Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.

Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.

Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.

Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.

Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from ¹³C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Objective To overcome the limitations of existing human respiratory syncytial virus(hRSV)animal models,such as semi-permissiveness and short duration of infection,this study established an IL2rg gene knockout(IL2rg-/-)rat model using TALEN gene editing technology.Methods The animal model was infected with hRSV intranasally.Clinical characteristics,body weight,and temperature changes were observed over the infection period(0～35 days).The total viral loads in respiratory organs,such as the nasal tissue,trachea,and lungs,were measured at various time points(4,11,20,and 35 days post-infection).Pathological analysis was conducted on target organs at the endpoint of observation(35 days post-infection).Changes in peripheral blood T,B,NK,and NKT cells and various cytokines were assessed at various time points(4,20,and 35 days post-infection).Results(1)IL2rg/-knockout rats sustained high viral loads in the nasal cavity upon intranasal inoculation with hRSV.The average peak titer rapidly reached 1 × 1010 copies/g in nasal tissue and 1 × 107 copies/g up to 5 weeks post-infection.(2)However,no significant pathological changes were noted in nasal,tracheal,or lung tissues.(3)An increase was observed in the content of peripheral blood B cells in hRSV-infected IL2rg--rats.(4)IL-6 and MCP-1 were increased in the early stage of infection and then decreased at the end of the observation period.Conclusions This study established a new IL2rg-/-rat model using TALEN technology and found that this model effectively supported high-level replication and long-term infection of hRSV,providing a good basis for antiviral drug screening and in vivo efficacy evaluation of anti-hRSV antibodies.

OBJECTIVE To study the toxicokinetics and tissue distribution characteristics of alpha-amanitin in rats.METHODS The tail venous blood was collected from SD rats before and 5,10,20,30 and 45 min,1,1.5,2.5,4 and 8 h after intraperitoneal injection of alpha-amanitin(1.5 mg·kg-1),and the concentration of alpha-amanitin in blood was determined by liquid chromatography-mass spectrometry(LC-MS/MS).DAS 2.0 software was used to analyze and plot the drug-time curve with toxicokinetic parame-ters.Based on the toxicokinetics results,18 SD rats were randomly divided into three groups.The rats were sacrificed,and left ventricular arterial(LVA)blood and 9 types of tissue samples involving the heart,liver,spleen,lung,kidney,whole brain,small intestine,stomach wall and testis were collected 15 min,40 min and 2.5 h after dosing,and the concentrations of alpha-amanitin were measured by LC-MS/MS to obtain the tissue distribution results of alpha-amanitin in SD rats.RESULTS Toxicokinetics studies revealed that the peak blood concentration(Cmax)was(633±121)μg·L-1,the elimination half-life(T1/2)was(0.72±0.37)h,and the peak time(Tmax)was(0.52±0.16)h.The total clearance rate(CLz)was(1.62±0.26)L·h·kg-1,the area under the curve(AUC0-t)was(946±183)μg·h·L-1,and the mean reten-tion time(MRT0-t)was(1.18±0.17)h.The apparent volume of distribution(Vz)was(1.65±0.86)L·kg-1.The results of tissue distribution study showed that alpha-amanitin was widely distributed in SD rats with the highest concentration in the kidney,followed by the lung,small intestines,stomach wall,LVA blood and liver,but was low in the heart,spleen,testicles and other tissues,and very low in the brain.Alpha-amanitin was absorbed and eliminated quickly,peaked at 40 min in each tissue,and the concen-tration was minimized after 2.5 h.CONCLUSION The absorption and elimination of alpha-amanitin by intraperitoneal injection are rapid in SD rats,and the blood concentration reaches the peak about 31 min after administration,but can not be detected 4 h later.Alpha-amanitin is mainly distributed in the kidney,followed by the tissues and metabolic organs with rich blood flow,such as the lung,small intestines,stomach wall,LVA blood and liver.The content of alpha-amanitin is low in the heart,spleen,testicles and other tissues,and very low in the brain.It is speculated that it may have toxic targeting effect on the kidney and low blood-brain barrier permeability.

[摘 要] 目的：探讨不同途径输注DC-CIK对中晚期原发性肝癌（PLC）的治疗效果和预后价值。方法：回顾性分析2018年10月至2021年9月间东部战区总医院肿瘤科DC-CIK治疗的69例中晚期PLC患者的临床资料，根据DC-CIK治疗时采用的输注方式不同将患者分为肝动脉灌注（HAI）组（n = 29）和静脉输注（IV）组（n = 40），比较两组患者的临床疗效、外周血T淋巴细胞亚群（CD3+、CD4 +、CD8 + T和CD4+/CD8+ T细胞比值），以及细胞因子（IL-2、IL-6、IFN-γ和TNF-α）、甲胎蛋白（AFP）的变化、总生存期（OS）和不良反应发生情况。结果：69例PLC患者经DC-CIK治疗后，HAI组患者的客观缓解率（ORR）为0%，疾病控制率（DCR）为75.8%；IV组患者的ORR为0%，DCR为72.5%（P > 0.05）。两组患者治疗前后T淋巴细胞亚群指标变化差异无统计学意义（均P > 0.05），两组患者治疗后外周血IL-2、IL-6、IFN-γ和TNF-α的平均水平均显著高于治疗前（均P < 0.01），两组间比较无显著差异（P > 0.05）；HAI组患者平均OS为48.17个月，IV组OS为39.65个月，两组间比较无显著差异（P > 0.05）。治疗过程中无严重不良反应发生。结论：自体DC-CIK HAI治疗PLC安全有效，较IV治疗有提升临床获益的趋势，值得临床借鉴。

BACKGROUND:Epidemiologic studies have shown a correlation between type 2 diabetes mellitus and bone mineral density,but the causal association between the two and whether it is age-related remains unknown. OBJECTIVE:To study the correlation between type 2 diabetes mellitus and whole body bone mineral density at unspecified age and at all ages based on the Mendelian randomization technique. METHODS:The genome-wide association study(GWAS)data of type 2 diabetes mellitus and bone mineral density at all ages were selected from the IEU GWAS database of the University of Bristol.The exposure data were single nucleotide polymorphisms with significant correlation with type 2 diabetes mellitus as instrumental variables,and bone mineral density at all ages was selected as the outcome variable.Two-sample Mendelian randomization analysis of type 2 diabetes mellitus and bone mineral density was performed using inverse variance weighted method,weighted median estimator,and MR-Egger regression.The βvalue was used to evaluate the causal relationship between type 2 diabetes mellitus and bone mineral density at all ages. RESULTS AND CONCLUSION:A total of 118 single nucleotide polymorphisms were extracted from the GWAS summary data as instrumental variables.The MR-Egger regression results showed that there was no horizontal pleiotropy,but there was heterogeneity.Therefore,this study was based on the inverse variance weighted results.Inverse variance weighted results showed that type 2 diabetes mellitus may be a potential protective factor for bone mineral density and is associated with age:age-unspecified bone mineral density[β=0.038,95%confidence interval(CI):1.01-1.07,P=0.002],bone mineral density over 60 years old(β=0.052,95%CI:1.01-1.09,P=0.027),bone mineral density between 45-60 years old(β=0.049,95%CI:1.01-1.09,P=0.009),bone mineral density between 30-45 years old(β=0.033,95%CI:0.99-1.07,P=0.127).bone mineral density of 15-30 years old(β=0.025,95%CI:0.95-1.10,P=0.506),bone mineral density of 0-15 years old(β=0.006,95%CI:0.96-1.04,P=0.716).Similar results were obtained from the MR-Egger regression and weighted median estimator analyses.These findings indicate that type 2 diabetes mellitus may be one of the protective factors of bone mineral density,and there is a correlation with age.