Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

Objective To develop an endothelialized microfluidic chip model that simulates the spatial architecture and bioactivity of retinal vasculature,enabling thrombosis modeling and thrombolytic efficacy validation.Methods A tri-level microvascular network chip(300/200/100 μm diameters)with bifurcated architecture was fabricated using soft lithography.Human retinal microvascular endothelial cells(HRMECs)were perfused into channels,with endothelial coverage monitored via phase-contrast microscopy and F-actin staining.Cellular bioactivity was assessed using mitochondrial membrane potential probes(5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide,JC-1)and nitric oxide(NO)quantification.Fresh blood samples from 10 healthy donors(Yongchuan Hospital Affiliated to Chongqing Medical University,March to June 2024)were perfused with digital injection pump to mimic blood flow in human body into 3 experimental groups:normal whole blood,and TNF-α-activated endothelium+normal blood,TNF-α-activated endothelium+TNF-α-treated blood.Three inlet blood flow rates of 37.8、11.1 and 3.5 μL/min were set in each group.Two experimental groups,normal saline and recombinant human tissue-type plasminogen activator(rtPA),were established using the endothelialized microfluidic thrombosis model to validate thrombolytic efficacy.Endothelial functional impacts were assessed through integrated DAPI/NO staining and thrombosis model analysis across 3 intervention phases:pre-thrombosis,post-thrombosis,and post-thrombolysis.Results A tri-level microfluidic vascular model(300/200/100 μm diameters)was successfully constructed.In 72 h after endothelial cell perfusion,complete channel coverage was achieved,with phase-contrast microscopy and F-actin staining confirming confluent cellular alignment.JC-1/NO assays validated preserved endothelial bioactivity.Compared with the whole blood group,both TNF-α-activated endothelium+normal blood and TNF-α-activated endothelium+TNF-α-treated blood groups exhibited significantly increased thrombus occupancy rates at identical flow rates(all P<0.001).Notably,TNF-α-activated endothelium+TNF-α-treated blood group demonstrated the highest thrombus ratio at 3.5 μL/min(P<0.001).The rtPA group showed superior thrombolytic efficacy versus saline(P<0.001).Endothelial monolayer integrity was maintained across intervention phases,with thrombosis triggering significant NO elevation(P<0.001).Conclusion Our retinal vasculature-mimetic microfluidic model enables precise thrombosis modeling and drug evaluation,providing new methodology for studying retinal vascular occlusive diseases.

Objective To study the effect of Salidroside(Sal)on platelet activation and aggregation and the interaction between human platelets and MDA-MB-468 cells of breast cancer.Methods Human platelets were collected,platelet sus-pension was prepared,and platelets were treated with different concentrations of Sal.The effects of Sal on platelet activation and aggregation were detected by thromboelastogram(TEG)and flow cytometry.Breast cancer MDA-MB-468 cells were cul-tured in vitro,and human platelets were treated with different concentrations of Sal,and then activated by thrombin.The effects of Sal on the interaction between platelets and MDA-MB-468 cells were analyzed by adhesion test and scratch test.Re-sults TEG detection:The ADP inhibition rate in the blank control group was(10.97±12.69)%,and the ADP inhibition rate in all Sal intervention groups was higher than that in the blank control group(P＜0.05).The AA inhibition rate was(8.11±7.84)%in the control group and(25.96±15.18)%in the 5 μmol/L Sal intervention group,and the difference was statistically significant(P＜0.05).Flow cytometry:The expression of CD62P on platelet surface in 40 and 60 μmol/L Sal groups was(56.5±0.17)%and(65.50±0.36)%,respectively,and the difference was statistically significant compared with the positive control group(76.53±0.49)%(P＜0.05).The percentages of PAC-1 expression on platelet surface in 40 and 60 μmol/L Sal groups were(62.20±0.10)%and(58.47±0.15)%,and the difference was statistically significant com-pared with the positive control group(72.10±0.20)%(P＜0.05).Adhesion experiment:Platelets can have adhesion with MDA-MB-468 cells,and activated platelets have stronger adhesion ability.The adhesion rate in the Sal group was signifi-cantly lower than that in the positive control group,and was negatively correlated with the concentration of Sal.Scratch test:The cell mobility at 24 h in the positive control group was(12.71±0.70)%,and the cell mobility in each Sal treatment group was(4.51±0.44)%,(3.85±0.11)%,(5.37±0.36)%,(4.15±0.13)%and(3.55±0.38)%,respectively,showing significant decrease compared with the positive control group(P＜0.05).After 48 h of Sal treatment,the cell mobility of 10,20,40 and 60μmol/L Sal groups decreased,and there was a statistical difference compared with the positive control group(P＜0.05).Conclusion Sal can inhibit the adhesion between activated platelets mediated by thrombin and MDA-MB-468 cells and the migration of MDA-MB-468 cells.

As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified

Objective: To analyze the clinical features of dyslipidemia in patients with primary biliary cholangitis (PBC). Methods: The clinical and laboratory data of 136 PBC patients in Peking Union Medical College Hospital from 2010 to 2016 were retrospectively analyzed.The liver function was compared between patients with normal and abnormal blood lipids. Results: Among 136 PBC patients, 100(74%)had abnormal serum lipids. The incidence of increased cholesterol, low-density lipoprotein and triglyceride was 61%(59/96), 58%(48/83) and 47%(46/97), respectively; while that of reduced HDL-C was 26%(21/82). The incidences of pruritus [26%(26/100) vs. 8%(3/36), χ²=4.93, P=0.032], serum total bilirubin (TBIL) [17.3(12.2, 28.2) μmol/L vs. 14.5 (9.4, 21.1) μmol/L, Z=2.25, P=0.024], direct bilirubin (DBIL)[5. 5 (3.4, 12.4) μmol/L vs. 4.4(2.9, 7.1) μmol/L, Z=2.00, P=0.045], and glutamyl aminotransferase (GGT)[193.0(64.3, 454.8)U/L vs. 105.5(53.5, 179.5)U/L, Z=2.02, P=0.043], alkaline phosphatase(ALP)[183(86, 351)U/L vs. 135(85, 188) U/L, Z=1.98, P=0.048] in PBC patients with dyslipidemia were significantly higher than thosein patients with normal serum lipids.Pearson regression analysis showed that in PBC patients with dyslipidemia, the ALT was positively corrected with TG and TC(r=0.248 and 0.272, P=0.015 and 0.008); ALB was positively correlated with LDL-C(r=0.335, P=0.002); DBIL was positively corrected with HDL-C(r=0.252, P=0.022); TC was positively correlated with ALP and GGT(r=0.313 and 0.346, P=0.002 and 0.001); GGT was positively correlated with LDL-C(r=0.251, P=0.022). Conslusion Increased TC and LDL-C were more common in PBC patients. PBC patients with dyslipidemia have more severe liver damage than the patients with normal serum lipids.

Objective To investigate the health related quality of life score [primary biliary cholangitis (PBC)-40] in patients with PBC,and the relationship between PBC-40 and clinical presentations.Methods The PBC-40 score and clinical presentations in PBC patients (n=65) were adapted in this study.Patients were divided into the untreated group and the treated group,and the treated group was further divided into ursodesoxycholic acid (UDCA) response group and UDCA non-response group.PBC-40 scores of different groups were analyzed by t-test and the relationship between PBC-40 and clinical presentations were analyzed with Pearson's test.Results Dimensions of PBC-40 scores of this group of patients were as follows:symptoms were (15.8±4.1) points,itch was (4.9±2.8) points,atigue was (23.8±8.9) points,cognitive dysfunction score was (11.4±4.7) points,social activity score was (17.0±7.5) points,and the emotion score was (6.5±3.1) points.The untreated group had higher emotion scores than the treated group (t=2.024,P=0.045).Compared with the UDCA response group,UDCA non-response group had higher scores in cognitive,social and emotion dimension (t =2.126,2.309,2.062,respectively,P=0.039,0.025,0.045,respectively).Itch score was significantly correlated with total bilirubin (TBil),direct bilirubin (DBil),alkaline phosphatase (ALP) and total bile acid (TBA) (r=0.349,0.345,0.324,0.427,respectively,P＜0.01),while the social scores were correlated with TBil,DBil,aspartate aminotransferase (AST) and TBA (r=0.361,0.383,0.316,0.331,P＜0.01) and emotion scores were associated with ALT,TBil,GGT,ALP,AST and TBA (r=0.332,0.430,0.265,0.326,0.297,0.353,P＜0.05).ConclusionPBC-40 can be used as a health-related quality of life assessment for PBC patients inChinese population.Itch,social and emotion dimensions are correlated with clinical activity indicators.Hyperbilirubin,ALP and TBA can predict low health quality of life in PBC patients.Conclusion PBC-40 can be used as a health-related quality of life assessment for PBC patients in Chinese population.Itch,social and emotion dimensions are correlated with clinical activity indicators.Hyperbilirubin,ALP and TBA can predict low health related quality of life in PBC patients.

OBJECTIVETo investigate the influence of background color on veneered In-Ceram and Cercon dental ceramics including Vita In-Ceram Electroformed Alumina (AL2), Electroformed Zirconia (Z21), Cercon base color Zirconia and Cercon base Zirconia.

METHODSThe colorimetric values of all the materials on noble metal, Ni-Cr alloy, silver amalgam and resin background were measured with a spectrocolorimeter, and the color difference among the groups was calculated.

RESULTSAfter veneered, the color difference of Z21 Electroformed Zirconia was more distinct against the background of silver amalgam than against the backgrounds of noble metal and resin, but the color differences of the 4 veneered dental ceramics against different backgrounds were unidentifiable by human eyes (δE<1.5).

CONCLUSIONAfter veneered, AL2 electroformed alumina, Z21 electroformed zirconia, Cercon base Zirconia and Cercon base color Zirconia are less influenced by the background color, and covering the background color is therefore not necessary.