Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

In order to investigate the mitigating effect of Yin Chen aqueous extract on liver injury induced by LPS combined with D-GalN in mice,a mouse liver injury model was established by in-traperitoneal injection of LPS and D-GalN,and the mice were group-fed by instillation of saline,bi-phenyl dibenzyl ester,and Yin Chen aqueous extract with different concentrations of LPS and D-GalN.The liver index of mice was calculated,pathological tissue sections were observed,and the expression of ALT,AST,inflammatory cytokines,oxidative stress,hepatic enzymes,and IL-17/TNF pathway were detected in serum to investigate the effects and mechanisms of the aqueous ex-tracts of Yin Chen in alleviating the liver injury in mice.The results showed that the liver index of mice in the model group was significantly elevated,the serum levels of ALT and AST were signifi-cantly elevated,the levels of IL-iβ,IL-8 and TNF-α in liver tissue were significantly elevated,the levels of IL-4 were significantly reduced,the levels of GSH-Px,CAT and SOD were significantly reduced,the levels of ROS and MDA were significantly elevated,CYP2E1 and CYP1A2 protein content and mRNA expression were significantly up-regulated,and the expression levels of TNF,TNFR1,IL-17A,ACT1 and IL-6 mRNA were significantly up-regulated.The study showed that the aqueous extract of Yin Chen had a certain alleviating effect on the liver injury caused by LPS combined with D-GalN in mice.The mechanism of action includes decreasing the metabolic level of hepatic drug enzymes,alleviating oxidative stress,inhibiting the expression of IL-17/TNF pathway and down-regulating the level of inflammatory factors in mice.

Retinal neovascularization is a common pathological feature of many blinding eye diseases,and these neovessels are usually fragile and prone to rupture and hemorrhage,which can lead to severe visual impairment.Caveolin-1 is an important membrane protein involved in cellular signaling,lipid metabolism,and cytoskeleton regulation.Currently,it has been proven that Caveolin-1 expresses in a variety of retinal cell types and can participate in retinal neovascularization by regulating multiple signaling pathways.In this article,the domestic and international studies on the role and mechanism of Caveolin-1 in neovascularization were reviewed,and the therapeutic prospect of Caveolin-1 in retinal neovascularization ophthalmopathy was analyzed.This study aims to provide ideas for exploring the pathogenesis of the disease and seeking potential targeted interventions.

Retinal neovascularization is a common pathological feature of many blinding eye diseases,and these neovessels are usually fragile and prone to rupture and hemorrhage,which can lead to severe visual impairment.Caveolin-1 is an important membrane protein involved in cellular signaling,lipid metabolism,and cytoskeleton regulation.Currently,it has been proven that Caveolin-1 expresses in a variety of retinal cell types and can participate in retinal neovascularization by regulating multiple signaling pathways.In this article,the domestic and international studies on the role and mechanism of Caveolin-1 in neovascularization were reviewed,and the therapeutic prospect of Caveolin-1 in retinal neovascularization ophthalmopathy was analyzed.This study aims to provide ideas for exploring the pathogenesis of the disease and seeking potential targeted interventions.

In order to investigate the mitigating effect of Yin Chen aqueous extract on liver injury induced by LPS combined with D-GalN in mice,a mouse liver injury model was established by in-traperitoneal injection of LPS and D-GalN,and the mice were group-fed by instillation of saline,bi-phenyl dibenzyl ester,and Yin Chen aqueous extract with different concentrations of LPS and D-GalN.The liver index of mice was calculated,pathological tissue sections were observed,and the expression of ALT,AST,inflammatory cytokines,oxidative stress,hepatic enzymes,and IL-17/TNF pathway were detected in serum to investigate the effects and mechanisms of the aqueous ex-tracts of Yin Chen in alleviating the liver injury in mice.The results showed that the liver index of mice in the model group was significantly elevated,the serum levels of ALT and AST were signifi-cantly elevated,the levels of IL-iβ,IL-8 and TNF-α in liver tissue were significantly elevated,the levels of IL-4 were significantly reduced,the levels of GSH-Px,CAT and SOD were significantly reduced,the levels of ROS and MDA were significantly elevated,CYP2E1 and CYP1A2 protein content and mRNA expression were significantly up-regulated,and the expression levels of TNF,TNFR1,IL-17A,ACT1 and IL-6 mRNA were significantly up-regulated.The study showed that the aqueous extract of Yin Chen had a certain alleviating effect on the liver injury caused by LPS combined with D-GalN in mice.The mechanism of action includes decreasing the metabolic level of hepatic drug enzymes,alleviating oxidative stress,inhibiting the expression of IL-17/TNF pathway and down-regulating the level of inflammatory factors in mice.

Dopamine,a neurotransmitter ubiquitous in the body fluids,blood,and urine of mammals and humans,is responsible for regulating their functions and metabolism.The dopamine system is involved in the neurobiological mechanisms of narcolepsy in animals and humans.However,researchers have drawn different or even opposite conclusions when measuring the dopamine level in the cerebrospinal fluid of narcolepsy pa-tients.Studies have confirmed that the occurrence of narcolepsy is related to the irreversible loss of orexins.The autoimmune reaction caused by the interactions of environmental factors with genetic factors destroys the hypotha-lamic orexin neurons and reduces orexin secretion,thereby lowering the level of arousal.We introduce the re-search progress and current status of dopamine and clinical characterization of narcolepsy by reviewing more than 40 articles published from 1982 to 2023,aiming to provide a reference for studying the relationship between the dopamine level and clinical characterization of narcolepsy and searching for the biomarkers of type 2 narcolepsy.

Separation/conversion disorders in functional coma with pseudocataplexy are rare.On De-cember 9,2021,a young female patient with separation/conversion disorders was treated in the Department of Neurology in the First Affiliated Hospital of Shandong First Medical University.The main symptoms were episodic consciousness disorders,sudden fainting,and urinary incontinence.Complete laboratory tests and cranial mag-netic resonance imaging showed no obvious abnormalities.Standard multi-channel sleep monitoring and multiple sleep latency tests were performed.The patient was unable to wake up during nap and underwent stimulation tests.There was no response to orbital pressure,loud calls,or tapping,while the α rhythm in all electroenceph-alogram leads and the increased muscular tone in the mandibular electromyography indicated a period of wakeful-ness.The results of 24-hour sleep monitoring suggested that the patient had sufficient sleep at night and thus was easy to wake up in the morning.The results of daytime unrestricted sleep and wake-up test showed that the patient took one nap in the morning and one nap in the afternoon.When the lead indicated the transition from N3 to N2 sleep,a wake-up test was performed on the patient.At this time,the patient reacted to the surrounding environ-ment and answered questions correctly.Because the level of orexin in the cerebrospinal fluid was over 110 pg/mL,episodic sleep disorder was excluded and the case was diagnosed as functional coma accompanied by pseudocata-plexy.The patient did not present obvious symptom remission after taking oral medication,and thus medication withdrawl was recommended.Meanwhile,the patient was introduced to adjust the daily routine and mood.The follow-up was conducted six months later,and the patient reported that she did not experience similar symptoms after adjusting lifestyle.Up to now,no similar symptoms have appeared in multiple follow-up visits for three years.Functional coma with pseudocataplexy is prone to misdiagnosis and needs to be distinguished from true co-ma and episodic sleep disorders.

Objective To compare the hepatic lipid droplet metabolism in normal BKS-db/m mice and BKS-db/db mice,a model of type 2 diabetes mellitus (T2DM),and to investigate the characteristics of hepatic lipid droplet metabolism and the molecular mechanisms underlying the imbalance of metabolic homeostasis at the level of lipid droplet synthesis and lipid droplet catabolism in db/db mice. Methods Eight SPF 8 weeks BKS-db/m and 8 BKS-db/db mice were used in this study. The lipid metabolism level was tested. Oil red and HE staining was used to evaluate the degree of liver lipid deposition,and immunofluorescence staining and Western blot was used to observe the level of hepatic lipid droplet catabolism and metabolism. Results The body weight,liver weight,liver index,FPG,AUC of the OGTT,AUC of the ITT,TG,TC,HDL-C,LDL-C,FFA and SREBP1 positive fluorescence area and nuclear translocation were higher in db/db group than in db/m group (P<0.05). The lipophagia level of primary hepatocytes was higher in db/db group than in db/m group (P<0.05). Compared with the db/m group,the expressions of SREBP1,SCD1,PLIN2,LC3,LAMP2A and ATGL protein increased(P<0.05),while the expression of p-ACC/ACC protein decreased in the db/db group(P<0.05). Conclusions Compared with normal mice,T2DM mice had dyslipidemiaand marked hepatocellular lipid deposition.Although lipid droplet lipolysis and lipophagy were enhanced and catabolism was significant,the lipid droplet metabolism was in a state of imbalance between synthesis and catabolism,and the synthesis of lipid droplets was greater than that of catabolism,which led to the aggregation of hepatocellular lipids.

Objective To compare the hepatic lipid droplet metabolism in normal BKS-db/m mice and BKS-db/db mice,a model of type 2 diabetes mellitus (T2DM),and to investigate the characteristics of hepatic lipid droplet metabolism and the molecular mechanisms underlying the imbalance of metabolic homeostasis at the level of lipid droplet synthesis and lipid droplet catabolism in db/db mice. Methods Eight SPF 8 weeks BKS-db/m and 8 BKS-db/db mice were used in this study. The lipid metabolism level was tested. Oil red and HE staining was used to evaluate the degree of liver lipid deposition,and immunofluorescence staining and Western blot was used to observe the level of hepatic lipid droplet catabolism and metabolism. Results The body weight,liver weight,liver index,FPG,AUC of the OGTT,AUC of the ITT,TG,TC,HDL-C,LDL-C,FFA and SREBP1 positive fluorescence area and nuclear translocation were higher in db/db group than in db/m group (P<0.05). The lipophagia level of primary hepatocytes was higher in db/db group than in db/m group (P<0.05). Compared with the db/m group,the expressions of SREBP1,SCD1,PLIN2,LC3,LAMP2A and ATGL protein increased(P<0.05),while the expression of p-ACC/ACC protein decreased in the db/db group(P<0.05). Conclusions Compared with normal mice,T2DM mice had dyslipidemiaand marked hepatocellular lipid deposition.Although lipid droplet lipolysis and lipophagy were enhanced and catabolism was significant,the lipid droplet metabolism was in a state of imbalance between synthesis and catabolism,and the synthesis of lipid droplets was greater than that of catabolism,which led to the aggregation of hepatocellular lipids.

The prediction of compound-protein interaction (CPI) is a critical technological tool for discovering lead compounds and drug repurposing during the process of drug development.In recent years, deep learning has been widely used in CPI research, which has accelerated the development of CPI prediction in drug discovery.This review focuses on feature-based CPI prediction models.First, we described the datasets, as well as typical feature representation methods commonly used for compounds and proteins in CPI prediction.Based on the critical problems in modeling, we discussed models for CPI prediction from two perspectives: multimodal features and attention mechanisms.Then, the performance of 12 selected models was evaluated on 3 benchmark datasets for both classification and regression tasks.Finally, the review summarizes the existing challenges in this field and prospects for future directions.We believe that this investigation will provide some reference and insight for further research on CPI prediction.