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 evaluate the clinical efficacy and safety of stereotactic surgery in patients with refractory mental disorders.Methods:A retrospective analysis was performed; clinical data, postoperative complications and medication intake of 149 patients with refractory mental disorders accepted stereotactic surgery in Department of Neurosurgery, People's Hospital, Wuhan University from August 2019 to December 2023 were collected. Outcomes were assessed at 1, 6, 12, and 24 months after surgery by Clinical Global Impression-Global Improvement (CGI-GI). Before and 1, 6, and 12 months after surgery, severities were assessed by Clinical Global Impression-Severity of Illness (CGI-SI); cognition was assessed by Montreal Cognitive Assessment (MoCA); positive and negative symptoms were evaluated by Positive and Negative Symptom Scale (PANSS); psychotic symptoms were evaluated by Brief Psychiatric Rating Scale (BPRS) and Symptom Checklist 90 (SCL-90); obsessive-compulsive symptoms, depressive symptoms, anxiety symptoms and manic symptoms were assessed by Yale-Brown Obsessive-Compulsive Symptoms Scale (Y-BOCS), Beck Depression Inventory (BDI)-II, Beck Anxiety Inventory (BAI), and Young Mania Rating Scale (YMRS), respectively; social functioning and quality of survival were evaluated by Social Disability Screening Schedule (SDSS) and World Health Organization Quality of Life-Bref Form (WHOQOL-BREF).Results:(1) Increased sleep was noted in 47 patients and fatigue in 38 patients within 1 week after surgery. Behavioral laziness and emotional apathy were still presented at 1 month after surgery in 6 patients, and complications disappeared in the rest patients. Mildly reduced initiative was presented at 12 months after surgery in 5 patients. (2) CGI-GI indicated that 149 patients were followed up 1 month after surgery with an overall efficiency of 85.90%; 135 patients were followed up at 6 months after surgery with an overall efficiency of 83.21%, 106 patients were followed up at 12 months after surgery with an overall efficiency of 79.24%, and 63 patients were followed up at 24 months after surgery with an overall efficiency of 80.95%. (3) Compared with those before surgery, significantly lower BPRS scores, significantly lower PANSS positive, negative, and overall scores, statistically lower BAI, BDI-II, YMRS, and MOAS scores, significantly lower Y-BOCS obsessional thinking, compulsive behavior and total scores, significantly higher WHOQOL-BREF (physical and psychological domains) scores, and significantly lower SDSS and SCL-90 scores were noted in patients at 1, 6, and 12 months after surgery ( P<0.05). (4) At 12 months after surgery, withdrawal drug was noted in 13 patients, reduced drug in 38, same dose in 52, and increased drug in 2 patients. Conclusion:Stereotactic surgery can obviously improve obsession, anxiety, depression, mania and aggression, and modify social functioning and quality of survival in patients with refractory mental disorders, enjoying good safety.

Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

OBJECTIVE: To observe the therapeutic effect of electroacupuncture at acupoints of liver meridian in patients with diminished ovarian reserve (DOR) of liver depression. METHODS: A total of 62 patients with DOR of liver depression were randomly divided into an electroacupuncture group (31 cases, 1 case discontinued) and a western medication group (31 cases, 1 case was eliminated). Electroacupuncture was applied at bilateral Taichong (LR 3), Ligou (LR 5), Ququan (LR 8), Jimai (LR 12) in the electroacupuncture group, with continuous wave, in frequency of 2 Hz and current of 0.5-1.0 mA, 30 min each time, once every other day, 3 times a week. Femoston was taken orally in the western medication group, oral estradiol tablets were taken for the first 14 days, followed by oral estradiol/progesterone complex tablets for the rest 14 days, 1 tablet a day. Both groups were treated for 3 consecutive menstrual cycles. Before and after treatment, the scores of TCM syndrome, self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were observed, serum levels of follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) were detected, and antral follicle count (AFC), peak systolic velocity (PSV) and resistance index (RI) of ovarian artery were measured by color Doppler ultrasound in the two groups, and the clinical efficacy was evaluated after treatment. RESULTS: After treatment, the scores of primary symptom and secondary symptom, as well as the total scores of TCM syndrome were decreased compared with those before treatment (P<0.01), the scores of SAS and SDS, as well as the serum FSH levels and RI of ovarian artery were decreased compared with those before treatment (P<0.01), while the serum AMH levels, AFC and PSV of ovarian artery were increased compared with those before treatment (P<0.05, P<0.01) in the two groups. After treatment, in the electroacupuncture group, the primary symptom score of TCM syndrome was higher than that in the western medication group (P<0.01), the secondary symptom score of TCM syndrome and the scores of SAS and SDS were lower than those in the western medication group (P<0.05, P<0.01). The total effective rate was 70.0% (21/30) in the electroacupuncture group and 73.3% (22/30) in the western medication group respectively, there was no significant difference in the total effective rate between the two groups (P>0.05). CONCLUSION Electroacupuncture at acupoints of liver meridian can effectively improve the clinical symptoms, anxiety and depression, regulate the serum sex hormone levels, increase AFC and improve ovarian blood supply in DOR patients of liver depression.
Humans ; Female ; Electroacupuncture ; Adult ; Acupuncture Points ; Meridians ; Ovarian Reserve ; Young Adult ; Liver Diseases/physiopathology* ; Liver/metabolism* ; Ovary/physiopathology* ; Treatment Outcome ; Depression/therapy*

ObjectivePneumonia is an infectious inflammation of the alveoli， distal airway， and interstitium caused by bacterial， viral， and other pathogens. Maxing Shigantang， originated from Treatise On Cold Damage Diseases， is a classic prescription for treating pneumonia， with significant clinical efficacy. However， its treatment mechanism is still elusive. MethodIn that paper， the transcriptome-based multi-scale network pharmacology was used to reveal the overall pharmacological mechanism of Maxing Shigantang in treating pneumonia from six scales of tissue， cell， pathological process， biological process， signaling pathway， and target. ResultAt the tissue level， Maxing Shigantang mainly acted on the focal tissue of pneumonia-lung and the main inflammatory immune tissues-blood and spleen. Analysis of cell， pathological process and biological process suggested that Maxing Shigantang could treat pneumonia by reversing inflammatory and immune functions and improving cardiopulmonary and vascular injury caused by pneumonia. Analysis of signaling pathway and target showed that Maxing Shigantang regulated inflammatory immune response pathways such as "coronavirus disease-COVID-19" and "Toll-like receptor signaling pathway"， and related targets such as "MAPKAPK3" and "NRG1". ConclusionThis paper， from molecular to tissue levels， indicated Maxing Shigantang treated pneumonia mainly by regulating inflammatory immune response and improving cardiopulmonary and vascular injury.

Objective:To explore the effect of mind mapping teaching of gastroenterology in the standardized training for general practitioners, and provide new ideas for general practice education.Methods:A total of 65 physicians who were enrolled in the standardized training of general practice from January to December 2017 were collected as the control group, and the traditional teaching method was adopted; another 58 physicians from January to December 2018 were selected as the experimental group, and the mind mapping was adopted based on the traditional teaching method. The learning effect (theoretical and operational results) and the satisfaction questionnaire of trainees and teachers were used as evaluation indicators. SPSS 21.0 was used for t test and chi-square test. Results:The theory exam and clinical skills examination results of experimental group (80.80±5.30, 82.66±5.90) were significantly higher than those of the control group (71.60±5.20, 75.72±4.57), and the difference was statistically significant ( P<0.05). Compared with the control group, the experimental group had better understanding of knowledge points of this discipline, clinical thinking ability, higher learning interest, teamwork ability, innovation ability and teacher satisfaction, with statistical significance ( P<0.05). Conclusion:The mind mapping has more advantages than traditional teaching methods in the standardized training for general practitioners, which can be further extended.

A significant proportion of patients with chorea-acanthocytosis (ChAc) fail to respond to standard therapies. Recent evidence suggests that globus pallidus internus (GPi) deep brain stimulation (DBS) is a promising treatment option; however, reports are few and limited by sample sizes. We conducted a systematic literature review to evaluate the clinical outcome of GPi-DBS for ChAc. PubMed, Embase, and Cochrane Library databases were searched for relevant articles published before August 2021. The improvement of multiple motor and nonmotor symptoms was qualitatively presented. Improvements in the Unified Huntington’s Disease Rating Scale motor score (UHDRS-MS) were also analyzed during different follow-up periods. A multivariate linear regression analysis was conducted to identify potential predictors of clinical outcomes. Twenty articles, including 27 patients, were eligible. Ninety-six percent of patients with oromandibular dystonia reported significant improvement. GPi-DBS significantly improved the UHDRS-motor score at < 6 months (p < 0.001) and ≥ 6 months (p < 0.001). The UHDRS-motor score improvement rate was over 25% in 75% (15/20 cases) of patients at long-term follow-up (≥ 6 months). The multiple linear regression analysis showed that sex, age at onset, course of disease, and preoperative movement score had no linear relationship with motor improvement at long-term follow-up (p > 0.05). GPi-DBS is an effective and safe treatment in most patients with ChAc, but no reliable predictor of efficacy has been found. Oromandibular dystonia-dominant patients might be the best candidates for GPi-DBS.

Buruli ulcer (BU), caused by

Objective To analyze the factors affecting the prognosis of esophageal cancer and construct a reasonable prognostic model. Methods A total of 672 patients diagnosed with esophageal cancer in 2010 were selected as the study data. The factors affecting the specific survival rate of esophageal cancer were screened and modeled by LASSO COX regression analysis. The prediction was performed by R 3.5.3 software. The model was visually constructed and the value of the predictive model was analyzed. Results The 1, 3, and 5 years tumor-specific survival rates of 672 patients with esophageal cancer were 55.32% (95% CI: 51.56% to 59.08%), 30.07% (95% CI: 26.58% to 33.56%), and 25.04% (95% CI: 21.75% to 28.33%), respectively. LASSO regression analysis screened for 11 variables most relevant to prognosis, i.e., chemotherapy, primary site, tumor grade, T stage, N stage, M stage, radiotherapy sequence, surgery, tumor size, age, and ethnicity. Univariate and multivariate COX regression analyses showed that tumor grade, N stage, M stage, surgery and tumor size were independent risk factors for the prognosis of esophageal cancer. By visualizing the prognostic analysis, a Nomogram was constructed, and the consistency index C-index was 0.726 (95% CI: 0.703-0.749), which was significantly better than that of the 7th edition of AJCC's TNM staging system (C-index=0.654, 95% CI: 0.628-0.680). There was also good agreement between the predicted survival rates of the 1, 3 and 5 year calibration curves of this prognostic model and the actual survival rate. At the same time, the ROC curve results showed that if the patient's total score was greater than 15.570, the sensitivity and specificity were the best, the patient could be judged as a high-risk group. And the Nomogram prognostic model constructed in this paper had AUC=0.831, 95% CI: 0.801-0.859, and the prediction ability was significantly better than that of the traditional AJCC 7 version TNM staging system (AUC=0.759, 95% CI: 0.725-0.791). At the same time, a formula for predicting tumor-specific survival rate was constructed: CSS=5.988×10-5×points3+(-1.740×10-3)×points2+(-2.004×10-2)×points+0.685. Conclusion This study used LASSO regression to screen the variables that affected the prognosis of esophageal cancer and visually constructed relevant independent risk factors. It has high clinical value and is of great significance for the screening of high-risk population and the formulation of subsequent personalized diagnosis and treatment plans.

Objective: To investigate the nutritional status of children with autism spectrum disorders, and to provide a reference for improving their nutritional status. Methods: 120 children with autism spectrum disorder who were treated in the rehabilitation center of Affiliated Children s Hospital of Zhengzhou University from September 2016 to September 2018 were selected as case group,and 120 normal children in the physical examination center of the same hospital were selected as the healthy group.The children s status was assessed by using the Clancy Autism Behavior Scale(CABS), and the serum nutrients levels were compared between these two groups. Results: Compared with the healthy group,the Vitamin A[(83.44±9.20,59.45±4.42)mg/L],Vitamin B6[(64.15±11.22,32.02±5.75)mg/L],Vitamin C[(60.62±10.26,47.63±13.12)mg/L],protein[(120.45±30.51,104.46±9.38)g/L], iron[(134.25±18.16,112.17±6.02)mg/L], calcium[(72.96±10.62,66.57±4.11)mg/L], zinc[(70.85±5.76,62.52±10.66)mg/L] and folic acid[(31.38±6.77,20.29±6.26)mg/L], eicosapentaenoic acid(EPA)[(0.72±0.22,0.55±0.14)μmol/L], decosahexaenoic acid(DHA)[(1.54±0.35,1.22±0.26)μmol/L] and arachidonic acid(AA)[(5.51±0.76,5.03±0.16)μmol/L] were lower(t=25.75，27.92，8.54，5.49，12.64，6.30，7.53，13.18，7.14，8.04，6.77，P<0.05), the low body weight(49.17%,63.33%) and wasting(38.33%,46.67%) in autism spectrum disorder group were higher significantly(χ2=4.89，6.71，P<0.05). Conclusion The nutritional status of children with autism spectrum disorder is different from that of normal children. The lack of serum nutrients will lead to a high incidence of malnutrition.