Targeting the PDK/PDH axis to reverse metabolic abnormalities by structure-based virtual screening with in vitro and in vivo experiments.

In humans and animals, the pyruvate dehydrogenase kinase (PDK) family proteins (PDKs 1-4) are excessively activated in metabolic disorders such as obesity, diabetes, and cancer, inhibiting the activity of pyruvate dehydrogenase (PDH) which plays a crucial role in energy and fatty acid metabolism and impairing its function. Intervention and regulation of PDH activity have become important research approaches for the treatment of various metabolic disorders. In this study, a small molecule (g25) targeting PDKs and activating PDH, was identified through multi-level computational screening methods. In vivo and in vitro experiments have shown that g25 activated the activity of PDH and reduced plasma lactate and triglyceride level. Besides, g25 significantly decreased hepatic fat deposition in a diet-induced obesity mouse model. Furthermore, g25 enhanced the tumor-inhibiting activity of cisplatin when used in combination. Molecular dynamics simulations and in vitro kinase assay also revealed the specificity of g25 towards PDK2. Overall, these findings emphasize the importance of targeting the PDK/PDH axis to regulate PDH enzyme activity in the treatment of metabolic disorders, providing directions for future related research. This study provides a possible lead compound for the PDK/PDH axis related diseases and offers insights into the regulatory mechanisms of this pathway in diseases.

ToxMPNN: A deep learning model for small molecule toxicity prediction.

Machine learning (ML) has shown a great promise in predicting toxicity of small molecules. However, the availability of data for such predictions is often limited. Because of the unsatisfactory performance of models trained on a single toxicity endpoint, we collected toxic small molecules with multiple toxicity endpoints from previous study. The dataset comprises 27 toxic endpoints categorized into seven toxicity classes, namely, carcinogenicity and mutagenicity, acute oral toxicity, respiratory toxicity, irritation and corrosion, cardiotoxicity, CYP450, and endocrine disruption. In addition, a binary classification Common-Toxicity task was added based on the aforementioned dataset. To improve the performance of the models, we added marketed drugs as negative samples. This study presents a toxicity predictive model, ToxMPNN, based on the message passing neural network (MPNN) architecture, aiming to predict the toxicity of small molecules. The results demonstrate that ToxMPNN outperforms other models in capturing toxic features within the molecular structure, resulting in more precise predictions with the ROC_AUC testing score of 0.886 for the Toxicity_drug dataset. Furthermore, it was observed that adding marketed drugs as negative samples not only improves the predictive performance of the binary classification Common-Toxicity task but also enhances the stability of the model prediction. It shows that the graph-based deep learning (DL) algorithms in this study can be used as a trustworthy and effective tool to assess small molecule toxicity in the development of new drugs.

The diagnostic value of prostate cancer between holmium laser enucleation of the prostate and transurethral resection of the prostate for benign prostatic hyperplasia: A retrospective comparative study.

BACKGROUND: To compare the diagnostic value of prostate cancer (PCa) between holmium laser enucleation of the prostate (HoLEP) and transurethral resection of the prostate (TURP). METHODS: We retrospectively analyzed the clinical data of 2909 patients who underwent surgery for benign prostatic hyperplasia (BPH) from January 2008 to June 2018. A total of 1362 patients received HoLEP, and 1547 patients received TURP. The baseline patient characteristics were collected. We then compared the perioperative outcomes of these patients who diagnosed with incidentally diagnosed prostatic carcinoma (IDPC) or PCa after BPH surgeries. RESULTS: The total detection rate of PCa in HoLEP group was higher than that in TURP group (85/6.24% vs. 61/3.94%, p = 0.005). Specifically, 55(4.6%) patients were diagnosed with IDPC in HoLEP group with prostate-specific antigen (PSA) less than 4 ng/ml, and 37(2.7%) patients in TURP group (p = 0.014). For the patients with PSA between 4 and 10 ng/ml, 15(13.9%) patients were diagnosed with PCa after HoLEP, and 6(5.0%) patients after TURP (p = 0.023). But the detection rate of PCa was not significantly different between the two groups when PSA was over 10 ng/ml. On the other hand, 57 in 1215 patients with no prostate biopsy preoperatively were diagnosed with PCa after HoLEP, while 42 in 1370 patients after TURP (4.7% vs. 3.1%, p = 0.040), respectively. Twenty-six patients received once biopsy and diagnosed with PCa in HoLEP group, while 15 patients in TURP group (18.4% vs. 8.9%, p = 0.018), respectively. However, no significant difference was observed for patients who received twice prostate biopsy in the two groups. CONCLUSIONS: The present study showed that HoLEP can provide a higher total detection rate of PCa when compared with TURP. Besides, this superiority was especially embodied in patients with PSA less than 10 ng/ml.

Comparison of Diode Laser (980 nm) Enucleation vs Holmium Laser Enucleation of the Prostate for the Treatment of Benign Prostatic Hyperplasia: A Randomized Controlled Trial with 12-Month Follow-Up.

Objective: To compare the clinical efficacy and safety between diode laser (980 nm) enucleation of the prostate (DiLEP) and holmium laser enucleation of the prostate (HoLEP) for treating benign prostatic hyperplasia (BPH). Patients and Methods: One hundred twenty-six BPH patients in our hospital from December 2016 to December 2017 were enrolled in this study. They were randomized to the DiLEP group or HoLEP group, which were administrated with DiLEP and HoLEP treatment, respectively. The patient's characteristics, such as age, body mass index, comorbidities, prostate volume, and prostate-specific antigen, were recorded before surgery. The perioperative outcomes and complications were also compared. The maximum flow rate (Qmax), postvoid residual (PVR), international prostate symptom score (IPSS), and quality-of-life (QoL) score were assessed at baseline and 3, 6, and 12 months postoperatively. Results: No significant differences were observed for the patient's baseline characteristics between both groups. For the perioperative outcomes, including operative time, resected tissue weight, catheter duration, and hospital stay, no significant difference was found between the two groups. However, the DiLEP group showed less blood loss and decrease in hemoglobin compared with the HoLEP group. The incidence of early or late complications was similar for both groups. The Qmax, PVR, IPSS, and QoL for both groups of patients were dramatically improved after surgery. By comparing the Qmax, PVR, IPSS, and QoL between the two groups, no significant differences were detected in the 3-, 6-, or 12-month follow-up. Conclusions: This study demonstrated that both DiLEP and HoLEP are efficient and safe treatments for BPH patients. DiLEP showed less blood loss and decrease in hemoglobin than HoLEP, which indicated that the diode laser (980 nm) generates a better hemostasis effect.

Occurrence of nitrosamines and their precursors in drinking water systems around mainland China.

N-Nitrosamines (NAs) in drinking water have attracted considerable attention in recent years due to their high carcinogenicity, frequent occurrence, and their potential regulation. During the past three years, we have collected about 164 water samples of finished water, tap water, and source water from 23 provinces, 44 cities from large cities to small towns, and 155 sampling points all over China. The occurrence of NAs in the finished and tap water was much higher in China than that in the U.S. Nine NAs were measured and NDMA had the highest concentration. The occurrence of NDMA was in 33% of the finished waters of water treatment plants and in 41% of the tap waters. The average NDMA concentration in finished and tap waters was 11 and 13 ng/L, respectively. Formation potentials (FPs) of source waters were examined with an average NDMA FP of 66 ng/L. Large variations in NA occurrence were observed geographically in China and temporally in different seasons. The Yangtze River Delta area, one sub-area in East China, had the highest concentrations of NAs, where the average NDMA concentrations in the finished and tap water were 27 and 28.5 ng/L, respectively, and the average NDMA FP in the source water was 204 ng/L. NA control may be achieved by applying breakpoint free chlorination and/or advanced treatment of ozone - granular activated carbon process to remove the NA precursors before disinfection.