Thus,CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss,suggesting that PPARg sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.