Liver diseases cannot be easily detected in the early stage， and although invasive diagnostic methods， such as liver biopsy， are relatively accurate， they tend to have a low degree of acceptance， which greatly limits the improvement in diagnosis and treatment techniques for liver diseases. Therefore， it is of great importance to search for new biomarkers and therapeutic targets. As an emerging biomarker for liquid biopsy， tRNA-derived small RNA （tsRNA） is abnormally expressed in various liver diseases including viral hepatitis， fatty liver disease， liver injury， and liver cancer， and it can affect the development and progression of liver diseases by regulating the biological functions such as gene expression， epigenetic regulation， and protein translation. This article reviews the origin， classification， and biological function of tsRNA， as well as the research advances in tsRNA as biomarkers and potential therapeutic targets for liver diseases， so as to provide ideas for the early diagnosis and treatment of liver diseases.

Objective To study the association between mean platelet volume(MPV),platelet distribution width(PDW)and procalcitonin(PCT)and cardiac function in patients with pulmonary hypertension(PH)and their diagnostic value on heart failure.Methods 103 patients with PH(PH group)in the 3rd People's Hospital of Chengdu from October 2021 to October 2022 and 103 healthy subjects with physical examination(control group)were selected as study subjects.Fasting peripheral venous blood was collected on the 1st day of admission and MPV,PDW and PCT were detected.The left ventricular ejection fraction(LVEF)was measured and the cardiac function was evaluated by New York Heart Association(NYHA)grading criteria.The patients with PH were divided into failure group and non-failure group according to the diagnosis results of heart failure.The relations of MPV,PDW and PCT with cardiac function in patients with PH and the diagnostic value on heart failure were analyzed.Results The levels of MPV,PDW,and PCT were all higher in the experimental group compared to the control group,while the LVEF was lower,and these differences were statistically significant(P<0.05);as the NYHA classification increased,the levels of MPV,PDW,and PCT showed an increasing trend,while LVEF showed a decreasing trend,and the differences between the groups were statistically significant(P<0.05);in the heart failure group n = 65,the levels of MPV,PDW,and PCT were higher compared to the non-heart failure group n = 38,while LVEF was lower,and these differences were statistically significant(P<0.05).The levels of MPV,PDW,and PCT werr signifi-cantly positively correlated with NYHA functional classification and LVEF(P<0.05).The levels of MPV,PDW,and PCT had good reference value for the diagnosis of heart failure in PH patients,with AUC values of 0.816,0.897,and 0.825 respectively,and the combined diagnostic AUC is 0.952,which wass statistically different from the application of the three indicators alone(P<0.05).Conclusion RDW,PDW and PCT are closely related to cardiac function in patients with PH,and can provide reference information for diagnosis and treatment of heart failure in patients with PH.

Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Objective:To investigate the efficacy of zicronapine on different animal models of schizophrenia and its affinity for dopamine D1 and D2 receptors in vitro.Methods:A total of 324 male SPF ICR mice, 72 male SPF Wistar rats, and 10 male and female each SPF SD rats were included in the study. (1) One hundred ICR mice were divided into 10 groups: Blank group (solvent+normal saline, Veh+NS), model group (Veh+APO 1 mg/kg), risperidone (0.03, 0.10, 0.30, 1.00 mg/kg, gavage)+APO group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+APO group; The effect of zicronapine on the climbing behavior of mice was observed. (2) Eighty-four ICR mice were divided into 10 groups: Blank group (Veh+NS), model group (Veh+MK-801 0.3 mg/kg), risperidone (0.01, 0.03, 0.10, 0.30 mg/kg, gavage)+MK-801 group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+MK-801 group; 8-10 rats were allocated in each group to observe the effect of zicronapine on MK-801-induced hyperactivity behavior in mice. (3) Seventy mice were divided into 7 groups: Blank group (Veh), risperidone 0.3, 1.0 and 3.0 mg/kg groups (gavage), and zicronapine15, 27 and 45 mg/kg groups (gavage), with 10 mice in each group. The maintaining immobilized time of rats was observed at 30 min, 60 min and 90 min after administration. (4) A total of 72 Wistar rats were selected for CAR training, and the successfully trained rats were divided into 7 groups: blank group, zicronapine20, 40 and 60 mg/kg groups, risperidone 0.2, 0.4 and 0.8 mg/kg groups, with 5 to 6 rats in each group. The effects of zicronapine on avoidance response times of rats were investigated. (5)Seventy ICR mice were divided into blank group (Veh+NS), model group (Veh+PCP) and risperidone 0.05 mg/kg+PCP group. The effects of zicronapine (0.5, 1.0, 2.0 mg/kg)+PCP groups on novel object recognition disorder in mice were investigated. (6) The affinity of zicronapine to D 1, D 2, 5-HT 2A, 5-HT 6 and 5-HT 2C was investigated by radiolig and receptor binding assay. One-way analysis of variance was used for measurement data, and non-parametric U test was used for count data. Results:(1) Compared with the model group, 3.0 and 10.0 mg/kg of zicronapine significantly inhibited APO-induced climbing behavior in mice ( Z=-3.43, -4.07; P<0.01), and its ED 50 was 4.31 mg/kg. Risperidone at doses of 0.10, 0.30 and 1.00 mg/kg significantly inhibited the climbing behavior of mice ( Z=-1.83, -2.48, -4.26; P<0.05 or P<0.01) and the ED 50 was 0.19 mg/kg. (2) Compared to the model group, zicronapine 3.0 and 10.0 mg/kg significantly inhibited MK-801-induced hyperactivity behavior in mice ( t=-7.18, 3.90; P<0.01), and the ED 50 was 2.63 mg/kg. Risperidone 0.01, 0.03, 0.10 and 0.30 mg/kg significantly inhibited hyperactivity behavior in mice ( t=-3.02, 4.98, -6.08, 7.10; all P<0.01), and the ED 50 was 0.011 mg/kg. (3) The ED 50 of zicronapine and risperidone were 35.36 mg/kg and 1.25 mg/kg, respectively. (4) Both zicronapine and risperidone could inhibit the number of avoidance responses in a dose-dependent manner. Zicronapine dose at 40 and 60 mg/kg significantly inhibited the number of conditioned avoidance responses in rats ( t=11.84, 13.07; P<0.01), and the ED 50 was 34.36 mg/kg. Risperidone of 0.8 mg/kg could significantly inhibit the number of conditioned avoidance responses in rats ( t=13.50, P<0.01), and the ED 50 was 0.60 mg/kg. (5) Compared to the model group, zicronapine 0.5 and 1.0 mg/kg could significantly improve the discrimination index of PCP-induced new object recognition disorder model mice ( t=-3.67, -2.12; P<0.05 and P<0.01) to improve cognitive ability. However, risperidone 0.05 mg/kg had no significant effect on the discrimination index of PCP-induced new object recognition disorder model mice. (6) Zilonapine had high affinity for D 1 (K i=3.21 nmol/L) and 5-HT 2A (K i=13.11 nmol/L) receptors, but weak affinity for D 2 (K i=563.20 nmol/L) receptors. In addition, chilonapine also had high affinity for 5-HT 6 (K i=21.49 nmol/L) and 5-HT 2C (K i=48.90 nmol/L). Risperidone had high affinity for 5-HT 2A , 5-HT 2C and D 2 receptors with K i of 2.37, 18.79 and 4.82 nmol/L, respectively. Risperidone had weak affinity for D 1 and 5-HT6 receptors. Conclusions:Zicronapine has good efficacy in multiple animal models with positive symptoms of schizophrenia and can improve the cognition of mice. Its in vivo efficacy may be related to dopamine D 1 and D 2 receptors and 5-HT 2A and 5-HT 6 receptors.

Objective:To investigate the efficacy of zicronapine on different animal models of schizophrenia and its affinity for dopamine D1 and D2 receptors in vitro.Methods:A total of 324 male SPF ICR mice, 72 male SPF Wistar rats, and 10 male and female each SPF SD rats were included in the study. (1) One hundred ICR mice were divided into 10 groups: Blank group (solvent+normal saline, Veh+NS), model group (Veh+APO 1 mg/kg), risperidone (0.03, 0.10, 0.30, 1.00 mg/kg, gavage)+APO group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+APO group; The effect of zicronapine on the climbing behavior of mice was observed. (2) Eighty-four ICR mice were divided into 10 groups: Blank group (Veh+NS), model group (Veh+MK-801 0.3 mg/kg), risperidone (0.01, 0.03, 0.10, 0.30 mg/kg, gavage)+MK-801 group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+MK-801 group; 8-10 rats were allocated in each group to observe the effect of zicronapine on MK-801-induced hyperactivity behavior in mice. (3) Seventy mice were divided into 7 groups: Blank group (Veh), risperidone 0.3, 1.0 and 3.0 mg/kg groups (gavage), and zicronapine15, 27 and 45 mg/kg groups (gavage), with 10 mice in each group. The maintaining immobilized time of rats was observed at 30 min, 60 min and 90 min after administration. (4) A total of 72 Wistar rats were selected for CAR training, and the successfully trained rats were divided into 7 groups: blank group, zicronapine20, 40 and 60 mg/kg groups, risperidone 0.2, 0.4 and 0.8 mg/kg groups, with 5 to 6 rats in each group. The effects of zicronapine on avoidance response times of rats were investigated. (5)Seventy ICR mice were divided into blank group (Veh+NS), model group (Veh+PCP) and risperidone 0.05 mg/kg+PCP group. The effects of zicronapine (0.5, 1.0, 2.0 mg/kg)+PCP groups on novel object recognition disorder in mice were investigated. (6) The affinity of zicronapine to D 1, D 2, 5-HT 2A, 5-HT 6 and 5-HT 2C was investigated by radiolig and receptor binding assay. One-way analysis of variance was used for measurement data, and non-parametric U test was used for count data. Results:(1) Compared with the model group, 3.0 and 10.0 mg/kg of zicronapine significantly inhibited APO-induced climbing behavior in mice ( Z=-3.43, -4.07; P<0.01), and its ED 50 was 4.31 mg/kg. Risperidone at doses of 0.10, 0.30 and 1.00 mg/kg significantly inhibited the climbing behavior of mice ( Z=-1.83, -2.48, -4.26; P<0.05 or P<0.01) and the ED 50 was 0.19 mg/kg. (2) Compared to the model group, zicronapine 3.0 and 10.0 mg/kg significantly inhibited MK-801-induced hyperactivity behavior in mice ( t=-7.18, 3.90; P<0.01), and the ED 50 was 2.63 mg/kg. Risperidone 0.01, 0.03, 0.10 and 0.30 mg/kg significantly inhibited hyperactivity behavior in mice ( t=-3.02, 4.98, -6.08, 7.10; all P<0.01), and the ED 50 was 0.011 mg/kg. (3) The ED 50 of zicronapine and risperidone were 35.36 mg/kg and 1.25 mg/kg, respectively. (4) Both zicronapine and risperidone could inhibit the number of avoidance responses in a dose-dependent manner. Zicronapine dose at 40 and 60 mg/kg significantly inhibited the number of conditioned avoidance responses in rats ( t=11.84, 13.07; P<0.01), and the ED 50 was 34.36 mg/kg. Risperidone of 0.8 mg/kg could significantly inhibit the number of conditioned avoidance responses in rats ( t=13.50, P<0.01), and the ED 50 was 0.60 mg/kg. (5) Compared to the model group, zicronapine 0.5 and 1.0 mg/kg could significantly improve the discrimination index of PCP-induced new object recognition disorder model mice ( t=-3.67, -2.12; P<0.05 and P<0.01) to improve cognitive ability. However, risperidone 0.05 mg/kg had no significant effect on the discrimination index of PCP-induced new object recognition disorder model mice. (6) Zilonapine had high affinity for D 1 (K i=3.21 nmol/L) and 5-HT 2A (K i=13.11 nmol/L) receptors, but weak affinity for D 2 (K i=563.20 nmol/L) receptors. In addition, chilonapine also had high affinity for 5-HT 6 (K i=21.49 nmol/L) and 5-HT 2C (K i=48.90 nmol/L). Risperidone had high affinity for 5-HT 2A , 5-HT 2C and D 2 receptors with K i of 2.37, 18.79 and 4.82 nmol/L, respectively. Risperidone had weak affinity for D 1 and 5-HT6 receptors. Conclusions:Zicronapine has good efficacy in multiple animal models with positive symptoms of schizophrenia and can improve the cognition of mice. Its in vivo efficacy may be related to dopamine D 1 and D 2 receptors and 5-HT 2A and 5-HT 6 receptors.