Identification of PLK1-PBD Inhibitors from the Library of Marine Natural Products: 3D QSAR Pharmacophore, ADMET, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study.

PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create new inhibitors for the PLK1-PBD by focusing on the PBD binding domain, which has the potential for greater selectivity. A 3D QSAR model was developed using a dataset of 112 compounds to evaluate 500 molecules. ADMET prediction was then used to select three molecules with strong drug-like characteristics. Scaffold hopping was employed to reconstruct 98 new compounds with improved drug-like properties and increased activity. Molecular docking was used to compare the efficient compound abbapolin, confirming the high-activity status of [(14S)-14-hydroxy-14-(pyridin-2-yl)tetradecyl]ammonium,[(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium. Molecular dynamics simulations and MMPBSA were conducted to evaluate the stability of the compounds in the presence of proteins. An in-depth analysis of [(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium identified them as potential candidates for PLK1 inhibitors.

In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries.

USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of "1, 2-dibromobenzene" was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein-ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates.

In silico analysis of small molecule compounds based on pharmacophore- and backbone-leaping peroxiredoxin 1 (PRDX1) inhibitors.

Abnormal expression of PRDX has been found to play a significant role in the growth of colorectal cancer and other types of tumors. Despite the identification of several PRDX1 inhibitory compounds in recent years, none of them have been utilized in clinical treatments. Therefore, we conducted a virtual screening of 210,331 small molecules from the SPECS library using PRDX1 and multiple methods. From this screening, we identified 13 compounds with the highest scores from the molecular docking analysis. To further validate the accuracy of our pharmacophore model, we constructed a structure-based pharmacophore model and analyzed the receiver operating characteristic curve (ROC curve). Through this process, we selected nine compounds using skeleton jumping and virtual screening based on the highest pharmacophore model scores. Subsequently, we examined the ADMET properties of these nine compounds to assess their drug-forming potential, resulting in three compounds with the best drug properties. Finally, we assessed the binding stability of these three candidate molecules to proteins using molecular dynamics and MM-PBSA calculations. After a comprehensive evaluation, we found that compounds 6 and 9 formed stable complexes with PRDX1 proteins and could potentially serve as competitive inhibitors of PRDX1 substrates.Communicated by Ramaswamy H. Sarma.

Cucurbitacin B targets STAT3 to induce ferroptosis in non-small cell lung cancer.

Cucurbitacin B (CuB) is a compound found in plants like Cucurbitaceae that has shown promise in fighting cancer, particularly in lung cancer. However, the specific impact of CuB on ferroptosis and how it works in lung cancer cells has not been fully understood. Our research has discovered that CuB can effectively slow down the growth of non-small cell lung cancer (NSCLC) cells. Even in small amounts, it was able to inhibit the growth of various NSCLC cell lines. This inhibitory effect was reversed when ferroptosis inhibitors DFO, Lip-1 and Fer-1 were introduced. CuB was found to increase the levels of reactive oxygen species (ROS), lipid ROS, MDA, and ferrous ions within H358 lung cancer cells, leading to a decrease in GSH, mitochondrial membrane potential (MMP) and changes in ferroptosis-related proteins in a dose-dependent manner. These findings were also confirmed in A549 lung cancer cells. In A549 cells, different concentrations of CuB induced the accumulation of intracellular lipid ROS, ferrous ions and changes in ferroptosis-related indicators in a concentration-dependent manner. Meanwhile, the cytotoxic effect induced by CuB in A549 cells was counteracted by ferroptosis inhibitors DFO and Fer-1. Through network pharmacology, we identified potential targets related to ferroptosis in NSCLC cells treated with CuB, with STAT3 targets showing high scores. Further experiments using molecular docking and cell thermal shift assay (CETSA) revealed that CuB interacts with the STAT3 protein. Western blot and immunofluorescence staining demonstrated that CuB inhibits the phosphorylation of STAT3 (P-STAT3) in H358 cells. Silencing STAT3 enhanced CuB-induced accumulation of lipid ROS and iron ions, as well as the expression of ferroptosis-related proteins. On the other hand, overexpression of STAT3 reversed the effects of CuB-induced ferroptosis. The results indicate that CuB has the capability to suppress STAT3 activation, resulting in ferroptosis, and could be a promising treatment choice for NSCLC.

In silico analysis of marine natural product for protein arginine methyltransferase 5(PRMT5) inhibitors based on pharmacophore and molecular docking.

Over the past few decades, various inhibitors of PRMT5 have been developed because of its involvement in a variety of tumor development processes. As of now, no drugs targeting PRMT5 have been approved, and multiple drugs entering clinical trials have proven to have side effects. In this study, PRMT5 was used to perform virtual screening of 52119 marine natural compounds by combining various methods. We constructed 20 pharmacophore models based on multiple ligands. The best pharmacophore model AARR_2 was selected by analyzing the statistical parameters of the pharmacophore model and the binding characteristics of the ligand active site, and then 3552 compounds were screened out. Compared with the positive compound, 46 compounds were selected based on the molecular docking fraction and docking mode analysis. Then, 3D-QSAR was used to analyze the relationship between structure and activity of the compounds. Then, in addition to marine compounds 36404, 36405 and 14436, we selected compound 46 (the positive control compound) and used the CLC-Pred online Web server to predict their cytotoxicity to human cell lines, making cell experiments possible. Finally, we conducted the prediction of ADMET in order to better promote clinical trials. After comprehensive judgment, we screened out the marine natural compounds 36404 and 36405 as candidates for PRMT5 substrate competitive inhibitors.Communicated by Ramaswamy H. Sarma.

Cardiovascular Autonomic Assessment in Guillain-Barré Syndrome: A Longitudinal Study.

Background: Severe dysautonomia is typically seen during acute phase of Guillain-Barré syndrome (GBS). Objective: To investigate the relationship of cardiovascular autonomic dysfunction with motor recovery in GBS. Materials and Methods: Consecutive GBS patients presented to our hospital were recruited. Clinical assessment was evaluated with the Medical Research Council (MRC) sum score and GBS disability score (GDS). All patients had series of autonomic testing on admission and after treatment at 6 and 24 weeks. Both computation-dependent tests (heart rate variability [HRV] and baroreflex sensitivity [BRS]) and autonomic maneuvers were performed. Age- and gender-matched healthy controls (HC) were recruited. The data obtained at admission, 6 weeks and 24 weeks were compared within groups for statistical difference. Results: Six patients (4 men; mean age 39.5 ± 14.3 years) were recruited over one year. Five had GBS and one Miller Fisher syndrome. The mean MRC sum score and GDS on admission were 52.3 ± 4.3 and 3.5 ± 0.8 respectively. During admission, time-domain average RR interval (AVNN) and BRS were significantly poorer among cases compared to HC. Active standing 30:15 ratio and cold pressor test at admission were also significantly abnormal when compared with HC. All the autonomic parameters had normalized by 6 weeks and these were significant for the high frequency-HRV, BRS, and active standing 30:15 ratio. For MRC and GDS, there were significant improvements in the scoring over a period of 24 weeks. Conclusions: Dysautonomia in GBS improved gradually and in keeping with motor and disability recovery.

Prolonged Exercise Test in Patients With History of Thyrotoxicosis.

PURPOSE: Thyrotoxic periodic paralysis is characterized by recurrent episodes of reversible, severe proximal muscle weakness associated with hypokalemia and hyperthyroidism. Prolonged exercise test is an easy, noninvasive method of demonstrating abnormal muscle membrane excitability in periodic paralyses. Although abnormal in thyrotoxic periodic paralysis patients, the effects thyroid hormone levels in non-thyrotoxic periodic paralysis thyrotoxicosis patients have not been well studied. The study aims to evaluate thyrotoxicosis patients (regardless of thyrotoxic periodic paralysis history) with prolonged exercise test and correlate it with their thyroid status. METHODS: This is a prospective, cross-sectional study of consecutive thyrotoxicosis patients seen at the endocrine clinic of a tertiary medical center. Thyroid status was determined biochemically before prolonged exercise test. Compound muscle action potential (CMAP) amplitudes postexercise were compared against pre-exercise amplitudes and recorded as percentage of mean baseline CMAP amplitude. Comparisons of time-dependent postexercise CMAP amplitudes and mean CMAP amplitude decrement were made between hyperthyroid and nonhyperthyroid groups. RESULTS: Seventy-four patients were recruited, 23 (31%) men, 30 (41%) Chinese, and the mean age was 48.5 ± 16.8 years. Of 74 patients, 32 (43%) were hyperthyroid and 42 (57%) were nonhyperthyroid viz. euthyroid and hypothyroid. Time-dependent CMAP amplitudes from 10 to 45 minutes after exercise were significantly lower in hyperthyroid patients compared with nonhyperthyroid patients (P < 0.01). Mean CMAP amplitude decrement postexercise was significantly greater in hyperthyroid than nonhyperthyroid patients (23.4% ± 11.4% vs. 17.3% ± 10.5%; P = 0.02). CONCLUSIONS: Compound muscle action potential amplitude declines on prolonged exercise test were significantly greater in hyperthyroid patients compared with nonhyperthyroid patients. Muscle membrane excitability is highly influenced by thyroid hormone level. Thyrotoxic periodic paralysis occurs from increased levels of thyroid hormone activity in susceptible patients.

Exploring the Temporal Correlation of Sarcopenia with Bone Mineral Density and the Effects of Osteoblast-Derived Exosomes on Myoblasts through an Oxidative Stress-Related Gene.

Sarcopenia is an age-related accelerated loss of muscle strength and mass. Bone and muscle are closely related as they are physically adjacent, and bone can influence muscle. However, the temporal association between bone mineral density (BMD) and muscle mass in different regions of the body after adjustment for potential indicators and the mechanisms by which bone influences muscle in sarcopenia remain unclear. Therefore, this study aimed to explore the temporal association between muscle mass and BMD in different regions of the body and mechanisms by which bone regulates muscle in sarcopenia. Here, cross-lagged models were utilized to analyze the temporal association between BMD and muscle mass. We found that low-density lipoprotein (LDL-C) positively predicted appendicular lean mass. Mean whole-body BMD (WBTOT BMD), lumbar spine BMD (LS BMD), and pelvic BMD (PELV BMD) temporally and positively predicted appendicular lean mass, and appendicular lean mass temporally and positively predicted WBTOT BMD, LS BMD, and PELV BMD. Moreover, this study revealed that primary mice femur osteoblasts, but not primary mice skull osteoblasts, induced differentiation of C2C12 myoblasts through exosomes. Furthermore, the level of long noncoding RNA (lncRNA) taurine upregulated 1 (TUG1) was decreased, and the level of lncRNA differentiation antagonizing nonprotein coding RNA (DANCR) was increased in skull osteoblast-derived exosomes, the opposite of femur osteoblast-secreted exosomes. In addition, lncRNA TUG1 enhanced and lncRNA DANCR suppressed the differentiation of myoblasts through regulating the transcription of oxidative stress-related myogenin (Myog) gene by modifying the binding of myogenic factor 5 (Myf5) to the Myog gene promoter via affecting the nuclear translocation of Myf5. The results of the present study may provide novel diagnostic biomarkers and therapeutic targets for sarcopenia.

Spraying sorbitol-chelated calcium affected foliar calcium absorption and promoted the yield of peanut (Arachis hypogaea L.).

The prevalent use of foliar calcium fertilizers in peanut production is inorganic, but calcium absorbed from the foliar has poor availability. Sorbitol-chelated calcium is a novel organic foliar calcium fertilizer that has rarely been studied for application in peanut production. To explore whether calcium absorption and peanut yields can be affected by foliar application of sorbitol-chelated calcium, this study conducted two field experiments using Virginia peanut (Huayu-22) in 2020 and 2021. The five spray treatments included: deionized water (CK), sorbitol (Sor), calcium nitrate (CaN), a mixture of sorbitol and calcium nitrate (SN), and sorbitol-chelated calcium (SC). The yield of peanuts treated with sorbitol-chelated calcium was increased by 12.31-16.63%, 10.22-11.83%, 6.31-9.69%, and 4.18-6.99% compared to the CK, Sor, CaN, and SN treatments, respectively. Sorbitol-chelated calcium had the lowest contact angle due to the wetting effect of sorbitol, which promoted calcium absorption by leaves. Sorbitol-chelated calcium improved the leaf calcium concentration by 13.12-19.32% and kernel calcium concentration by 6.49-8.15% compared to the CK treatment. Foliar fertilization increased the calcium concentration of each subcellular fraction of leaves and changed the distribution of calcium in mesophyll cells. This change was directly observed by transmission electron microscopy. Additionally, spraying sorbitol alone obtained similar effects to spraying calcium nitrate alone, indicating that the benefits of sorbitol itself were not negligible. The results of the principal component and correlation analysis showed that the increase in calcium concentrations and the change in calcium distribution improved the pod traits of the peanut, thus affecting the peanut yield. The above results showed that from the perspective of calcium absorption and distribution, sorbitol-chelated calcium is a more effective foliar calcium fortifier for peanuts and effectively improves peanut yields.

Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway.

As a newly approved oral hypoglycaemic agent, the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, which is derived from the natural product phlorizin can effectively reduce blood glucose. Recent clinical studies have found that dapagliflozin alleviates non-alcoholic fatty liver disease (NAFLD), but the specific mechanism remains to be explored. This study aimed to investigate the underlying mechanism of dapagliflozin in alleviating hepatocyte steatosis in vitro and in vivo. We fed the spontaneous type 2 diabetes mellitus rats with high-fat diets and cultured human normal liver LO2 cells and human hepatocellular carcinoma HepG2 cells with palmitic acid (PA) to induce hepatocellular steatosis. Dapagliflozin attenuated hepatic lipid accumulation both in vitro and in vivo. In Zucker diabetic fatty (ZDF) rats, dapagliflozin reduced hepatic lipid accumulation via promoting phosphorylation of acetyl-CoA carboxylase 1 (ACC1), and upregulating lipid ß-oxidation enzyme acyl-CoA oxidase 1 (ACOX1). Furthermore, dapagliflozin increased the expression of the autophagy-related markers LC3B and Beclin1, in parallel with a drop in p62 level. Similar effects were observed in PA-stimulated LO2 cells and HepG2 cells. Dapagliflozin treatment could also significantly activated AMPK and reduced the phosphorylation of mTOR in ZDF rats and PA-stimulated LO2 cells and HepG2 cells. We demonstrated that dapagliflozin ameliorates hepatic steatosis by decreasing lipogenic enzyme, while inducing fatty acid oxidation enzyme and autophagy, which could be associated with AMPK activation. Moreover, our results indicate that dapagliflozin induces autophagy via the AMPK-mTOR pathway. These findings reveal a novel clinical application and functional mechanism of dapagliflozin in the treatment of NAFLD.

Application of ultrasound on monitoring the evolution of the collagen fiber reinforced nHAC/CS composites in vivo.

To date, fiber reinforce scaffolds have been largely applied to repair hard and soft tissues. Meanwhile, monitoring the scaffolds for long periods in vivo is recognized as a crucial issue before its wide use. As a consequence, there is a growing need for noninvasive and convenient methods to analyze the implantation remolding process in situ and in real time. In this paper, diagnostic medical ultrasound was used to monitor the in vivo bone formation and degradation process of the novel mineralized collagen fiber reinforced composite which is synthesized by chitosan (CS), nanohydroxyapatite (nHA), and collagen fiber (Col). To observe the impact of cells on bone remodeling process, the scaffolds were planted into the back of the SD rats with and without rat bone mesenchymal stem cells (rBMSCs). Systematic data of scaffolds in vivo was extracted from ultrasound images. Significant consistency between the data from the ultrasound and DXA could be observed (P < 0.05). This indicated that ultrasound may serve as a feasible alternative for noninvasive monitoring the evolution of scaffolds in situ during cell growth.