This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
Animals ; Male ; Mice ; Aquatic Organisms/chemistry* ; Biological Availability ; Cytochrome P-450 Enzyme System/metabolism* ; Glucuronosyltransferase/metabolism* ; Microsomes, Liver/metabolism* ; Molecular Structure ; Biological Products/pharmacokinetics* ; Pyridines/pharmacokinetics*

Objective To employ three dimensional high-resolution vessel wall magnetic resonance imaging(3D hr-VW-MRI)for analyzing the imaging characteristics of posterior circulation non-stenotic intracranial atherosclerotic plaque and to discuss its diagnostic value in identifying culprit plaques.Methods Ninety-three patients(age[62.94±9.70]years old,67 males,26 females)with non-stenotic atherosclerosis in our hospital from Jan.2019 to Jan.2021 were retrospectively recruited.The imaging features of plaques,including luminal area,maximum wall thickness and minimum wall thickness at the most stenotic site,stenosis rate,plaque burden,remodeling index,eccentricity index,enhancement ratio at the most stenotic site,and intraplaque hemorrhage,were measured based on T1-weighted imaging(T1WI)and contrast-enhanced T1WI.The culprit plaque was defined as a lesion arising from the responsible vascular supply area to a fresh infarction on the diffusion weighted imaging(DWI)and T2 fluid attenuated inversion recovery(T2-FLAIR)images with accompanying ischemic stroke/transient ischemic attack(TIA).A plaque was considered to be a nonculprit plaque when it occurred in patients with presumed ischemic stroke/TIA,but without an infarct on DWI and T2-FLAIR.Results Sixty-one culprit plaques and 32 non-culprit plaques were analyzed.The proportions of patients with hyperlipidemia,National Institutes of Health stroke scale(NIHSS)score,narrowest plaque enhancement rate,and incidence of intraplaque hemorrhage in the culprit plaque group were significantly higher than those in the non-culprit plaque group(all P＜0.05).Multivariate logistic regression analyses showed that NIHSS score(odds ratio[OR]=1.799,95％confidence interval[CI]1.303-2.484,P＜0.001),enhancement ratio(OR=1.076,95％CI 1.027-1.128,P=0.002)and intraplaque hemorrhage(OR=30.708,95％CI 2.563-367.925,P=0.007)were associated with plaque type.Conclusion NIHSS score,enhancement ratio at the most stenotic site,and intraplaque hemorrhage are independent risk factors for culprit plaques in patients with posterior circulation non-stenotic intracranial atherosclerotic disease.These indicators may help identify such culprit plaques and could be used to screen individuals with plaques having these characteristics,thereby providing a basis for early preventive interventions.

BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit. REGISTRATION No. CRD42023427480; https://www.crd.york.ac.uk/prospero/display_record.php?
Humans ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Dose-Response Relationship, Drug ; Randomized Controlled Trials as Topic

The aim of this experiment was to study the effects of different feeding modes on growth performance,blood biochemical indexes and intestinal flora of lactating Holstein male calves.Twenty-four newborn Holstein male calves with body mass of(40.00±1.01)kg and similar day old were selected and randomly divided into four groups of six calves each.The subgroups were low-milk group(LM),high-milk group(HM),high-milk milk replacer feeding group(HMR),and low-milk switching to high-milk milk replacer feeding group(CMR).The results showed that:At 45 d,the body mass of calves in the HM group was significantly higher than that of calves in the other groups(P＜0.05),and at 60 d,the body mass of calves in the HM group was significantly higher than that of calves in the LM &.CMR groups(P＜0.05).At 90 d,the body mass of calves in the LM group was significantly higher than that of calves in the HM group.Throughout the ex-perimental period,the average daily weight gain and average pellet feed intake of calves in the LM group were significantly higher than that of calves in the HM group(P＜0.05).The calf globulin level in the HMR group was significantly higher than that in the LM and HM groups(P＜0.05);the plasma immunoglobulin A level of calves in the HM group was significantly lower than that of calves in the LM and HMR groups(P＜0.05);and the plasma immunoglobulin M level of calves in the HM group was significantly higher than that of calves in the LM and CMR groups(P＜0.05),and HMR group was also significantly higher than that of LM group(P＜0.05);plasma glutathione peroxidase level of calves in HMR group was significantly higher than that of LM group(P＜0.05);plasma malondialdehyde level of calves in LM group was significantly higher than that of calves in HMR and HM groups(P＜0.05),and CMR group was also significantly higher than that of HM group(P＜0.05).Relative abundance of Thermodesulfovibrio was higher in the HM group(P＜0.05),relative abundance of Bacteroidetes in the LM group was significantly higher than that in the HMR and HM groups(P＜0.05),relative abundance of Blautia in the HM group(P＜0.05),and relative abundance of Corynebacterium in the CMR group was significantly higher than that in the LM and HM groups(P＜0.05).In summary,calves in the LM group had better weaning weights and pellet feed intake;calves in the CMR group could compensate for growth by supplemental feeding of milk replacer to obtain more optimal weaning weights and pel-let feed intake;the HMR group proved that milk-free feeding could ensure stable growth of calves;and calves in the HM group had a better pre-lactation growth performance,lower levels of oxida-tive stress,and a healthier fecal flora.

The aim of this experiment was to study the effects of different feeding modes on growth performance,blood biochemical indexes and intestinal flora of lactating Holstein male calves.Twenty-four newborn Holstein male calves with body mass of(40.00±1.01)kg and similar day old were selected and randomly divided into four groups of six calves each.The subgroups were low-milk group(LM),high-milk group(HM),high-milk milk replacer feeding group(HMR),and low-milk switching to high-milk milk replacer feeding group(CMR).The results showed that:At 45 d,the body mass of calves in the HM group was significantly higher than that of calves in the other groups(P＜0.05),and at 60 d,the body mass of calves in the HM group was significantly higher than that of calves in the LM &.CMR groups(P＜0.05).At 90 d,the body mass of calves in the LM group was significantly higher than that of calves in the HM group.Throughout the ex-perimental period,the average daily weight gain and average pellet feed intake of calves in the LM group were significantly higher than that of calves in the HM group(P＜0.05).The calf globulin level in the HMR group was significantly higher than that in the LM and HM groups(P＜0.05);the plasma immunoglobulin A level of calves in the HM group was significantly lower than that of calves in the LM and HMR groups(P＜0.05);and the plasma immunoglobulin M level of calves in the HM group was significantly higher than that of calves in the LM and CMR groups(P＜0.05),and HMR group was also significantly higher than that of LM group(P＜0.05);plasma glutathione peroxidase level of calves in HMR group was significantly higher than that of LM group(P＜0.05);plasma malondialdehyde level of calves in LM group was significantly higher than that of calves in HMR and HM groups(P＜0.05),and CMR group was also significantly higher than that of HM group(P＜0.05).Relative abundance of Thermodesulfovibrio was higher in the HM group(P＜0.05),relative abundance of Bacteroidetes in the LM group was significantly higher than that in the HMR and HM groups(P＜0.05),relative abundance of Blautia in the HM group(P＜0.05),and relative abundance of Corynebacterium in the CMR group was significantly higher than that in the LM and HM groups(P＜0.05).In summary,calves in the LM group had better weaning weights and pellet feed intake;calves in the CMR group could compensate for growth by supplemental feeding of milk replacer to obtain more optimal weaning weights and pel-let feed intake;the HMR group proved that milk-free feeding could ensure stable growth of calves;and calves in the HM group had a better pre-lactation growth performance,lower levels of oxida-tive stress,and a healthier fecal flora.

Objective To analyze the impact of different clinical and rehabilitation characteristics on the prognosis of diabetic foot amputees. Methods Related literatures were searched in CNKI,Wanfang Data,PubMed,Cochrane Library and Google Scholar from establishment to August,2024.The literatures were screened and extracted by two researchers independent-ly,the Newcastle-Ottawa Scale(NOS)and the evaluation criteria recommended by Agency for Healthcare Re-search and Quality(US)were used for quality evaluation,and literatures with above medium quality were includ-ed,and a systematic review was conducted. Results A total of 17 articles involving 9 239 subjects were included,in which three were Chinese,and 14 were English.The study designs were case-control study,cohort study and cross-sectional study.They mainly came from the fields of rehabilitation medicine,orthopedics,sports medicine and disability studies,and were published between 1998 to 2023.Clinical and rehabilitation characteristics related to the prognosis of diabetic foot amputees includ-ed amputation level,socioeconomic determinants(educational attainment,economic status,social participation,etc.),psychological states(anxiety,depression,etc.)and physiological factors(age,gender,pain,prosthetic limb usage,and ambulatory capacity,etc.).These different characteristics could affect the quality of life of diabetic foot amputees,and even lead to re-amputation or death. Conclusion Factors of amputation level,socioeconomic status,psychological status and physiological status are impor-tant for poor prognosis in diabetic foot amputees.Controlling the above factors can effectively reduce the re-am-putation rate and mortality,and improve the quality of life in diabetic foot amputees,thus improving their progno-sis,and promoting functional rehabilitation.

Objective:To investigate the onset time distribution and influential factors in patients with acute myocardial infarction (ACI) with different body mass index (BMI) levels.Methods:A cross-sectional study was conducted to collect clinical data from 1 000 patients with AMI who received treatment at Heilongjiang Provincial Hospital from January 2016 to November 2022. The patients were divided into groups based on different BMI levels: < 18.5 kg/m 2 group ( n = 49), 18.5-24 kg/m 2 group ( n = 369), > 24-28 kg/m 2 group ( n = 338), and > 28 kg/m 2 group ( n = 244). The incidence of AMI was analyzed among patients with different BMI levels as per diurnal variation, seasonality, and weekday. Results:A total of 1 000 patients were included in this study, including 648 men and 352 women. The mean age of these patients was 65 years (range 56-74 years). The median body mass was 70 kg (range 60-76 kg), the median height was 1.69 m (range 1.60-1.72 m), and the median BMI was 24.49 kg/m 2 (range 22.22-26.79 kg/m 2). The onset time of AMI differed significantly among patients with different BMI levels in terms of the period from 0:00 to 5:59, winter, and Wednesday ( P = 0.047, 0.029, 0.005). Among all samples, the number of patients with a BMI of 18.5-24 kg/m 2 was the highest, reaching 369 cases. Conclusion:The incidence of AMI in patients with different BMI levels exhibits a regular distribution as per diurnal variation, seasonality, and weekday.

Objective:To establish a prediction model of risk factors for early Q-T interval prolongation after acute myocardial infarction (AMI), which helps prevent and reduce the occurrence of acute malignant events.Methods:This is a case-control study. A total of 100 patients with Q-T interval prolongation after AMI who received treatment at Heilongjiang Provincial Hospital from January 2018 to December 2022 were included in this study. An additional 100 patients without Q-T interval prolongation after AMI who concurrently received treatment in the same hospital were also included in this study. Two model groups, including model group 1 (with Q-T interval prolongation, n = 50) and model group 2 (without Q-T interval prolongation, n = 50), and two test groups, including test group 1 (with Q-T interval prolongation, n = 50) and test group 2 (without Q-T interval prolongation, n = 50), were designated. Logistic regression analysis was performed to construct a prediction model of risk factors for Q-T interval prolongation. The area under the receiver operating characteristic curve was determined to evaluate the prediction model. The value of the prediction model was validated in the test groups. Results:Multivariate logistic regression showed that female gender ( OR = 2.307, 95% CI: 0.09-0.91, P = 0.041) and heart failure ( OR = 3.087, 95% CI: 1.15-8.27, P = 0.025) were independent risk factors for early Q-T interval prolongation after AMI. The area under the receiver operating characteristic curve of the prediction model was 0.770, with a sensitivity of 84.0%, a specificity of 66.0%, the Jordan index of 0.44, and the corresponding optimal critical value of 0.43. This indicates good fit of the model. Conclusion:Female gender and heart failure are independent risk factors for early Q-T interval prolongation after AMI. The model constructed based on the above-mentioned risk factors fits well and has a high predictive value, which helps reduce the occurrence of early Q-T interval prolongation after AMI.

The impact of various anterior cervical surgeries on biomechanical properties of cervical vertebrae varies depending on the specific surgical techniques employed.However,accurately measuring the mechanical characteristics of individual parts of the cervical vertebrae or implants within them in a clinical setting can be challenging.As a result,the finite element method is commonly utilized in studies on anterior cervical surgery,allowing for the precise analysis of stress and strain distributions in different areas of interest through computer simulations.This method facilitates the study of biomechanical properties associated with different anterior cervical surgical approaches.This review discusses the progress of finite element analysis in anterior cervical surgery,summarizes current research findings on fusion and non-fusion procedures,hybrid surgeries,and minimally invasive techniques,so as to provide theoretical references for the selection of different anterior cervical surgical interventions from a biomechanical perspective.

Objective To investigate whether recombinant Newcastle disease virus(rL-RVG)induces iron death in gastric cancer cells through Nrf2-GCLC-GPX4 pathway.Methods After human gastric cancer HGC-27 cells were treated with rL-RVG,Newcastle disease virus(NDV)and PBS solution(control group),respectively,cell proliferation,invasion and migration were detected by CCK-8 assay and Transwell invasion assay and cell scratch test.Ferroptosis accelerator(erastin),and nuclear factor E2 related factor 2(Nrf2)accelerator(TBHQ)and inhibitor(ML385)were added respectively as controls.The content of malondialdehyde(MDA)in each treatment group was detected by lipid oxidation kit.The content of reactive oxygen species(ROS)was detected by DCFH-DA fluorescent probe and flow cytometry.Western blotting and immunofluorescence assay were employed to measure the expression levels of Nrf2-GCLC-GPX4 pathway related proteins.Results Compared with the control group,the survival rate of HGC-27 cells were significantly decreased after rL-RVG and NDV treatment in a dose-and time-dependent manner,and the effect was more significant in the rL-RVG treatment group(P＜0.05).The migration and invasion abilities of HGC-27 cells were obviously inhibited in the NDV and rL-RVG treatment groups,and the latter had more notable inhibition than the former.The protein levels of Nrf2,GCLC,SLC7A11 and GPX4 were statistically decreased(P＜0.05),and the contents of MDA and ROS were increased(P＜0.05)in the virus treatment groups than the control group,with the increasing or decreasing trend more significant in the rL-RVG group than the NDV group.What's more,the protein levels of SLC7A11 and GPX4 were decreased in the erastin group(P＜0.05).Compared with the control group,those of Nrf2,GCLC,SLC7A11 and GPX4 were increased in the TBHQ group and decreased in the ML385 group(P＜0.05),while the contents of MDA and ROS were decreased and increased respectively in the above 2 groups(P＜0.05).Compared with the rL-RVG group,the rL-RVG+TBHQ group and rL-RVG+ML385 group had enhanced and reduced protein expressio of Nrf2,GCLC,SLC7A11 and GPX4,respectively(P＜0.05),while the contents of MDA and ROS were in opposite trends(P＜0.05).Conclusion rL-RVG can induce ferroptosis of gastric cancer cells through Nrf2-GCLC-GPX4 pathway,and then inhibit the growth of tumor cells.