Microglia activation-mediated neuroinflammatory responses serve as a critical pathological ba-sis for the development and progression of various brain diseases.The role of circular RNAs(circRNAs)in the regulation of neuroinflammation is increasingly being recognized.This study aimed to investigate the effect and molecular mechanisms of targeted inhibition of circular RNA Homeodomain Interacting Pro-tein Kinase 3(HIPK3)(circHIPK3)on lipopolysaccharide(LPS)-induced microglial polarization in BV2 cells.The results showed that LPS stimulation significantly induced polarization of BV2 cells towards the pro-inflammatory M1 phenotype and upregulated circHIPK3 expression(P＜0.01).Engineered extra-cellular vesicles(EVs)with rabies viral glycoprotein(RVG)loaded with circHIPK3 siRNA(RVG-EVs-sicHIPK3)were successfully constructed.Transmission electron microscopy(TEM)revealed their typi-cal EV morphology.nanoparticle tracking analysis(NTA)indicated a peak particle size of 70 nmn.And Western blotting analysis confirmed the expression of characteristic membrane marker proteins.Treatment with RVG-EVs-sicHIPK3 significantly suppressed the LPS-induced elevation of inflammatory cytokines(TNF-α,IL-6,IL-1β)in the supernatant and reduced the expression of M1 phenotypic marker proteins(CD16 and CD86)(P＜0.01).Concurrently,RVG-EVs-sicHIPK3 increased the number of mitophago-somes within cells,upregulated the ratio of the autophagy-related proteins LC3-Ⅱ/LC3-I(P＜0.01),and downregulated the expression of the autophagy-related protein p62 and mitochondrial-specific proteins(TOMM20 and TIMM23)(P＜0.01).The mitophagy inhibitor Mdivi-1 significantly reversed the RVG-EVs-sicHIPK3-mediated downregulation of inflammatory cytokine levels,M1 marker proteins,and mito-chondrial protein expression(P＜0.01).This study demonstrates that inhibiting circHIPK3 reduces LPS-induced microglial polarization towards the M1 phenotype.The protective mechanism is closely associated with enhanced mitophagic flux and the promotion of damaged mitochondrial clearance.

Objective To investigate the analgesic effect of combined spinal-epidural analgesia and its impact on stress levels in multiparous women during labor in a high-altitude region.Methods A total of 86 multiparous women were enrolled as study subjects.They were divided into observation group(43 cases)and control group(43 cases)based on whether they received labor analgesia.The obser-vation group received combined spinal-epidural analgesia during the first stage of labor.Pain levels[Visual Analogue Scale(VAS)],labor psychological experience[Chinese version of the Childbirth Self-Efficacy Inventory(CBSEI-C32)and Coping with Childbirth(CCB)],stress levels[serum cor-tisol(Cor),norepinephrine(NE)and adiponectin(APN)]as well as maternal and neonatal out-comes were compared between the two groups.Results The VAS scores during the first,second and third stages of labor were significantly lower in the observation group than those in the control group(P＜0.05).The CBSEI-C32 and CCB scores at 24 hours postpartum in the observation group were significantly higher than those in the control group(P＜0.05).The serum levels of Cor,NE and APN at 12 hours postpartum in the observation group were significantly lower than those in the control group(P＜0.05).The incidence of adverse maternal and neonatal outcomes in the observation group was 0％,which was significantly lower than 9.30％in the control group(P＜0.05).Con-clusion In high-altitude regions,combined spinal-epidural analgesia is effective in reducing labor pain,improving labor psychological experience,lowering stress levels,and reducing adverse maternal and neonatal outcomes in multiparous women.

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

Objective To investigate the effect of propofol on bone metabolism in glucocorticoid induced osteoporo-sis(GIOP)in rat models by regulating the PI3K/AKT/mTOR signaling pathway.Methods Rats were grouped into a blank group,model(GIOP)group,2.5 mg/kg and 5 mg/kg propofol groups and a propofol+LY294002(5 mg/kg propofol+5 mg/kg LY294002)group,with 12 rats in each group.A small animal bone densitometer was used to measure the tibial bone density(BMD)of rats.ELISA was applied to detect the level of bone gla-protein(BGP),procollagen Ⅰ N-terminal propeptide(PINP)and type Ⅰ collagen cross-linked C-terminal peptide(CTX-Ⅰ)in rat serum.HE staining microscopy was applied to observe the pathological morphology of rat bone tis-sue.RT-qPCR was used to detect the mRNA expression of Pi3k,Akt,mTor,Beclin-1,and p62 in bone tissue.Western blot was used to detect the expression level of PI3K/AKT/mTOR signaling pathway related proteins and autophagy related proteins in rat bone tissue.Results Compared with the blank group,the tibial BMD,serum BGP,and CTX-Ⅰ levels of GIOP group decreased(P＜0.05).mRNA expression of Pi3k,Akt,mTor and Beclin-1 in bone tissue decreased(P＜0.05).mRNA and protein expression of p62 increased(P＜0.05).The expression of PI3K/AKT/mTOR signaling pathway related proteins and Beclin-1 protein in bone tissue decreased(P＜0.05).Compared to GIOP group,the changes of above indicators were obviously alleviated in the 2.5 mg/kg and 5 mg/kg propofol groups(P＜0.05).On the basis of treatment with 5 mg/kg propofol,the use of LY294002 inhibited activation of the PI3K/AKT/mTOR signaling pathway and autophagy and interfered with the positive regulatory effects of propofol on bone me-tabolism and bone tissue morphology improvement in GIOP rats(P＜0.05).Conclusions Propofol may improve bone metabolism in rat models of GIOP through potential mechanism of activating PI3K/AKT/mTOR signaling pathway.

Microglia activation-mediated neuroinflammatory responses serve as a critical pathological ba-sis for the development and progression of various brain diseases.The role of circular RNAs(circRNAs)in the regulation of neuroinflammation is increasingly being recognized.This study aimed to investigate the effect and molecular mechanisms of targeted inhibition of circular RNA Homeodomain Interacting Pro-tein Kinase 3(HIPK3)(circHIPK3)on lipopolysaccharide(LPS)-induced microglial polarization in BV2 cells.The results showed that LPS stimulation significantly induced polarization of BV2 cells towards the pro-inflammatory M1 phenotype and upregulated circHIPK3 expression(P＜0.01).Engineered extra-cellular vesicles(EVs)with rabies viral glycoprotein(RVG)loaded with circHIPK3 siRNA(RVG-EVs-sicHIPK3)were successfully constructed.Transmission electron microscopy(TEM)revealed their typi-cal EV morphology.nanoparticle tracking analysis(NTA)indicated a peak particle size of 70 nmn.And Western blotting analysis confirmed the expression of characteristic membrane marker proteins.Treatment with RVG-EVs-sicHIPK3 significantly suppressed the LPS-induced elevation of inflammatory cytokines(TNF-α,IL-6,IL-1β)in the supernatant and reduced the expression of M1 phenotypic marker proteins(CD16 and CD86)(P＜0.01).Concurrently,RVG-EVs-sicHIPK3 increased the number of mitophago-somes within cells,upregulated the ratio of the autophagy-related proteins LC3-Ⅱ/LC3-I(P＜0.01),and downregulated the expression of the autophagy-related protein p62 and mitochondrial-specific proteins(TOMM20 and TIMM23)(P＜0.01).The mitophagy inhibitor Mdivi-1 significantly reversed the RVG-EVs-sicHIPK3-mediated downregulation of inflammatory cytokine levels,M1 marker proteins,and mito-chondrial protein expression(P＜0.01).This study demonstrates that inhibiting circHIPK3 reduces LPS-induced microglial polarization towards the M1 phenotype.The protective mechanism is closely associated with enhanced mitophagic flux and the promotion of damaged mitochondrial clearance.

Objective To investigate the effects of dexmedetomidine(Dex)on osteoporosis(OP)rats and possible mechanisms.Methods The rats were divided into sham operation group,osteoporosis model group(OP,replica-ting the OP rat model with bilateral ovariectomies),Dex-L,M,and H(Dex low,medium,and high dose treat-ments)groups and Dex-H+XAV-939 group(Wnt/β-catenin pathway inhibitor).Micro-CT was applied to meas-ure bone mineral density(BMD)and bone microstructure of rat femurs.The three-point bending experiment was applied to analyze the biomechanics of the femur(maximum load,fracture deflection,elastic modulus).HE stai-ning was applied to observe pathological changes in the femur of rats.ELISA method was applied to evaluate bone metabolism indicators such as alkaline phosphatase(ALP),typeⅠ procollagen amino-terminal peptide(PINP)and typeⅠcollagen cross-linked C-telopeptide(CTX-Ⅰ).The expression of Runx2 and Wnt3a was examined by Immunohistochemistry.Western blot was applied to detect the protein expression of Runx2 and Wnt3a/β-catenin pathway in femoral tissue.Results Compared to the Sham group,the bone volume and number of trabeculae in OP group were obviously reduced,the maximum load,fracture deflection,elastic modulus,BMD,Tb.Th,Tb.N,BV/TV,ALP,PINP,Runx2,Wnt3a,β-catenin expression decreased,CTX-Ⅰ increased(P＜0.05).Compared to the OP group,the bone trabecular structure in the Dex-L,M,and H groups was restored,the maxi-mum load,fracture deflection,elastic modulus,BMD,Tb.Th,Tb.N,BV/TV,ALP,PINP,Runx2,Wnt3a,β-catenin expression all increased but CTX-Ⅰ decreased(P＜0.05).Compared to the Dex-H group,the bone trabecular injury in the Dex-H+XAV-939 group showed a more severe damage.The maximum load,fracture de-flection,elastic modulus,BMD,Tb.Th,Tb.N,BV/TV,ALP,PINP,Runx2,Wnt3a,β-catenin expression decreased while CTX-Ⅰ increased(P＜0.05).Conclusions Dex may antagonize OP effects by improving bone density,biomechanical properties and microstructure.The underlying mechanism might be related to the activation of the Wnt/β-catenin signaling pathway.

Lecanemab (product name Leqembi ® ) is an anti-amyloid monoclonal antibody treatment approved for use in Korea for patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease. The Korean Dementia Association has created recommendations for the appropriate use of lecanemab to assist clinicians. These recommendations include selecting patients for administration, necessary pre-administration tests and preparations,administration methods, monitoring for amyloid related imaging abnormalities (ARIA), and communication with patients and caregivers. Lecanemab is recommended for patients with MCI or mild dementia who confirmed positive amyloid biomarkers, and should not be administered to patients with severe hypersensitivity to lecanemab or those unable to undergo magnetic resonance imaging (MRI) evaluation. To predict the risk of ARIA before administration, apolipoprotein E genotyping is conducted, and regular brain MRI evaluations are recommended to monitor for ARIA during treatment. The most common adverse reactions are infusion-related reactions, which require appropriate management upon occurrence. Additional caution is needed when co-administering with anticoagulants or tissue plasminogen activator due to the risk of macrohemorrhage. Clinicians should consider the efficacy and necessary conditions for administration, as well as the safety of lecanemab, to make a comprehensive decision regarding its use.

Objective: Geriatric patients requiring gynecological surgery is increasing worldwide. However, older patients are at higher risk of postoperative morbidity and mortality, particularly cardiopulmonary complications. Laparoscopic surgery is widely used as a minimally invasive method for reducing postoperative morbidities. We compared the outcomes of open and laparoscopic gynecologic surgeries in patients older than 55 years. Methods: We included patients aged >55 years who underwent gynecological surgery at a single tertiary center between 2010 and 2020, excluding vaginal or ovarian cancer surgeries were excluded. Surgical outcomes were compared between the open surgery and laparoscopic groups, with age cutoff was set at 65 years for optimal discriminative power. We performed linear or logistic regression analyses to compare the surgical outcomes according to age and operation type. Results: Among 2,983 patients, 28.6% underwent open surgery and 71.4% underwent laparoscopic surgery. Perioperative outcomes of laparoscopic surgery were better than those of open surgery in all groups. In both the open and laparoscopic surgery groups, the older patients showed worse overall surgical outcomes. However, age-related differences in perioperative outcomes were less severe in the laparoscopic group. In the linear regression analysis, the differences in estimated blood loss, transfusion, and hospital stay between the age groups were smaller in the laparoscopy group. Similar results were observed in cancer-only and benign-only cohorts. Conclusion Although the surgical outcomes were worse in the older patients, the difference between age groups was smaller for laparoscopic surgery. Laparoscopic surgery offers more advantages and safety in patients aged >65 years.

Lecanemab (product name Leqembi ® ) is an anti-amyloid monoclonal antibody treatment approved for use in Korea for patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease. The Korean Dementia Association has created recommendations for the appropriate use of lecanemab to assist clinicians. These recommendations include selecting patients for administration, necessary pre-administration tests and preparations,administration methods, monitoring for amyloid related imaging abnormalities (ARIA), and communication with patients and caregivers. Lecanemab is recommended for patients with MCI or mild dementia who confirmed positive amyloid biomarkers, and should not be administered to patients with severe hypersensitivity to lecanemab or those unable to undergo magnetic resonance imaging (MRI) evaluation. To predict the risk of ARIA before administration, apolipoprotein E genotyping is conducted, and regular brain MRI evaluations are recommended to monitor for ARIA during treatment. The most common adverse reactions are infusion-related reactions, which require appropriate management upon occurrence. Additional caution is needed when co-administering with anticoagulants or tissue plasminogen activator due to the risk of macrohemorrhage. Clinicians should consider the efficacy and necessary conditions for administration, as well as the safety of lecanemab, to make a comprehensive decision regarding its use.

Lecanemab (product name Leqembi ® ) is an anti-amyloid monoclonal antibody treatment approved for use in Korea for patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease. The Korean Dementia Association has created recommendations for the appropriate use of lecanemab to assist clinicians. These recommendations include selecting patients for administration, necessary pre-administration tests and preparations,administration methods, monitoring for amyloid related imaging abnormalities (ARIA), and communication with patients and caregivers. Lecanemab is recommended for patients with MCI or mild dementia who confirmed positive amyloid biomarkers, and should not be administered to patients with severe hypersensitivity to lecanemab or those unable to undergo magnetic resonance imaging (MRI) evaluation. To predict the risk of ARIA before administration, apolipoprotein E genotyping is conducted, and regular brain MRI evaluations are recommended to monitor for ARIA during treatment. The most common adverse reactions are infusion-related reactions, which require appropriate management upon occurrence. Additional caution is needed when co-administering with anticoagulants or tissue plasminogen activator due to the risk of macrohemorrhage. Clinicians should consider the efficacy and necessary conditions for administration, as well as the safety of lecanemab, to make a comprehensive decision regarding its use.