Objective To explore the correlation of MET status in patients with advanced prostatic acinar adenocarcinoma with the clinical pathological parameters and prognosis. Methods The specimen from 135 patients with advanced prostatic acinar adenocarcinoma was included. The expression of c-MET protein was detected via immunohistochemistry, and MET gene amplification was assessed by fluorescence in situ hybridization. The relationships of c-MET expression and gene amplification with clinicopathological features and prognosis were analyzed. Results The positive expression rate of c-MET was 52.60% (71/135). Compared with the c-MET expression in adjacent tissues, that in tumor tissues showed lower heterogeneous expression. Among the cases, 1.71% (2/117) exhibited MET gene polyploidy, but no gene amplification was detected. Positive c-MET expression was significantly correlated with high Gleason scores and grade groups (P=0.0073). However, no significant relationship was found between c-MET expression and progression-free survival or post-treatment t-PSA levels. Conclusion c-MET protein is expressed at a relatively low level in advanced prostatic acinar adenocarcinoma, suggesting that c-MET may not be a viable target for ADC drug development in prostatic acinar adenocarcinoma.

Objective:To evaluate the effect of esketamine on learning and memory function after chronic stress and the signaling pathway of N-methyl-D-aspartate receptor (NMDAR)-calmodulin-dependent protein kinase type 2 (CaMKⅡ)-cAMP-responsive element-binding protein (CREB) in the hippocampus of developing rats.Methods:Sixty clean-grade healthy Sprague-Dawley rats of either sex, aged 7 days, weighing 10-15 g, were divided into 3 groups ( n=20 each) using a random number table method: control+ normal saline group (CN group), chronic stress+ normal saline group (NS group), and chronic stress+ esketamine group (ES group). A chronic stress model was established using a chronic unpredictable stress method. After the end of stress stimulation, esketamine 10 mg/kg was intraperitoneally injected once a day for 7 consecutive days in ES group, and the equal volume of normal saline was given instead in NS group. Y maze test and Morris water maze test were used to assess the learning and memory function after intraperitoneal administration. Venous blood samples were obtained to measure the serum cortisol and reactive oxygen species (ROS) concentrations by enzyme-linked immunosorbent assay. The animals were then sacrificed under anesthesia, the brain was removed and the hippocampal tissue was isolated for examination of the pathological changes in the hippocampal CA1 region and for determination of the ratios of phosphorylated NMDAR (p-NMDAR)/NMDAR, phosphorylated CaMKII (p-CaMKⅡ)/CaMKⅡ, and phosphorylated CREB (p-CREB)/CREB (by Western blot). Results:Compared with CN group, the time spent in the novel arm was significantly shortened, the number of entries into the novel arm was reduced, the escape latency was prolonged, the number of crossing the original platform was reduced, the serum cortisol and ROS concentrations were increased, the p-NMDAR/NMDAR ratio, p-CaMKⅡ/CaMKⅡ ratio and p-CREB/CREB ratio were decreased ( P<0.05), and the pathological changes of neurons were marked in NS group. Compared with NS group, the time spent in the novel arm was significantly prolonged, the number of entries into the novel arm was increased, the escape latency was shortened, the number of crossing the original platform was increased, the serum cortisol and ROS concentrations were decreased, the p-NMDAR/NMDAR ratio, p-CaMKⅡ/CaMKⅡ ratio and p-CREB/CREB ratio were increased ( P<0.05), and the pathological changes of neurons were significantly attenuated in ES group. Conclusions:Esketamine can improve the learning and memory function after chronic stress in developing rats, and the mechanism may be related to reduction of oxidative stress and enhancement of the activity of hippocampal NMDAR-CaMKII-CREB signaling pathway.

AIM:To investigate the effect of vaccarin(VAC)on endothelial dysfunction in type 2 diabetes mellitus(T2DM),and to uncover the underlying mechanisms.METHODS:(1)C57BL/6 mice received intraperitoneal injection of streptozotocin and were fed with a high-fat diet(21.8 kJ/kg,60%of the energy source was fat)to construct a T2DM mouse model.Thirty mice were randomly divided into control,T2DM and T2DM+VAC groups,with 10 mice in each group.The mice in T2DM+VAC group were given 1 mg/kg VAC via oral gavage for 6 weeks,while those in control and T2DM groups were given the same volume of PBS.The mRNA and protein expression levels of BCL2-interacting pro-tein 3(BNIP3),PTEN-induced kinase 1(PINK1)and parkin in the thoracic aorta were detected by RT-qPCR and West-ern blot.(2)Human umbilical vein endothelial cells(HUVECs)were stimulated by high glucose(HG;35 mmol/L glu-cose).Mitochondrial membrane potential,autophagy and mitochondrial superoxide levels were detected using JC-1,acri-dine orange(AO)and MitoSOX staining,respectively.RESULTS:Compared with control group,the mRNA and protein levels of BNIP3,PINK1 and parkin were significantly increased in the thoracic aorta of T2DM mice(P<0.05).Compared with T2DM group,the mRNA and protein levels of BNIP3,PINK1 and parkin in the thoracic aorta were significantly re-duced in T2DM+VAC group(P<0.05).The results of JC-1,AO and MitoSOX staining showed that VAC attenuated the decrease in mitochondrial membrane potential and the increase in autophagy and mitochondrial superoxide levels in HG-in-duced HUVECs.Treatment with VAC also inhibited HG-mediated mitochondrial damage in HUVECs after BNIP3 overex-pression.The effect of miR-570-3p mimic on mitochondrial damage was similar to VAC.RT-qPCR and Western blot showed that both miR-570-3p mimic and VAC significantly reduced the mRNA and protein levels of BNIP3,PINK1 and parkin.In contrast,inhibition of miR-570-3p exhibited the opposite effects.CONCLUSION:Treatment with VAC alle-viated endothelial dysfunction in T2DM by inhibiting HG-induced mitochondrial dysfunction through miR-570-3p/BNIP3.

Objective To investigate the clinical experience of cochlear implantation(CI)in patients with postlingual hearing loss accompanied by cholesterol granuloma(CG)in the middle ear.Methods A retrospective study was conducted on the clinical data of 6 patients with postlingual hearing loss who underwent CI with middle ear CG at Fuyang hospital of Anhui Medical University from December 2018 to December 2022.The selection of surgical methods,surgical efficacy,and postoperative complications of patients undergoing CI surgery during the same period were summarized and analyzed.The categories of auditory performance(CAP)and speech intelligibility rating(SIR)were used to evaluate the effectiveness of auditory speech rehabilitation.Results Six patients were treated by individualized surgical methods based on preoperative CT findings and successfully completed cochlear im-plant surgery.According to the scope of the lesion,three patients were treated with canal wall up mastoidectomy(CWUM)and CI,the other three patients were treated with radical mastoidectomy(RM),CI and middle ear clo-sure(MEC).All patients did not experience complications such as incision infection,facial paralysis,labyrinthitis,intracranial infection,recurrence,or electrode exposure after surgery and during follow-up.The CAP and SIR scores of postoperative patients were significantly improved compared to preoperative with statistical significance(P＜0.05).Conclusion For patients with severe sensorineural hearing loss and middle ear CG,simultaneous cochlear implantation can achieve good auditory rehabilitation effects.However,appropriate surgical methods should be se-lected based on the lesion range,and the lesion must be completely removed to prevent postoperative complications.

Objective:To evaluate the role of ubiquitin-specific peptidase 22 (USP22) in myocardial ischemia-reperfusion (I/R) injury in diabetic mice.Methods:Seventy-eight SPF male C57BL/6 mice, aged 6-8 weeks, were divided into 6 groups using a random number table method: sham operation group (Sham group, n=12), type 1 diabetes mellitus + sham operation group (T1D+ Sham group, n=12), myocardial I/R injury group (I/R group, n=12), type 1 diabetes mellitus + myocardial I/R injury group (DI/R group, n=12), type 1 diabetes mellitus + myocardial I/R injury + empty vector group (DI/R+ V group, n=15), and type 1 diabetes mellitus + myocardial I/R injury + USP22 overexpression group (DI/R+ U group, n=15). Type 1 diabetes mellitus was induced by intraperitoneal injection of streptozotocin-citrate buffer. Myocardial I/R was induced by ligation of the left coronary artery. At 1 day before developing the myocardial I/R injury model, DI/R+ U group and DI/R+ V group received an intramyocardial injection of USP22 overexpression plasmid or empty vector plasmid, respectively. At 24 h of reperfusion, cardiac function was assessed using the echocardiography to measure the left ventricular ejection fraction and left ventricular fractional shortening. The mice were then sacrificed, and their hearts were harvested for measurement of the myocardial infarct size, for microscopic examination of pathological changes (using HE staining) and for determination of the apoptosis rate (TUNEL staining), reactive oxygen species(ROS) activity (DHE staining), and USP22 expression (by Western blot, immunofluorescence, and immunohistochemistry). Proteomic analysis was performed to identify downstream proteins regulated by USP22, and protein-protein interactions were investigated using co-immunoprecipitation. Results:Compared with Sham group, the cardiac function indices were significantly decreased, the apoptosis rate of myocardial cells and ROS activity were increased, and USP22 expression in myocardial tissues was down-regulated in I/R group ( P<0.05). Compared with I/R group, the percentage of myocardial infarct size was significantly increased, the cardiac function indices were decreased, the apoptosis rate of myocardial cells and ROS activity were increased, and USP22 expression in myocardial tissues was up-regulated ( P<0.05), and the pathological damage to myocardial tissues was aggravated in DI/R group. Compared with DI/R+ V group, the percentage of myocardial infarct size was significantly decreased, the cardiac function indices were increased, the apoptosis rate of myocardial cells and ROS activity were decreased, and USP22 expression in myocardial tissues was up-regulated ( P<0.05), and the pathological damage to myocardial tissues was alleviated in DI/R+ U group. The results of proteomics combined with co-immunoprecipitation experiments showed an interaction between calponin 1 and USP22. Conclusions:During myocardial I/R injury in diabetic mice, USP22 may act as an endogenous protective mechanism, and calponin 1 might be a downstream mechanism through which USP22 exerts its protective effects.

The thalamocortical (TC) circuit is closely associated with pain processing. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channel is predominantly expressed in the ventral posterolateral thalamus (VPL) that has been shown to mediate neuropathic pain. However, the role of VPL HCN2 in modulating TC circuit activity is largely unknown. Here, by using optogenetics, neuronal tracing, electrophysiological recordings, and virus knockdown strategies, we showed that the activation of VPL TC neurons potentiates excitatory synaptic transmission to the hindlimb region of the primary somatosensory cortex (S1HL) as well as mechanical hypersensitivity following spared nerve injury (SNI)-induced neuropathic pain in mice. Either pharmacological blockade or virus knockdown of HCN2 (shRNA-Hcn2) in the VPL was sufficient to alleviate SNI-induced hyperalgesia. Moreover, shRNA-Hcn2 decreased the excitability of TC neurons and synaptic transmission of the VPL-S1HL circuit. Together, our studies provide a novel mechanism by which HCN2 enhances the excitability of the TC circuit to facilitate neuropathic pain.
Animals ; Mice ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics* ; Neuralgia ; RNA, Small Interfering ; Thalamus/metabolism* ; Up-Regulation

Objective:To evaluate the effect of esketamine on long-term cognitive dysfunction induced by propofol anesthesia in the developing rats and the role of phosphatidylinositol-3-kinase (PI3K)/serine-threonine protein kinase (Akt) signaling pathway.Methods:Forty-eight clean-grade healthy Sprague-Dawley rats of either sex, aged 7 days, weighing 10-15 g, were divided into 4 groups ( n=12 each) using a random number table method: fat emulsion group (C group), propofol group (P group), esketamine + propofol group (EP group), and PI3K inhibitor LY294002 + esketamine + propofol group (LYEP group). Medium/long-chain fat emulsion injection 100 mg/kg was intraperitoneally injected in C group. Propofol was intraperitoneally injected at a dose of 50 mg/kg, followed by an additional dose of 50 mg/kg after the righting reflex was restored (40-60 min later) in P group. In group EP, esketamine 10 mg/kg was intraperitoneally injected, followed by propofol administration using the same method as previously described in P group. In LYEP group, LY294002 25 μg was injected via the lateral ventricle, 30 min later ketamine 10 mg/kg was intraperitoneally injected, and then propofol was given using the same method as previously described in P group. Six rats in each group were randomly sacrificed at 2 h after emergence for microscopic examination of pathological changes of hippocampal neurons and for determination of Akt, phosphorylated Akt (p-Akt), Bax, and cleaved caspase-3 in the hippocampal tissues (using Western blot). The remaining 6 rats in each group were subjected to Y-maze test to evaluate their learning and memory abilities at 30 days after birth. The p-Akt/Akt ratio was calculated. Results:Compared with C group, the p-Akt/Akt ratio in the hippocampal tissues was significantly decreased, the expression of Bax and cleaved caspase-3 was up-regulated, the number of training sessions required for learning was increased, the correct response rate was decreased ( P<0.05), and the pathological damage to neurons in hippocampal CA1 region was found in P, EP and LYEP groups. Compared with P group, the p-Akt/Akt ratio in the hippocampal tissues was significantly increased, the expression of Bax and cleaved caspase-3 was down-regulated, the number of training sessions required for learning was decreased, the correct response rate was increased ( P<0.05), and the pathological damage to neurons in hippocampal CA1 region was significantly attenuated in EP and LYEP groups. Compared with EP group, the p-Akt/Akt ratio in the hippocampal tissue was significantly decreased, and the expression of Bax and cleaved caspase-3 was up-regulated, the number of training sessions required for learning was increased, the correct response rate was decreased ( P<0.05), and the pathological damage to neurons in hippocampal CA1 region was aggravated in LYEP group. Conclusions:Esketamine can alleviate long-term cognitive impairment caused by propofol anesthesia in the developing rats, and the mechanism may be related to activation of the PI3K/Akt signaling pathway and inhibition of apoptosis in neurons.

Premature ejaculation (PE) is the most common male sexual dysfunction with a high incidence, which seriously affects the relationship between a husband and wife and family harmony. Drug therapy is a first-line treatment for PE patients with premature ejaculation, and has achieved good efficacy, but the clinically available drugs are single and the abandonment rate is high. Coupled with the ineffective treatment of some patients, new drug research and development is imminent. This paper systematically reviews the current status of drug treatment for premature ejaculation, focusing on the research and development of new drugs and research progress in order to provide a reference for clinicians.

Objective:To analyze the relationship between stress hyperglycemia (SHG) and the prognosis of acute myocardial infarction (AMI) without diabetes mellitus (DM).Methods:Using a retrospective cohort study method, 396 AMI patients without DM or impaired glucose tolerance (IGT) and admitted glycated hemoglobin A 1c (HbA 1c)≤6.0% from January 2018 to December 2020 in Xuanwu Hospital, Capital Medical University were selected. Among them, 238 patients did not have SHG at admission (group A), 85 patients had SHG at admission but their blood glucose level did not reach the diagnostic criteria for DM (group B), and 73 patients had SHG at admission and their blood glucose level reached the diagnostic criteria for DM (group C). The baseline data and the incidence of main adverse cardiovascular and cerebrovascular events (MACCE) were recorded. Multivariate Cox regression was used to analyze the independent risk factors of MACCE after discharge in AMI patients without DM. Results:The incidence of MACCE after discharge in group B and group C was significantly higher than that in group A: 29.4% (25/85) and 35.6% (26/73) vs. 18.5% (44/238), the incidence in group C was significantly higher than that in group B, and there was statistical difference ( P<0.05). Multivariate Cox regression analysis result showed that SHG on admission was an independent risk factor for MACCE after discharge in AMI patients without DM ( P<0.05), and LVEF on admission was an independent protective factor for MACCE after discharge in AMI patients without DM ( P<0.01). Conclusions:SHG on admission is the independent risk factor of MACCE in AMI patient without DM. Early detection, assessment and proper intervention measures based on clinical reality should be advocated for the AMI patients with SHG to further improve the prognosis.

Depression is one of the most common mental disorders, which can be accompanied by cognitive symptoms in addition to core symptoms.With the improvement of the awareness of the disease, people pay more attention to the cognitive symptoms of depression. The cognitive impairment of patients not only appears in the onset of the disease, but also persists during the remission of the disease, which has a negative impact on the patients’ social function. Some cognitive assessment tools such as cognitive tests, event-related potential(ERP) and eye movement tracking technology have been used to assess cognitive impairment in patients with depression, which show that there are multidimensional cognitive impairments. Some therapeutic methods such as exercise therapy, repetitive transcranial magnetic stimulation(rTMS) and drug therapy have shown the potential to improve the cognitive function of patients with depression. This article reviews related researches in recent years to explore the cognitive impairment and therapeutic methods of patients with depression.