OBJECTIVE To evaluate the mechanisms underlying the antidepressant effect of ZBH2012001,a novel serotonin and norepinephrine reuptake inhibitor(SNRI),in general and its ability to enhance monoaminergic transmission and suppress neuroinflammation in particular.METHODS① Male ICR mice were divided into vehicle(distilled water),duloxetine(DLX,10 or 20 mg·kg-1)and ZBH2012001(5,10 and 20 mg·kg-1)groups.One hour following ig administration,the antidepressant effect of ZBH2012001 was evaluated using the tail suspension test(TST)and forced swimming test(FST).② Radioligand binding assay was conducted to evaluate the affinity of ZBH2012001 for human serotonin transporters(hSERTs)and human norepinephrine transporters(hNETs).③ Mice were divided into vehicle(distilled water),DLX(10 or 20 mg·kg-1)and ZBH2012001(5,10 and 20 mg·kg-1)groups.One hour following drug administration,the 5-hydroxytryptophan(5-HTP)-induced head-twitch test or yohimbine-induced lethality test were performed to evaluate the effect of ZBH2012001 on the function of the 5-hydroxytryptamine(5-HT)and norepinephrine(NE)systems.④ Mice were divided into vehicle(distilled water+0.1%acetic acid),reserpine model(distilled water+reserpine 5 mg·kg-1),DLX(DLX 20 mg·kg-1+reserpine 5 mg·kg-1)and ZBH2012001(ZBH2012001 5,10 and 20 mg·kg-1+reserpine 5 mg·kg-1)groups.One hour following drug administration,reserpine was injected intraperitoneally to establish a monoamine-depletion model.The ptosis,akinesia,and hypothermia assays were performed to evaluate the effect of ZBH2012001 on the down-regulation of the reserpine-induced monoamine system.The TST in mice was used to evaluate the effect of ZBH2012001 on reserpine-induced depressive-like behavior while high-performance liquid chromatography with electrochemical detection(HPLC-ECD)was used to measure the levels of monoamines and their metabolites in the hippocampal tissue of reserpine-induced monoamine-depletion mice.ELISA was employed to detect the contents of tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6)in the hippocampal tissue of reserpine-induced monoamine-depletion mice.Western blotting was used to assess the expressions of ionized calcium-binding adapter molecule-1(Iba-1)and nuclear factor-kappa B(NF-κB)in the hippocampal tissue of reserpine-induced monoamine-depletion mice.RESULTS ① Compared with the vehicle group,ZBH2012001(5,10 and 20 mg·kg-1)significantly reduced the immobility time both in the TST in mice(P<0.01,respectively),and ZBH2012001(20 mg·kg-1)and in the FST in mice(P<0.05).② ZBH2012001 competitively inhibited the binding of[3H]-imipramine to hSERTs and[3H]-nisoxetine to hNETs,with the half maximal inhibitory concentration(IC50)values of 84.95 and 712.90 nmol·L-1,respectively.③Com-pared with the vehicle group,ZBH2012001(10 and 20 mg·kg-1)significantly increased the head twitches induced by 5-HTP in mice(P<0.01,respectively)and increased the mortality rate in mice induced by yohimbine(P<0.05,P<0.01).④ In the reserpine-induced monoamine-depletion model in mice,compared with the vehicle group,mice in the reserpine model group exhibited ptosis,akinesia and hypothermia feature(P<0.01,respectively),significantly prolonged immobility time in the TST(P<0.01),significantly decreased the levels of NE,5-HT and dopamine(DA)(P<0.05,P<0.01),significantly increased the metabolic conversion rate of 5-HT and DA(P<0.01,respectively),significantly elevated levels of TNF-α and IL-6(P<0.05,respectively),and significantly increased expressions of Iba-1 and NF-κB(P<0.05,respectively)in the hippocampus.Compared with the model group,ZBH2012001(5,10 and 20 mg·kg-1)significantly antagonized ptosis and hypothermia behaviors induced by reserpine(P<0.01,respectively),ZBH2012001(10 and 20 mg·kg-1)significantly shortened the immobility time in reserpine-treated mice(P<0.05,P<0.01),ZBH2012001(20 mg·kg-1)significantly increased the levels of NE and 5-HT in the hippocampus of reserpine-treated mice(P<0.05,respectively),decreased the metabolic conversion rate of 5-HT(P<0.05),significantly reduced the contents of TNF-α and IL-6 in the hippocampus of reserpine-treated mice(P<0.05,respectively),ZBH2012001(5,10 and 20 mg·kg-1)significantly reduced the expression of Iba-1 protein in the hippocampus of reserpine-treated mice(P<0.01,respec-tively),and ZBH2012001(20 mg·kg-1)significantly reduced the expression of NF-κB protein in the hippocampus of reserpine-treated mice(P<0.05).CONCLUSION ZBH2012001 exerts its antidepres-sant effect through a dual mechanism involving monoamine enhancement and inflammation suppres-sion.

AIM:To investigate of the effect of Shenqifuzheng injection(SFI)combined with PD-L1 antibody on tumor immune microenvironment and its efficacy.METHODS:A subcutaneous transplanta-tion tumor model for B16F10-LUC melanoma was created.The expression of Ki67,CD31,CD8,CD16,CD163,FOXP3,LY6C,LY6G with labeling antibodies was used to detect CD8+T cells,Treg cells,NK cells,MDSCs cells,centrocytes,and granulocytes in the tumor tissues via immunohistochemistry.Flow cy-tometry was used to measure the ratios of CD11c+,IA/IE+,and CD80+cells in splenic tissue,as well as the ratios of CD8+T,CD4+T,and Treg cells in tumor tissue.Additionally,granulocyte count and NK cell expression were analyzed.RESULTS:The immuno-histochemistry results indicate that the drug admin-istration group effectively suppressed tumor angio-genesis and cell proliferation,while decreasing the expression level of immunosuppressive cytokines CD4+T cells,Treg cells,MDSCs and centroblasts.Ad-ditionally,CD8 and NK cell infiltration was promot-ed compared to the control group.The results of the flow analysis demonstrated a significant in-crease in the expression level of CD8+T cells within tumor tissues,as well as inhibition of CD4+T,Treg,and DC cell infiltration within the spleen in the drug administration group.Additionally,the tumor volume analysis indicated that the drug administra-tion group effectively inhibited tumor growth.The flow results illustrate that the group administering treatment exhibited significant increases in CD8+T cell expression levels in tumor tissue and DC cells in the spleen.Furthermore,the treatment effec-tively inhibited the infiltration of CD4+T and Treg cells.The results also indicate that the treatment significantly reduced tumor growth,with the tumor inhibition rate being better with PD-L1 antibody alone than with the SFI group.Additionally,combin-ing drugs resulted in superior results compared to the PD-L1 antibody group alone.CONCLUSION:SFI combined with a PD-L1 antibody can have synergis-tic anti-tumor effects,potentially enhancing DC cell infiltration and promoting T cell activation.Immu-nohistochemistry results indicate a positive impact on the tumor immune microenvironment.

Objective:To observe the inhibiting effects of manual acupuncture(MA)on bladder cell apoptosis in rats with diabetic neurogenic bladder(DNB)based on the protein and mRNA expression of B-cell lymphoma-leukemia(Bcl)-2,Bcl-2-associated X(Bax)protein,caspase-3,and the protein expression of α-smooth muscle actin(α-SMA),transforming growth factor(TGF)-β in the bladder tissue. Methods:A DNB rat model was established via intraperitoneal injection of streptozotocin(STZ).The rats were randomly divided into a control group,a model group,and an MA group,with 10 rats in each group.For the MA group,MA was applied after modeling.The body mass,fasting blood glucose(FBG),bladder wet weight,and bladder histomorphology were observed.Protein and mRNA expression levels of Bcl-2,Bax,and caspase-3 and the protein expression of α-SMA and TGF-β in the bladder tissue were determined.The apoptotic index of bladder cells was also evaluated. Results:After STZ injection,compared with the control group,the model group and the MA group both showed higher FBG from week 3 and lower body mass from week 9(P<0.05),and had a larger bladder wet weight(P<0.05).Compared with the model group,the MA group showed a smaller bladder wet weight(P<0.05).The histopathological evaluation indicated that MA improved muscle fiber alignment and detrusor cell compensatory hypertrophy in the bladder tissue.In addition,compared with the control group,the apoptotic index increased significantly in the model group and the MA group(P<0.05);the protein and mRNA expression levels of Bax and caspase-3 and the protein expression level of TGF-β in the bladder tissue in the model group and the MA group increased significantly(P<0.05),while the protein and mRNA expression levels of Bcl-2 and the protein expression level of α-SMA in the bladder tissue decreased significantly(P<0.05).Compared with the model group,the apoptotic index of the MA group decreased significantly(P<0.05);the protein and mRNA expression levels of Bax and caspase-3 and the protein expression level of TGF-β in the bladder tissue decreased significantly(P<0.05),while the protein and mRNA expression levels of Bcl-2 and the protein expression level of α-SMA in the bladder tissue increased significantly(P<0.05). Conclusion:MA can protect the bladder by inhibiting the excessive apoptosis of bladder cells,which may be related to the down-regulation of Bax and caspase-3 proteins and mRNAs and TGF-β protein expression,and the up-regulation of Bcl-2 protein and mRNA and α-SMA protein expression.

Objective: Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors. Our study showed that long non-coding RNA (lncRNA) linc01194 plays an important role in EC. We explored the mechanism of lncRNA linc01194 in EC. Methods: The expression of lncRNA linc01194 was detected in The Cancer Genome Atlas database and starBase database. The potential targeted protein of linc01194 was predicted through the starBase database. To determine the role of linc01194 in EC, we downregulated or upregulated the level of linc01194 in EC cell lines and analyzed the cell behaviors and the changes of its potential target proteins. Results: The expression of linc01194 in EC tissues is higher than that in normal endometrial tissues. The knockdown of linc01194 inhibited the cell proliferation, invasion and migration and promoted the apoptosis of EC cells, while overexpression of linc01194 promoted cell proliferation, invasion and migration and inhibited the apoptosis of EC cells. The starBase database revealed that linc01194 could bind to insulin-like growth factor 2 binding protein 1 (IGF2BP1). Previous results showed that in EC, IGF2BP1 could promote the expression of sexdetermining region Y-box 2 (SOX2) by promoting the stability of SOX2 mRNA. Our results showed that linc01194 regulate the expression of IGF2BP1 and SOX2. Conclusion Linc01194 can promote the expression of downstream protein SOX2 through binding to IGF2BP1, thus promoting the occurrence and development of EC.

Objective:To observe the effects of Zhulian stimulant type Ⅰ acupuncture on the expression of brain-derived neurotrophic factor (BDNF) and its receptor TrkB and tissue homogenate cyclic adenosine phosphate (cAMP) in rats with diabetic bladder (DCP); To explore the mechanism of Zhulian stimulant type Ⅰacupuncture on DCP.Methods:Totally 50 SD rats were divided into control group, model group, Western medicine group, ordinary acupuncture group, Zhulian stimulant type Ⅰ acupuncture treatment group (acupuncture treatment group) according to random number table method, with 10 rats in each group. DCP rat model was prepared by intraperitoneal injection of streptozotocin (STZ), except for the control group. The Western medicine group was given mecobalamine for gavage; acupoints of "Zhongji", "Sanyinjiao", "Liechou" and "Taichong" were selected. The ordinary acupuncture group was treated with ordinary acupuncture technique, and the acupuncture treatment group was treated with Zhulian stimulant type Ⅰ acupuncture, 1 time/d, 30 minutes/time. Samples were taken after 4 weeks of treatment. The maximum bladder volume, residual urine volume and wet weight of the bladder were detected. The morphology of rat bladder was observed by HE staining. The expression level of BDNF was detected by immunohistochemistry. The expression of cAMP was detected by Western blot. The level of TrkB was determined by ELISA. Real-time fluorescence quantitative PCR (RT-PCR) was used to detect the mRNA expressions of BDNF and cAMP.Results:Compared with model group, maximum bladder volume, residual urine volume and wet weight of bladder in Western medicine group, ordinary acupuncture group and acupuncture treatment group decreased ( P<0.01), and those in Western medicine group and acupuncture treatment group were lower than those in ordinary acupuncture group ( P<0.01). The expressions of BDNF mRNA and protein, cAMP mRNA and protein in Western medicine group, ordinary acupuncture group and acupuncture treatment group increased ( P<0.05), and the level of TrkB increased, and the Western medicine group and acupuncture treatment group were higher than that in ordinary acupuncture group ( P<0.05). Conclusions:Zhuliping stimulant type Ⅰ acupuncture has a protective effect on the bladder function of diabetic rats. The mechanism may be related to the up-regulation of BDNF and mRNA, TrkB, cAMP and mRNA expressions.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

BackgroundPostoperative cognitive dysfunction （POCD） is a common complication in elderly patients after surgery， and has a great impact on postoperative rehabilitation of patients. ObjectiveTo explore the effect of mindfulness-based therapy on cognitive function and sleep quality in elderly patients after surgery under local anesthesia， so as to provide references for reducing their incidence risk of POCD and improving sleep quality. MethodsThe simple random sampling method was utilized to select 78 elderly patients who underwent surgery under local anesthesia in The Third Hospital of Mianyang from March 2022 to March 2023. Participants were assigned into study group and control group， each with 39 cases. All patients were subjected to conventional treatment and nursing interventions， and study group added mindfulness-based therapy on this basis. Mini-Mental State Examination （MMSE） was administered to patients on 1 day before surgery， and on the 1^st， 3^rd and 5^th day after surgery. Pittsburgh Sleep Quality Index （PSQI） was employed on 1 day before surgery and on the 3^rd day after surgery. ResultsMMSE scores revealed a significant time effect， group effect and time×group interaction effect （F=78.251， 197.071， 371.915， P<0.05）. Analysis of simple effect denoted that study group scored higher on MMSE on the 1^st， 3^rd and 5^th day after surgery compared with control group， with statistical significance （t=-3.579， -1.764， -0.253， P<0.05）. Study group reported lower incidence rates of POCD on the 1^st， 3^rd and 5^th day after surgery compared with control group， with statistical significance （χ²=2.631， 3.471， 5.135， P<0.05）. On the 3^rd day after surgery，study group scored lower on PSQI than control group（P<0.05）， and PSQI total score， sleep latency， subjective sleep quality， daytime dysfunction and hypnotic drug use factor scores of study group were lower than baseline， with statistical significance（F=43.175， 12.594， 11.092， 4.579， 3.514， P<0.01）. ConclusionMindfulness-based therapy may have certain value in reducing incidence of POCD and improving sleep quality in elderly patients who underwent surgery under local anesthesia.

OBJECTIVE To provide reference for the rational use of antiemetic drugs in tumor chemotherapy patients. METHODS The data of tumor patients who were given antiemetic drugs were collected from 9 departments of our hospital with hospital information system from Oct. 1st to Nov. 30th in 2022， such as oncology department， radiotherapy department， gynecology department， and gastroenterology department. The application of chemotherapy drugs and the use of antiemetic drugs were analyzed statistically， and the irrational use of antiemetic drugs was analyzed. RESULTS A total of 520 patients were included， involving 248 （47.69%） using chemotherapy drugs with a moderate emetogenic risk level and 135 （25.96%） with a high emetogenic risk level. A total of 461 cases （73.06%） of 5-hydroxytryptamine 3-receptor antagonists were used， including palonosetron in 333 cases， ondansetron in 106 cases， tropisetron in 15 cases and granisetron in 7 cases， and only 148 cases of patients were prioritized for the use of nationally procured medicines and national essential medicines （32.10%）. Neurokinin-1 receptor antagonists were used in 170 cases （26.94%）， including fosaprepitant in 112 cases and aprepitant in 58 cases. The use of antiemetic drugs was unreasonable in 162 patients （31.15%）； among the types of irrational drugs， the antiemetic regimen was unreasonable in the largest number of cases （22.40%）， followed by the irrational pharmacoeconomics （19.13%）. CONCLUSIONS The emetogenic risk levels of chemotherapy drugs used for tumor patients in our hospital are primarily moderate to high， and there is irrational use of antiemetic regimen and pharmacoeconomics. Clinicians， nurses， pharmacists and hospital departments should collaborate as multiple teams to strengthen full supervision of the standardization of antiemetic drugs， reasonably select antiemetic drugs based on emetogenicity rating， and improve the compliance of doctors with the guidelines to ensure the safety， effectiveness， and cost-effective of patient medication.

Objective:To investigate the molecular mechanisms of chronic rhinosinusitis (CRS), to identify key cell subgroups and genes, to construct effective diagnostic models, and to screen for potential therapeutic drugs.Methods:Key cell subgroups in CRS were identified through single-cell transcriptomic sequencing data. Essential genes associated with CRS were selected and diagnostic models were constructed by hdWGCNA (high dimensional weighted gene co-expression network analysis) and various machine learning algorithms. Causal inference analysis was performed using Mendelian randomization and colocalization analysis. Potential therapeutic drugs were identified using molecular docking technology, and the results of bioinformatics analysis were validated by immunofluorescence staining. Graphpad Prism, R, Python, and Adobe Illustrator software were used for data and image processing.Results:An increased proportion of basal and suprabasal cells was observed in CRS, especially in eosinophilic CRS with nasal polyps (ECRSwNP), with P=0.001. hdWGCNA revealed that the "yellow module" was closely related to basal and suprabasal cells in CRS. Univariate logistic regression and LASSO algorithm selected 13 key genes ( CTSC, LAMB3, CYP2S1, TRPV4, ARHGAP21, PTHLH, CDH26, MRPS6, TENM4, FAM110C, NCKAP5, SAMD3, and PTCHD4). Based on these 13 genes, an effective CRS diagnostic model was developed using various machine learning algorithms (AUC=0.958). Mendelian randomization analysis indicated a causal relationship between CTSC and CRS (inverse variance weighted: OR=1.06, P=0.006), and colocalization analysis confirmed shared genetic variants between CTSC and CRS (PPH4/PPH3>2). Molecular docking results showed that acetaminophen binded well with CTSC (binding energy:-5.638 kcal/mol). Immunofluorescence staining experiments indicated an increase in CTSC +cells in CRS. Conclusion:This study integrates various bioinformatics methods to identify key cell types and genes in CRS, constructs an effective diagnostic model, underscores the critical role of the CTSC gene in CRS pathogenesis, and provides new targets for the treatment of CRS.

Objective:This report presents the initial outcomes of endoscopic intermuscular dissection (EID), a novel technique introduced by our team for the diagnostic resection of early rectal cancer, focusing on the postoperative status of the vertical margins.Methods:On January 26, 2024, a patient with early rectal cancer (cT1-2N0M0) underwent Endoscopic Intermuscular Dissection. The EID procedure consists of six steps: (1) mucosal incision; (2) submucosal dissection; (3) superficial muscular layer incision; (4) intermuscular dissection; (5) complete tumor removal; (6) wound management.Results:The patient was a 70-year-old male with rectal cancer (cT1-2N0M0). The tumor was located on the left anterior wall of the rectum, approximately 9 cm from the anal margin, and measured 20mm in size. The dissection rate was 2.68 mm2/minute, and the total duration of the surgery was 109 minutes. The patient was successfully discharged on the fifth day after surgery. Pathological examination of the post-endoscopic surgery specimen revealed pT1b, with negative vertical margins. Follow-up after more than one month showed good recovery with no complications such as bleeding, perforation, infection, or stricture occurring. Colonoscopy indicated the presence of a granulation tissue suggestive of inflammation.Conclusion:Endoscopic Intermuscular Dissection for the diagnostic resection of early rectal cancer is potentially safe and may achieve negative vertical margins.