BACKGROUND:Spondylolisthesis is a common disease,and there is a lack of effective drugs to treat it.There is still a need to further define the pathogenesis and screen out more suitable therapeutic targets for spondylolisthesis.Mendelian randomization analysis can be used to explore the drugable genes associated with spondylolisthesis and provide valuable guidance for the development of more effective and targeted therapeutic drugs.OBJECTIVE:To explore potential therapeutic targets and effective drugs for spondylolisthesis by means of pharmaceutically available genome-wide Mendelian randomization analysis.METHODS:Using the Finnish database,eQTLGen consortium,drug signature database,drug-gene interaction database,protein-protein interaction database,organic small molecule biological activity database and protein structure database,which contains genome and health information of half a million Finns,data on druggable genes were subjected to two-sample Mendelian randomization analysis and co-localization analysis with data from genome-wide association studies of spondylolisthesis to identify genes highly associated with spondylolisthesis.In addition,GO and KEGG enrichment analysis,protein network construction,drug prediction and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic agents.RESULTS AND CONCLUSION:In this study,we identified 34 potential drug target genes that were significantly associated with spondylolisthesis,particularly the gene APOBEC3G.This gene showed a significant association with spondylolisthesis outcomes through Mendelian analysis and co-localization analysis,suggesting that APOBEC3G may be a priority therapeutic target.As for other potential mechanisms and drugs,we still need to conduct more in-depth research to determine their roles.This study used a database from a European population,which can be used as a reference for the study of population genetics in China.

ObjectiveThis study aims to explore the mechanism by which Yishen Huoxue Tongqiao Formula improves metabolism-neuroplasticity and treats unilateral vestibular labyrinth destruction by regulating the metabolic balance of glutamate （Glu）/γ-aminobutyric acid （GABA）. Methods48 Sprague-Dawley （SD） adult rats were randomly divided into the sham operation group， model group， Yishen Huoxue Tongqiao Formula groups with low， medium， and high doses （9.20， 18.39， 36.78 g·kg^-1）， and betahistine group （1.62 mg·kg^-1）. A unilateral vestibular labyrinth destruction （vestibular dysfunction） model was established by intratympanic injection of chloroform into the right ear， while the control group received intratympanic injection of normal saline. Drugs were administered once daily for seven consecutive days. During the period， behavioral tests were performed to evaluate the behaviors of rats after unilateral vestibular labyrinth destruction. Hematoxylin-eosin （HE） staining and Nissl staining were used to observe the neuronal morphology in the medial vestibular nucleus. Golgi staining was employed to assess the number of dendritic spines of neurons in the medial vestibular nucleus. Ultra-performance liquid chromatography-tandem mass spectrometry （LC-ESI-MS/MS） was utilized to detect Glu/GABA. Immunofluorescence and immunohistochemistry were used to detect the expressions of neuronal nuclei （NeuN）， growth-associated protein 43 （GAP-43）， and glial fibrillary acidic protein （GFAP）. Western blot and real-time fluorescent quantitative polymerase chain reaction （Real-time PCR） were applied to determine the expressions of glutamate-immunoreactive （Glu-IR）， GABA， GFAP， postsynaptic density protein 95 （PSD-95）， and GAP-43. ResultsCompared with the sham operation group， the model group presented with head deviation， balance disorder， increased tail suspension score， nuclear consolidation of medial vestibular nerve neurons， and decreased Nissl bodies （P<0.01）. The number of dendritic spines in neurons and NeuN-positive cells decreased. The content of Glu decreased. The content of GABA increased （Glu/GABA decreased）. The expression of GAP-43 was down-regulated， and GFAP was up-regulated （P<0.05， P<0.01）. The expressions of Glu-IR， PSD-95， and GAP-43 proteins， as well as Glu-IR mRNA decreased， while the expressions of GABA and GFAP proteins and mRNA increased （P<0.05， P<0.01）. Compared with those in the model group， the head deviation， imbalanced behavior， and tail suspension scores in each treatment group decreased， with alleviated neuronal injury and recovered Nissl bodies （P<0.01）. The number of dendritic spines of neurons increased， and the number of NeuN-positive cells rebounded. The content of Glu increased， and the content of GABA decreased （Glu/GABA increased）. GFAP was down-regulated， and GAP-43 was up-regulated （P<0.05， P<0.01）. The expressions of Glu-IR， PMD-95， and GAP-43 proteins， as well as Glu-IR mRNA increased， while the expressions of GABA and GFAP proteins and mRNA decreased. The effect was more significant in the high-dose group （P<0.01）. ConclusionThe Yishen Huoxue Tongqiao Formula can alleviate vestibular dysfunction， and its mechanism may be associated with regulating the metabolic balance of Glu/GABA， mitigating neural damage， improving synaptic plasticity （promoting GAP-43 expression and inhibiting GFAP expression）， and facilitating vestibular compensation.

BACKGROUND:Spondylolisthesis is a common disease,and there is a lack of effective drugs to treat it.There is still a need to further define the pathogenesis and screen out more suitable therapeutic targets for spondylolisthesis.Mendelian randomization analysis can be used to explore the drugable genes associated with spondylolisthesis and provide valuable guidance for the development of more effective and targeted therapeutic drugs.OBJECTIVE:To explore potential therapeutic targets and effective drugs for spondylolisthesis by means of pharmaceutically available genome-wide Mendelian randomization analysis.METHODS:Using the Finnish database,eQTLGen consortium,drug signature database,drug-gene interaction database,protein-protein interaction database,organic small molecule biological activity database and protein structure database,which contains genome and health information of half a million Finns,data on druggable genes were subjected to two-sample Mendelian randomization analysis and co-localization analysis with data from genome-wide association studies of spondylolisthesis to identify genes highly associated with spondylolisthesis.In addition,GO and KEGG enrichment analysis,protein network construction,drug prediction and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic agents.RESULTS AND CONCLUSION:In this study,we identified 34 potential drug target genes that were significantly associated with spondylolisthesis,particularly the gene APOBEC3G.This gene showed a significant association with spondylolisthesis outcomes through Mendelian analysis and co-localization analysis,suggesting that APOBEC3G may be a priority therapeutic target.As for other potential mechanisms and drugs,we still need to conduct more in-depth research to determine their roles.This study used a database from a European population,which can be used as a reference for the study of population genetics in China.

Background: and Purpose Vertebrobasilar fusiform aneurysms (VBFAs) carry substantial morbidity and mortality, but optimal management for unruptured VBFAs remains unclear. We compared the safety and efficacy of conservative management (CM), stent-assisted coiling (SAC), and flow diverters (FDs) in patients with unruptured VBFAs, focusing on long-term prognosis. Methods: This study included data from a nationwide Chinese cohort of patients with vertebrobasilar dissecting aneurysms. Inverse probability of treatment weighting (IPTW) balanced confounders across groups. The primary outcome was poor prognosis (modified Rankin Scale score >2). Secondary outcomes included aneurysm rupture, ischemic stroke, compression symptoms, and VBFA-related deaths. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed. Results: Among 1,115 patients with unruptured VBFAs, 838 (median age, 54 years; 655 men) were included. After IPTW, baseline characteristics were balanced. Median follow-up was 54 months. FD was associated with a lower risk of poor prognosis than CM (OR, 0.48 [95% CI, 0.30 to 0.77]; p=0.002), with no difference between CM and SAC. FD also reduced aneurysm rupture (OR, 0.20 [95% CI, 0.07 to 0.60]; p=0.004) and compression symptoms (OR, 0.30 [95% CI, 0.13 to 0.68]; p=0.004) versus CM. Time-to-event analyses further revealed significant differences in vertebral artery lesions and Type I–II VBFAs, whereas no significant differences were observed in basilar or vertebrobasilar junction lesions or in Type III–IV VBFAs. Conclusions Compared with CM, FD was associated with improved long-term outcomes in unruptured VBFAs, particularly in vertebral artery lesions and Type I–II VBFAs, although residual confounding cannot be excluded.

Objective To evaluate the feasibility and efficacy of the three-guidewire technique for retrograde stent placement in the treatment of ureteral mucosal sleeve avulsion (UMSA). Methods A retrospective analysis was conducted on the clinical data of 12 patients with UMSA secondary to ureteroscopic lithotripsy for ureteral calculi in our hospital during Jul. 2010 and Oct. 2023. The three-guidewire technique was employed for retrograde stent placement during the procedure. A secondary ureteroscopic lithotripsy was performed one month postoperatively.Results Double-J stent was successfully placed in all 12 patients, with a mean stent insertion time of 23.3(16-30)minutes. No intraoperative exacerbation of mucosal avulsion occurred. One patient was lost to follow-up. At the one-month postoperative ureteroscopic examination and lithotripsy, 81.8% (9/11) cases exhibited unobstructed ureters, while 18.2%(2/11) developed annular membranous strictures, which were resolved following dilation. During subsequent follow-up, the postoperative creatinine level after double-J stent removal showed a mild decrease compared to the preoperative level [87.9(72-100)μmol/L vs. 90.1(69-108)μmol/L]. Up to 90.9%(10/11) patients remained free of hydronephrosis, with only 1 case (9.1%) requiring laparoscopic ureterovesical reimplantation for hydronephrosis 4 months postoperatively. Conclusion The three-guidewire technique for retrograde stent placement in the treatment of UMSA demonstrates strong operability, high success rates, favorable outcomes, and a low incidence of ureteral stricture, which warrant wide clinical promotion.

Objective This study reports on the obligatory parasitism of water mites Arrenurus sp. on Anopheles messeae at the Manzhouli Port, Inner Mongolia, China. Methods Duing July 2024, a survey on the mosquito diversity was conducted at the Manzhouli Port. Captured mosquitoes and their ectoparasites were identified to species level. Results A total of 1840 adult mosquitoes were collected, representing species from three genera: Culex(Cx. modestus, Cx. pipiens pallens), Aedes(Ae. dorsalis, Ae. flavidorsalis, Ae. flavescens), and Anopheles (An. messeae). Among all the mosqutioes specimens,3 out of 150 captured An. messeae were found to carry ectoparasitic mites, with number of 2,4,27 mites separately. Morphological and molecular identification reached the same result as water mites(Hydrachnidiae, Hydracrina). COI gene sequence showed 94% similarity with the closest species Arrenurus truncatellus. Conlusions Literature review suggests water mites are host-specific parasitism of mosquito species and herein with the first record of Arrenurus sp. parasiting on An. Messeae in the most high-latitude region globally.

Objective:To investigate the functional characteristics of the prefrontal cortex in patients with schizophrenia (SCZ) during resting state and analyze its association with clinical symptoms.Methods:Twenty-eight hospitalized patients with SCZ (SCZ group) were selected from November 2023 to May 2024, and 28 healthy controls (HC group) were recruited concurrently. By using functional near-infrared spectroscopy (fNIRS) technology, data on the concentration changes of oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (HbR) in the prefrontal cortex during resting state were collected from all subjects to measure cortical hemodynamic activity. Regional activation values and functional connectivity (FC) values among brain areas were analyzed. Clinical symptoms in patients were assessed using the positive and negative syndrome scale (PANSS).SPSS 25.0 software was employed for statistical analysis. Between-group comparisons were performed using independent samples t-tests or Mann-Whitney U tests. Spearman correlation analysis and general linear regression models were applied to examine relationships between prefrontal cortical functional characteristics and clinical symptoms. Results:The levels of HbO in the right inferior frontal gyrus and left frontal pole area were significantly higher in the SCZ group (1.5 (1.0, 3.0)μmol/L, 1.0 (1.0, 2.8)μmol/L) than those in the HC group (-0.01 (-0.05, 0.02)μmol/L, -0.02 (-0.07, 0.03)μmol/L) ( Z=-6.46, -6.50, both P<0.01). The levels of HbR in the bilateral dorsolateral prefrontal cortex were significantly higher in the SCZ group (0.02 (-0.01, 0.07)μmol/L, 0.01 (-0.01, 0.03)μmol/L) than those in the HC group (-0.01 (-0.03, 0.01)μmol/L, -0.01 (-0.02, 0.01)μmol/L) ( Z=-2.46, -1.98, both P<0.05).The SCZ group showed significantly higher HbO-based FC values in the frontal pole-temporal pole (0.49±0.21) and temporal pole-dorsolateral prefrontal cortex (0.36±0.25) compared to the HC group (0.33±0.18, 0.15±0.19) ( t=3.02, 3.44, both P<0.01). Conversely, the SCZ group exhibited significantly lower HbR-based FC in the frontal pole-inferior frontal gyrus (0.15±0.13) and inferior frontal gyrus-temporal pole (0.27±0.37) compared to the HC group (0.33±0.26, 0.77±0.48) ( t=-3.17, -4.23, both P<0.01). Correlation analysis revealed that in the SCZ group, the level of HbO in the right inferior frontal gyrus was positively correlated with negative symptoms, positive symptoms, excitement/hostility, and PANSS total score ( r=0.45-0.64, all P<0.05), and the level of HbO in the left frontal pole area was positively correlated with excitement/hostility and PANSS total score ( r=0.57, 0.50, both P<0.01), while the FC value between the frontal pole and temporal pole areas showed a negative correlation with excitement/hostility ( r=-0.39, P<0.05). Regression analysis demonstrated that, the HbO concentration in the right inferior frontal gyrus significantly positively predicted PANSS total score, positive symptoms, and negative symptoms ( β=0.70, 0.64, 0.55, all P<0.01).The HbO concentration in the left frontal pole area significantly positively predicted excitement/hostility ( β=0.77, P<0.01).The frontal pole-temporal pole HbO-based FC significantly negatively predicted excitement/hostility scores ( β=-0.42, P<0.01). Conclusion:Patients with SCZ exhibit hyperactivation of localized prefrontal cortex brain regions and dysfunction of functional connectivity during resting state, which are significantly associated with core clinical symptoms including positive, negative, and excitement/hostility symptoms.

Aim To explore the role and mechanism of epimedokoreanin B(EKB)in HepaRG cell pyroptosis through endoplasmic reticulum stress and NLRP1-me-diated pyroptosis pathway.Methods The effect of EKB on the viability of HepaRG cells at different con-centrations was determined by MTT assay,and the cell growth status was recorded by Incucyte.Four groups of HepaRG cells were set up.The control group was cul-tured with complete medium for 24 h;the drug admin-istration group was cultured with three concentration gradients of 6.25,12.5 and 25 μmol·L-1 of EKB for 24 h.Western blot was used to detect the expression levels of endoplasmic reticulum stress-related proteins and pyroptosis-related proteins in the cells of each group.Results HepaRG cells showed cytotoxicity at a concentration of 6.25 μmol·L-1 for 24 h,and the half maximal inhibitory concentration(IC50)was 12.41 μmol·L-1.Incucyte recordings of the cell growth status showed that the cells in the control group were in good growth status,and the vesicular pyropto-sis cells appeared in the different concentrations of EKB and the cells swelled and ruptured after 24 h.Western blot showed that the protein expression levels of endoplasmic reticulum stress-related proteins pERK,eIF-2α,ATF-4,GRP78,and CHOP significantly in-creased in HepaRG cells at 25 μmol·L-1 of EKB compared with the control group.The proteins of the classical pathway of cellular pyroptosis mediated by NLRP1,caspase-1,cleaved caspase-1,GSDMD,GS-DMD-N significantly increased in HepaRG cells.Con-clusion EKB administration induces HepaRG cell py-roptosis,and EKB activates HepaRG cells to undergo endoplasmic reticulum stress and activates the NLRP1/caspase-1/GSDMD-mediated pyroptosis pathway.

Objective:To investigate the functional characteristics of the prefrontal cortex in patients with schizophrenia (SCZ) during resting state and analyze its association with clinical symptoms.Methods:Twenty-eight hospitalized patients with SCZ (SCZ group) were selected from November 2023 to May 2024, and 28 healthy controls (HC group) were recruited concurrently. By using functional near-infrared spectroscopy (fNIRS) technology, data on the concentration changes of oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (HbR) in the prefrontal cortex during resting state were collected from all subjects to measure cortical hemodynamic activity. Regional activation values and functional connectivity (FC) values among brain areas were analyzed. Clinical symptoms in patients were assessed using the positive and negative syndrome scale (PANSS).SPSS 25.0 software was employed for statistical analysis. Between-group comparisons were performed using independent samples t-tests or Mann-Whitney U tests. Spearman correlation analysis and general linear regression models were applied to examine relationships between prefrontal cortical functional characteristics and clinical symptoms. Results:The levels of HbO in the right inferior frontal gyrus and left frontal pole area were significantly higher in the SCZ group (1.5 (1.0, 3.0)μmol/L, 1.0 (1.0, 2.8)μmol/L) than those in the HC group (-0.01 (-0.05, 0.02)μmol/L, -0.02 (-0.07, 0.03)μmol/L) ( Z=-6.46, -6.50, both P<0.01). The levels of HbR in the bilateral dorsolateral prefrontal cortex were significantly higher in the SCZ group (0.02 (-0.01, 0.07)μmol/L, 0.01 (-0.01, 0.03)μmol/L) than those in the HC group (-0.01 (-0.03, 0.01)μmol/L, -0.01 (-0.02, 0.01)μmol/L) ( Z=-2.46, -1.98, both P<0.05).The SCZ group showed significantly higher HbO-based FC values in the frontal pole-temporal pole (0.49±0.21) and temporal pole-dorsolateral prefrontal cortex (0.36±0.25) compared to the HC group (0.33±0.18, 0.15±0.19) ( t=3.02, 3.44, both P<0.01). Conversely, the SCZ group exhibited significantly lower HbR-based FC in the frontal pole-inferior frontal gyrus (0.15±0.13) and inferior frontal gyrus-temporal pole (0.27±0.37) compared to the HC group (0.33±0.26, 0.77±0.48) ( t=-3.17, -4.23, both P<0.01). Correlation analysis revealed that in the SCZ group, the level of HbO in the right inferior frontal gyrus was positively correlated with negative symptoms, positive symptoms, excitement/hostility, and PANSS total score ( r=0.45-0.64, all P<0.05), and the level of HbO in the left frontal pole area was positively correlated with excitement/hostility and PANSS total score ( r=0.57, 0.50, both P<0.01), while the FC value between the frontal pole and temporal pole areas showed a negative correlation with excitement/hostility ( r=-0.39, P<0.05). Regression analysis demonstrated that, the HbO concentration in the right inferior frontal gyrus significantly positively predicted PANSS total score, positive symptoms, and negative symptoms ( β=0.70, 0.64, 0.55, all P<0.01).The HbO concentration in the left frontal pole area significantly positively predicted excitement/hostility ( β=0.77, P<0.01).The frontal pole-temporal pole HbO-based FC significantly negatively predicted excitement/hostility scores ( β=-0.42, P<0.01). Conclusion:Patients with SCZ exhibit hyperactivation of localized prefrontal cortex brain regions and dysfunction of functional connectivity during resting state, which are significantly associated with core clinical symptoms including positive, negative, and excitement/hostility symptoms.

AIM To investigate the effects of Yiqi Juanbi Formula on chondrocyte pyroptosis in rat models of collagen-induced arthritis(CIA).METHODS Fifty rats were subcutaneously injected at the tail base with an emulsion containing equal volumes of bovine type Ⅱ collagen and incomplete Freund's adjuvant(IFA)to establish the CIA models.These rats were then randomly assigned to the model group,the methotrexate group(0.35 mg/kg),and the low-dose,medium-dose,and high-dose Yiqi Juanbi Formula groups(9.4,18.7,37.4 g/kg),in contrast to the ten intact rats serving in the normal control group.Following four weeks of intragastric administration,the rats had their general conditions observed;their joint swelling and arthritis indices measured;their ankle joint pathology assessed by HE staining;their serum levels of IL-1β,IL-18 and TNF-ɑ detected by ELISA;their mRNA expressions of NLRP3,Caspase-1,GSDMD,IL-1β,IL-18 and TNF-ɑ in ankle cartilage quantified by RT-qPCR;their protein expressions of NF-κB,NLRP3 and Caspase-1 in ankle cartilage analyzed by Western blot;and their NLRP3 and GSDMD positive expressions in ankle cartilage examined by immunohistochemistry.RESULTS Compared to the control group,the model group showed significantly increased joint swelling and arthritis indices(P＜0.01);elevated serum levels of IL-1 β,IL-18 and TNF-ɑ(P＜0.01);pathological changes including cartilage surface defects,reduced cell count,altered cellular morphology,irregular cell arrangement,and significant inflammatory cell infiltration in synovial tissue;upregulated mRNA expressions of NF-κB,NLRP3,Caspase-1,GSDMD,IL-1β,IL-18 and TNF-ɑ(P＜0.01)and increased protein expressions of NF-κB,NLRP3 and Caspase-1(P＜0.01)in ankle cartilage;enhanced positive expressions of NLRP3 and GSDMD in ankle cartilage(P＜0.01).Compared to the model group,the groups intervened with methotrexate or medium-or high-dose Yiqi Juanbi Formula exhibited reduced joint swelling and arthritis indices(P＜0.01);alleviated pathological damage in ankle joints;decreased serum levels of IL-1β,IL-18 and TNF-ɑ(P＜0.01);downregulated mRNA expressions of NF-κB,NLRP3,Caspase-1,GSDMD,IL-1β,IL-18 and TNF-ɑ(P＜0.05,P＜0.01),and reduced protein expressions of NF-κB,NLRP3 and Caspase-1(P＜0.05,P＜0.01)in ankle cartilage;and diminished positive expressions of NLRP3 and GSDMD in ankle cartilage(P＜0.01).CONCLUSION Yiqi Juanbi Formula alleviates inflammation in CIA rats,potentially by inhibiting the activation of the NF-κB/NLRP3/Caspase-1 signaling pathway,thereby suppressing chondrocyte pyroptosis.