OBJECTIVES: Whether vortioxetine has a utility as an adjuvant drug in the treatment of bipolar depression remains controversial. This study aimed to validate the efficacy and safety of vortioxetine in bipolar depression. METHODS: Patients with bipolar Ⅱ depression were enrolled in this prospective, two-center, randomized, 12-week pilot trial. The main indicator for assessing treatment effectiveness was a Montgomery-Asberg Depression Rating Scale (MADRS) of ≥50%. All eligible patients initially received four weeks of lurasidone monotherapy. Patients who responded well continued to receive this kind of monotherapy. However, no-response patients were randomly assigned to either valproate or vortioxetine treatment for eight weeks. By comprehensively comparing the results of MADRS over a period of 4‍‒‍12 weeks, a systematic analysis was conducted to determine whether vortioxetine could be used as an adjuvant drug for treating bipolar depression. RESULTS: Thirty-seven patients responded to lurasidone monotherapy, and 60 patients were randomly assigned to the valproate or vortioxetine group for eight weeks. After two weeks of combined valproate or vortioxetine treatment, the MADRS score in the vortioxetine group was significantly lower than that in the valproate group. There was no difference in the MADRS scores between the two groups at 8 and 12 weeks. The incidence of side effects did not significantly differ between the valproate and vortioxetine groups. Importantly, three patients in the vortioxetine group appeared to switch to mania or hypomania. CONCLUSIONS This study suggested that lurasidone combination with vortioxetine might have potential benefits to bipolar II depression in the early stage, while disease progression should be monitored closely for the risk of switching to mania.
Humans ; Bipolar Disorder/drug therapy* ; Vortioxetine/therapeutic use* ; Male ; Female ; Middle Aged ; Adult ; Valproic Acid/administration & dosage* ; Lurasidone Hydrochloride/administration & dosage* ; Prospective Studies ; Treatment Outcome ; Pilot Projects ; Drug Therapy, Combination ; Sulfides/therapeutic use* ; Antidepressive Agents/therapeutic use*

OBJECTIVES: To investigate the regulatory role of astrocytes in the dorsomedial hypothalamus (DMH) during sevoflurane anesthesia emergence. METHODS: Forty-two male C57BL/6 mice were randomized into 6 groups (n=7) for assessing astrocyte activation in the dorsomedial hypothalamus (DMH) under sevoflurane anesthesia. Two groups of mice received microinjection of agfaABC1D promoter-driven AAV2 vector into the DMH for GCaMP6 overexpression, and the changes in astrocyte activity during sevoflurane or air inhalation were recorded using calcium imaging. For assessing optogenetic activation of astrocytes, another two groups of mice received microinjection of an optogenetic virus or a control vector into the DMH with optic fiber implantation, and sevoflurane anesthesia emergence was compared using behavioral experiments. In the remaining two groups, electroencephalogram (EEG) recording during sevoflurane anesthesia emergence was conducted after injection of the hChR2-expressing and control vectors. Anesthesia induction and recovery were assessed by observing the righting reflex. EEG data were recorded under 2.0% sevoflurane to calculate the burst suppression ratio (BSR) and under 1.5% sevoflurane for power spectrum analysis. Immunofluorescence staining was performed to visualize the colocalization of GFAP-positive astrocytes with viral protein signals. RESULTS: Astrocyte activity in the DMH decreased progressively as sevoflurane concentration increased. During 2.0% sevoflurane anesthesia, the mice injected with the ChR2-expressing virus exhibited a significantly shortened wake-up time (P<0.05), and optogenetic activation of the DMH astrocytes led to a marked reduction in BSR (P<0.001). Under 1.5% sevoflurane anesthesia, optogenetic activation resulted in a significant increase in EEG gamma power and a significant decrease in delta power in ChR2 group (P<0.01). CONCLUSIONS Optogenetic activation of DMH astrocytes facilitates sevoflurane anesthesia emergence but does not significantly influence anesthesia induction. These findings offer new insights into the mechanisms underlying anesthesia emergence and may provide a potential target for accelerating postoperative recovery and managing anesthesia-related complications.
Animals ; Astrocytes/physiology* ; Sevoflurane ; Mice, Inbred C57BL ; Mice ; Male ; Electroencephalography ; Anesthetics, Inhalation/pharmacology* ; Hypothalamus/cytology* ; Anesthesia Recovery Period ; Methyl Ethers/pharmacology*

Objective : To investigate the effect of laminarin(LAM) on nonproliferative diabetes retinopathy by high throughput sequencing(RNA-seq). Methods : The diabetes model was established by intraperitoneal injection of streptozotocin(STZ), and the effect of LAM on diabetic mice was observed.C57BL/6 mice were randomly divided into three groups: Control group, Model group, and LAM group, with 8 mice in each group. After 8 weeks of modeling, the LAM group received a 4-week intraperitoneal injection of LAM treatment. Changes in blood glucose and body weight of the three groups of mice were recorded, HE staining was performed to examine retinal lesions, and RNA-seq was used to identify differentially expressed genes(DEGs) in diabetic retinopathy(DR) under the action of STZ and LAM. Results : STZ successfully established the model of DR, and LAM reduced the blood sugar in diabetic mice to a certain extent and improved the pathological morphology of retinal structural looseness in diabetic mice. After RNA-seq analysis of DEGs, it was found that there were a total of 214 DEGs in the retina of the Model group mice compared to the Control group. Enrichment analysis revealed that DR could exacerbate the lesions through the PI3K Akt signaling pathway. There were a total of 42 DEGs in the retina of the Model group and LAM group mice, and enrichment showed that LAM improved the lesions through the neutrophil extracellular trap pathway. Early growth response factor 1(Egr1), FBJ osteosarcoma oncogene(Fos), nuclear receptor subfamily 4A member 1(Nr4a1), and salt-induced kinase 1(Sik1) were regulated by STZ, and LAM significantly regulated their expression, which might be closely related to LAM′s treatment of diabetic retinopathy. Conclusion DEGs can exacerbate the severity of diabetic retinopathyviathe PI3K-Akt signaling pathway. LAM can mitigate diabetic retinopathyviathe neutrophil extracellular trap pathway. Egr1, Fos, Nr4a1, and Sik1 are key genes involved in LAM treatment of STZ-induced DR.

Objective To investigate the role of glutamatergic neurons in the dorsomedial periaqueductal grey(dmPAG)in regulating excessive defensive behaviors in mice with post-traumatic stress disorder(PTSD).Methods Eight-week-old male C57BL/6 mice were subjected to stereotactic injections of different recombinant adeno-associated viral vectors(rAAV2/9-CaMKⅡ-mCherry,rAAV2/9-CaMKⅡ-hM3Dq-mCherry and rAAV2/9-CaMKⅡ-hM4Di-mCherry)into the bilateral dmPAG for chemogenetic activation or inhibition of the glutamatergic neurons,followed 2 weeks later by PTSD modeling by single prolonged stress.The looming test,response to whisker stimulation test and contextual fear conditioning(CFC)test were used to observe changes in defensive behaviors of the PTSD mice.The activity of glutamatergic neurons in the dmPAG were observed using immunofluorescence staining.Results Compared with the control mice,the mouse models of PTSD showed a shortened latency of flights with increased time spent in the nest,response scores of defensive behaviors and freezing time(all P<0.01).Immunofluorescence staining revealed significantly increased c-fos-positive glutamatergic neurons in the dmPAG of PTSD mice with defensive behaviors.Activation of the glutamatergic neurons in the dmPAG(in PTSD hM3Dq group)did not cause significant changes in the latency of flights or time in nest but obviously increased response scores of defensive behaviors and freezing time of the mice,whereas inhibiting the glutamatergic neurons in the dmPAG(in PTSD hM4Di group)caused the reverse changes and obviously alleviated defensive behaviors in the PTSD mice(P<0.05 or 0.01).Conclusion Inhibiting the activity of glutamatergic neurons in the dmPAG can alleviate defensive behaviors in mice with PTSD.

Objective To investigate the role of glutamatergic neurons in the dorsomedial periaqueductal grey(dmPAG)in regulating excessive defensive behaviors in mice with post-traumatic stress disorder(PTSD).Methods Eight-week-old male C57BL/6 mice were subjected to stereotactic injections of different recombinant adeno-associated viral vectors(rAAV2/9-CaMKⅡ-mCherry,rAAV2/9-CaMKⅡ-hM3Dq-mCherry and rAAV2/9-CaMKⅡ-hM4Di-mCherry)into the bilateral dmPAG for chemogenetic activation or inhibition of the glutamatergic neurons,followed 2 weeks later by PTSD modeling by single prolonged stress.The looming test,response to whisker stimulation test and contextual fear conditioning(CFC)test were used to observe changes in defensive behaviors of the PTSD mice.The activity of glutamatergic neurons in the dmPAG were observed using immunofluorescence staining.Results Compared with the control mice,the mouse models of PTSD showed a shortened latency of flights with increased time spent in the nest,response scores of defensive behaviors and freezing time(all P<0.01).Immunofluorescence staining revealed significantly increased c-fos-positive glutamatergic neurons in the dmPAG of PTSD mice with defensive behaviors.Activation of the glutamatergic neurons in the dmPAG(in PTSD hM3Dq group)did not cause significant changes in the latency of flights or time in nest but obviously increased response scores of defensive behaviors and freezing time of the mice,whereas inhibiting the glutamatergic neurons in the dmPAG(in PTSD hM4Di group)caused the reverse changes and obviously alleviated defensive behaviors in the PTSD mice(P<0.05 or 0.01).Conclusion Inhibiting the activity of glutamatergic neurons in the dmPAG can alleviate defensive behaviors in mice with PTSD.

Aim The key genes for necroptosis in atherosclerosis were screened by bioinformatics methods and verified with the help of in vitro experiments to provide new strategies for the prevention and treatment of atherosclerosis from the perspective of necroptosis.Methods Genes related to atherosclerotic plaques were downloaded from GEO da-tabase,and genes related to necroptosis were downloaded from GeneCards database and intersected to obtain atherosclerotic necroptosis genes,and the mechanism of action and signalling pathways of the genes were further analysed by GO and KEGG enrichment analysis,and the protein-protein interaction(PPI)network was constructed and screened for key genes.Finally,macrophages were treated with oxidized low density lipoprotein(oa-LDL)at a final concentration of 100 mg/L,and the expression of key genes was detected by RT-PCR and Western blot.Results A total of 81 atherosclerotic nec-roptosis genes were obtained.GO and KEGG enrichment analyses revealed that they were mainly enriched in the positive regulation of endopeptidase activity,IκB kinase(IKK)/nuclear factor-KB(NF-κB)signalling,and autophagy signalling pathway.Five key genes including HSPA8,STAT3,HMOX1,SQSTM1 and FAS were obtained by using five computa-tional methods of Cytoscape software cytoHubba plug-in.Compared with the normal control group,the HMOX1 gene was highly expressed in THP-1 macrophages treated with ox-LDL(P＜0.05),while the expression of the HSPA8,STAT3,SQSTM1 and FAS genes showed no significant changes(P＞0.05);the HMOX1 and SQSTM1 genes were highly expressed in RAW264.7 macrophages treated with ox-LDL(P＜0.05),while HSPA8,STAT3 and FAS genes showed no significant changes(P＞0.05).The expression of HMOX1 protein in THP-1 macrophages was also increased.Conclusion HMOX1 may be the key gene of atherosclerotic necroptosis,and it is expected to become a new target for the prevention and treatment of atherosclerosis.

The incidence of osteoporotic thoracolumbar vertebral fracture (OTLVF) in the elderly is gradually increasing. The kyphotic deformity caused by various factors has become an important characteristic of OTLVF and has received increasing attention. Its clinical manifestations include pain, delayed nerve damage, sagittal imbalance, etc. Currently, the definition and diagnosis of OTLVF with kyphotic deformity in the elderly are still unclear. Although there are many treatment options, they are controversial. Existing guidelines or consensuses pay little attention to this type of fracture with kyphotic deformity. To this end, the Lumbar Education Working Group of the Spine Branch of the Chinese Medicine Education Association and Editorial Committee of Chinese Journal of Trauma organized the experts in the relevant fields to jointly develop Clinical guidelines for the diagnosis and treatment of osteoporotic thoracolumbar vertebral fractures with kyphotic deformity in the elderly ( version 2024), based on evidence-based medical advancements and the principles of scientificity, practicality, and advanced nature, which provided 18 recommendations to standardize the clinical diagnosis and treatment.

OBJECTIVE To explore the effect of paeoniflorin on glucose metabolism， inflammation and oxidative stress in rats with gestational diabetes mellitus （GDM） and its potential mechanism based on nuclear factor-erythroid 2-related factor 2 （Nrf2）/ heme oxygenase-1 （HO-1）/nicotinamide adenine dinucleotide phosphate：quinone oxidoreductase 1 （NQO1） signaling pathway. METHODS The female rats fed with high fat and high sugar diet and the male rats fed with an ordinary diet were caged， the successfully conceived rats were collected， and streptozotocin was injected intraperitoneally once to induce the GDM model. The successfully modeled rats were randomly divided into the model group， metformin hydrochloride group （200 mg/kg metformin by gavage）， paeoniflorin low-， high-dose groups （45， 90 mg/kg paeoniflorin by gavage， respectively）， paeoniflorin+ML385 group （90 mg/kg paeoniflorin by gavage and intraperitoneal injection of 30 mg/kg Nrf2 inhibitor ML385）， with 12 rats in each group； in addition， another 12 conceived rats fed with an ordinary diet were selected as the control group. The rats in each drug group were given the corresponding drug/normal saline， once a day， for 2 consecutive weeks. Glucose metabolism indexes [fasting blood glucose （FBG）， fasting insulin （FINS）， insulin resistance index （HOMA-IR）]， serum inflammatory factors [interleukin-6 （IL-6）， tumor necrosis factor- α （TNF- α）] and renal tissue oxidative stress indexes [superoxide dismutase （SOD）， malondialdehyde （MDA）， glutathione peroxidase （GSH-Px）] were detected； the pathological changes of renal tissue were observed， and the protein expressions of Nrf2， HO-1 and NQO1 in renal tissue were detected. RESULTS Compared with the control group， the renal tissue lesions of the model group were obvious， including glomerular atrophy， edema degeneration of renal tubular epithelial cells and a large number of inflammatory cell infiltration； the levels of FBG and FINS， HOMA-IR， the levels of IL-6 and TNF-α in serum， and the level of MDA in renal tissue were significantly increased （P＜0.05）， while the levels of SOD and GSH-Px and the protein expressions of Nrf2， HO-1 and NQO1 in renal tissue were significantly decreased （P＜0.05）. Compared with the model group， the renal tissue lesions of rats in paeoniflorin low-dose and high-dose groups were reduced， the above quantitative indexes were significantly improved， and the improvement effect was better in high-dose group （P＜0.05）， while ML385 could significantly reverse the improvement effect of paeoniflorin on the above indexes （P＜0.05）. CONCLUSIONS Paeoniflorin can improve the abnormal glucose metabolism， inflammation and oxidative stress damage of renal tissue in GDM rats， which may be related to the activation of Nrf2/HO-1/NOQ1 signaling pathway.

BackgroundSuicide is one of the serious public health problems worldwide. The relationship between suicide and neutrophil-to-lymphocyte ratio （NLR） may vary in different regions and different age. It is necessary to further investigate the relationship between NLR and suicidal ideation in Chinese children and adolescents with depression. ObjectiveTo explore the correlation between NLR and suicidal ideation in children and adolescents with depression， so as to provide clues for exploring the biomarkers of suicide. MethodsA retrospective analysis of 536 children and adolescents with depression who were hospitalized in the Third People's Hospital of Fuyang from January 2020 to December 2022 and met the diagnostic criteria of the International Classification of Diseases， tenth edition （ICD-10） was performed. Patients were divided into two groups according to whether they reported suicidal ideation. Demographic data， discharge diagnosis， Hamilton Depression Scale-17 item （HAMD-17） score and hematological test data （neutrophil counts， lymphocyte counts） on the second day were collected from medical records. Receiver operating characteristic （ROC） curve was used to determine the optimal cut-off point of NLR for predicting suicidal ideation in children and adolescents with depression， and binary Logistic regression was used to analyze the risk factors for suicidal ideation. ResultsAmong the 536 patients， 429 cases （80.04%） had no suicidal ideation， and 107 cases （19.96%） had suicidal ideation. Compared with patients without suicidal ideation， the HAMD-17 score ［（25.28±8.86） vs. （21.21±8.46）， F=19.400， P<0.01］， neutrophil level ［（3.85±1.68）×10⁹/L vs. （3.15±1.14）×10⁹/L， Z=4.073， P<0.01］， and NLR level ［（1.96±1.50） vs. （1.52±0.71）， Z=3.532， P<0.01］ in the suicidal ideation patients were significantly higher. The optimal critical NLR value determined by the ROC curve was 1.52 （59.80% sensitivity， 58.50% specificity）， with an area under the curve of 0.610. Logistic regression analysis showed that the risk of suicidal ideation was 1.94 times higher in those with high NLR than in the low NLR after controlling for age， sex， age at onset， duration of illness， and HAMD-17 score （OR=1.940， 95% CI： 1.251~3.009， P=0.003）. ConclusionNLR may be a risk factor and potential biomarker influencing suicidal ideation in the children and adolescents with first-episode depression. ［Funded by Scientific Research Project of Fuyang Municipal Health Commission （number， FY2020xg14）］

OBJECTIVE: To explore the regulatory effects of GABAergic neurons in the zona incerta (ZI) on sevoflurane and propofol anesthesia. METHODS: Forty-eight male C57BL/6J mice divided into 8 groups (n=6) were used in this study. In the study of sevoflurane anesthesia, chemogenetic experiment was performed in 2 groups of mice with injection of either adeno-associated virus carrying hM3Dq (hM3Dq group) or a virus carrying only mCherry (mCherry group). The optogenetic experiment was performed in another two groups of mice injected with an adeno-associated virus carrying ChR2 (ChR2 group) or GFP only (GFP group). The same experiments were also performed in mice for studying propofol anesthesia. Chemogenetics or optogenetics were used to induce the activation of GABAergic neurons in the ZI, and their regulatory effects on anesthesia induction and arousal with sevoflurane and propofol were observed; EEG monitoring was used to observe the changes in sevoflurane anesthesia maintenance after activation of the GABAergic neurons. RESULTS: In sevoflurane anesthesia, the induction time of anesthesia was significantly shorter in hM3Dq group than in mCherry group (P < 0.05), and also shorter in ChR2 group than in GFP group (P < 0.01), but no significant difference was found in the awakening time between the two groups in either chemogenetic or optogenetic tests. Similar results were observed in chemogenetic and optogenetic experiments with propofol (P < 0.05 or 0.01). Photogenetic activation of the GABAergic neurons in the ZI did not cause significant changes in EEG spectrum during sevoflurane anesthesia maintenance. CONCLUSION Activation of the GABAergic neurons in the ZI promotes anesthesia induction of sevoflurane and propofol but does not affect anesthesia maintenance or awakening.
Male ; Animals ; Mice ; Mice, Inbred C57BL ; Propofol/pharmacology* ; Sevoflurane/pharmacology* ; Zona Incerta ; Anesthesia, General ; GABAergic Neurons