A PARP1-related prognostic signature constructing and PARP-1 inhibitors screening for glioma.

The current standard treatments of glioma include surgical resection, supplemented with radiotherapy and chemotherapy, but the prognosis is poor. PARP-1 (Poly ADP-ribose polymerase 1) is a hot spot for cancer-targeted therapy and was reported to be significantly elevated in glioma. In this study, we analyzed the role of PARP-1 in DNA damage repair, constructed a PARP1-related DNA-repair prognostic signature (DPS), and screened targeted drugs for glioma. RNA-seq data of 639 glioma samples were downloaded from the GEO (Gene Expression Omnibus) database and divided into PARP1_H and PARP1_L according to the front and rear thirds of the expression level of PARP-1. First, we systematically analyzed the influence of PARP-1 on DNA damage repair, prognosis, and chemoradiotherapy sensitization of glioma. All glioma patients and patients with radiotherapy or chemotherapy had a better prognosis in PARP1_L than in PARP1_H. Next, differentially expressed DNA-repair related genes (DEGs) were identified between PARP1_H and PARP1_L by LASSO (Least Absolute Shrinkage and Selection Operator) Cox analysis and applied for constructing DPS. Based on the four-gene DPS, we then developed a new nomogram to assess overall survival in glioma patients. Additionally, PARP-1 was proved an effective target for glioma therapy. So, a series of computer-aided techniques, including Discovery Studio 4.5, Schrodinger, and PyMol, were applied for the virtual screening of favorable PARP-1 inhibitors. In conclusion, this study investigated the effect of PARP-1 on glioma prognosis and the sensitization effect of radiotherapy and chemotherapy, established a novel nomogram to evaluate the overall survival of glioma patients, and further explored targeted therapy for glioma.

Computational research of Belnacasan and new Caspase-1 inhibitor on cerebral ischemia reperfusion injury.

Cerebral ischemia-reperfusion injury is one of the most severe diseases in terms of mortality and disability, which seriously threatens human life and health. In clinical treatment, drug thrombolysis or mechanical interventional thrombolysis are used to quickly restore the blood supply of ischemic brain tissue. But with the rapid recovery of blood flow, complex pathophysiological processes such as oxidative stress and inflammation will further aggravate brain tissue damage, namely cerebral ischemia-reperfusion injury, for which there is no effective treatment. Recent studies have shown that the medical community has paid the role of inflammation and pyroptosis in cerebral ischemia-reperfusion injury more and more attention. And Caspase-1 was found to play a vital role in regulating inflammation pathways and pyroptosis in many inflammation-associated diseases, especially in cerebral ischemia-reperfusion injury. Not only that, Caspase-1 inhibitors have been shown to reduce the damage of cerebral ischemia-reperfusion injury by inhibiting inflammation and pyroptosis. And the Caspase-1 inhibitor, Belnacasan, has been proved to modify the active site of Caspase-1 and lead to the blocking of Caspase-1, thus correlating with tissue protection of inflammatory diseases in animal models. Therefore, it's essential to screen and design potential Caspase-1 inhibitors to reduce cerebral ischemia-reperfusion injury and protect brain function by reducing inflammation and pyroptosis, which provides a new idea for clinical treatment of the cerebral ischemia-reperfusion injury. This study applied a group of computer-aided technology, such as Discovery Studio 4.5, Schrodinger, and PyMol, to screen and assess potential Caspase-1 inhibitors. Moreover, the ADME (absorption, distribution, metabolism, excretion) and TOPKAT (Toxicity Prediction by Computer Assisted Technology) molecules of Discovery Studio 4.5 were conducted to evaluate molecules' pharmacological and toxicological features. Then, precise molecular docking was applied to assess the binding mechanism and affinity between Caspase-1 and selected compounds. Besides, molecular dynamics simulations were performed to determine the stability of ligand-receptor complexes in the natural environment. In summary, this study lists promising drug candidates and their pharmacological properties, promoting the development of Caspase-1 inhibitors and deepening the understanding of the interaction between inhibitors and Caspase-1.

Computational research of mTORC1 inhibitor on cerebral ischemia-reperfusion injury.

Ischemic stroke contributes to more than 80% of all strokes and has the four characteristics of high prevalence, high disability, high mortality, and high recurrence. Stroke is a preventable and controllable disease. In addition to controlling the primary disease, effective prevention and control measures need to be given to the occurrence and development of stroke. With the development and progress of modern treatment methods for ischemic stroke, the mortality and disability rate have decreased significantly. At present, the main treatment methods for ischemic stroke include thrombolysis, thrombus removal at the ultra-early stage, and treatment of improving collateral circulation in the acute phase. However, the ultra-early and early blood reperfusion involves reperfusion injury, which will cause secondary nerve damage, which is called cerebral ischemia/reperfusion injury (CIRI). Studies have found that autophagy is involved in the entire process of CIRI and can reduce the damage of CIRI. The mammalian target of Rapamycin (mTORC1) is the primary signal pathway regulating autophagy. And the mTORC1 inhibitor, Rapamycin, has been proved to exert neuroprotective effects in the ultra-early and early cerebral ischemia-reperfusion. Therefore, screening and designing mTORC1 inhibitors is very important to control reperfusion injury and reduce neuronal death and apoptosis. In this research, plenty of computer-assisted was applied to virtually screen and select potential mTORC1's inhibitors. We used Libdock to screen the structure and performed toxicity predictions, ADME (absorption, distribution, metabolism, excretion) to predict small molecules' pharmacological and toxicological properties. To assess the binding mechanism and affinity between the mTORC1 dimer and the ligand, molecular docking was performed. Then, the pharmacophore of small molecules in the docking conformation with the protein was supplemented by Schrodinger. Additionally, molecular dynamics simulations were conducted to assess if the ligand-receptor complex was stable in a natural environment. Furthermore, an experiment was performed to verify the inhibitory effect of compound 1 and compound 2 on mTOR protein. All in all, the study provides a hand of candidate drugs as well as pharmacological properties, which can play an essential role in mTORC1 inhibitors.

Feasibility of microwave ablation of the vertebral growth plate for spine growth regulation: a preliminary study.

PURPOSE: To explore the feasibility of microwave ablation (MWA) of the vertebral growth plate as a minimally invasive treatment for early-onset scoliosis. MATERIALS AND METHODS: One side of the L1-L3 vertebral growth plates were ablated using different MWA powers. Ablation safety and size were examined. Subsequently, L1-L3 vertebral growth plates were ablated on one side for 40 s at 20 W. At 2, 4, and 6 weeks after the ablation, growth changes of the spine were observed. RESULTS: No piglets died during and after ablation, and all had modified Tarlov Grade 5. The safe MWA time (time for safely ablating the vertebral growth plate) was 17.0 ± 1.5 s at 50 W, 23.0 ± 2.3 s at 40 W, 31.0 ± 3.1 s at 30 W, 47.0 ± 3.7 s at 20 W, 70.0 ± 4.2 s at 15 W, and 158.0 ± 5.0 s at 10 W. With power <15 W, the vertebral growth plate could not be effectively ablated within the safe ablation time. Within the safe ablation times, the MWA size on hematoxylin and eosin slices on a transverse diameter was between 7 and 10 mm; and that on longitudinal diameter was mainly determined by the ablation needle length. Moreover, the growth plate and annulus fibrosus on the ablated side grew poorly over time, the vertebral body showed significant wedge-shaped changes, and the spine showed significant unbalanced growth. CONCLUSION: MWA of the vertebral growth plate can be performed safely when accompanied with appropriate thermometry, and could be a new minimally invasive strategy in regulating spine growth.

Computational study on new natural compound agonists of dopamine receptor.

Dopamine receptor, a polypeptide chain composed of 7 hydrophobic transmembrane regions, is a new and vital drug target, especially Dopamine receptor 2(D2). Targeting dopamine receptors, Dopamine receptor agonists are a class of drugs similar in function and structure to dopamine and can directly act on dopamine receptors and activate it. Clinically, Dopamine receptor agonist drugs have achieved significant therapeutic effects on prolactinoma and Parkinson's Disease. In the study, we virtually screened a series of potential effective agonists of Dopamine receptor by computer techniques. Firstly, we used the Molecular Docking (LibDock) step to screen out some molecules that can dock well with the protein. Then, analysis of toxicity prediction and ADME (adsorption, distribution, metabolism and excretion) were carried out. More precise molecular docking (CDOCKER) and 3-Dimensional Quantitative Structure-Activity Relationship Modeling Study(3D-QSAR) pharmacophore generation were implemented to research and explore these compounds' binding mechanism with Dopamine receptor. Last but not least, to assess compound's binding stabilities, we carried out a molecular dynamic analysis. As the results show, two compounds (ZINC000008860530 and ZINC000004096987) from the small molecule database (ZINC database) were potential effective agonists of Dopamine receptor. These two compounds can combine with Dopamine receptor with higher affinity and proved to be no toxic. The cell experiment showed that two compounds could inhibit the proliferation and PRL secretion of MMQ cells (pituitary tumor cells). Thus, this study provided valuable information about Dopamine receptor agonist-based drug discovery. So, this study will benefit patients with prolactinoma and Parkinson's disease a lot.

Effect of Spinal Shortening for Protection of Spinal Cord Function in Canines with Spinal Cord Angulation.

BACKGROUND Posterior vertebral column resection (PVCR) has been widely used as a treatment for severe spinal deformity. By using the canine model of vertebral column resection, this study explored the effect of spinal shortening on blood flow and function of the spinal cord during spinal cord angulation. MATERIAL AND METHODS The canine model of L1 vertebral column resection was constructed with the PVCR technique. The canines were divided into 5 groups according to the degree of shortening: the 0/4 group, the 1/4 group, the 2/4 group, the 3/4 group, and the control group. Spinal cord blood flow, neuroelectrophysiology, HE staining, nitric oxide, and endothelin-1 were measured during the procedure of vertebral column resection and spinal cord angulation. RESULTS The results showed that, in the 1/4 group and the 2/4 group, the blood flow of the spinal cord decreased by 16.5% and 10.6%, respectively, with no obvious damage in the spinal cord; in the 0/4 group and the 3/4 group, the blood flow decreased by 23.5% and 23.1%, respectively, with significant damage in the spinal cord. CONCLUSIONS When the spinal cord is shortened by 1/4 to 2/4, the tolerance of the spinal cord can increase and spinal cord injury resulting from angulation can be avoided. However, when the shortening reaches 3/4, it is harmful to the spinal cord. Proper shortening of the spinal cord by 1/4 to 2/4 may increase the tolerance of the spinal cord to the damage caused by angulation during PVCR.