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.

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 ischemiareperfusion 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.

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 agonistbased drug discovery. So, this study will benefit patients with prolactinoma and Parkinson's disease a lot.

Methylmalonic acidemia is a severe heterogeneous disorder of methylmalonate and cobalamin (Cbl; vitamin B12) metabolism with poor prognosis. Around 90% of reported patients with methylmalonic acidemia (MMA) are severe infantile early onset, while cases with late-onset MMA have been rarely reported. Few reported late-onset MMA patients presented with atypical clinical symptoms, therefore, often misdiagnosed if without family history. Herein, we report a 29-year-old female who was admitted to our hospital due to symptoms manifested as encephalitis. The brain MRI showed symmetrical bilateral cerebellar lesions with Gd enhancement. Laboratory tests showed significantly elevated levels of homocysteine and methylmalonic acid. A genetic analysis identified a novel homozygous mutation (c.484G>A; p.Gly162 Arg) in the MMACHC gene. The patient was diagnosed with MMA, and her symptoms improved dramatically with intramuscular adenosine cobalamin treatment. In conclusion, for patients with symmetrical lesions in the brain, the possibility of metabolic diseases should be considered, detailed medical and family history should be collected, and metabolic screening tests as well as gene tests are necessary for correct diagnosis. The mutation diversity in MMACHC gene is an important factor leading to the heterogeneity of clinical manifestations of patients with MMA.

As the most common intracranial malignancy in adults, glioblastoma (GBM) has limited improvement in prognosis with traditional treatment methods, such as surgery, chemotherapy, and radiotherapy. Currently, immunotherapy has revolutionized treatment outcomes for many cancers. However, special immunosuppressive microenvironment of GBM results in patients’ resistance to immunotherapy and poor prognosis. The mucosa-associated lymphoid tissue translocation gene 1 (MALT1) was reported to be involved in NF-κB activation and promote cancer cell’s proliferation and migration. And inhibition of MALT1 could attenuate the mesenchymal phenotype of GBM. Therefore, uncovering the role of MALT1 in the immunosuppressive microenvironment of GBM is of great importance. In this study, RNA-seq data of 169 GBM patients were downloaded from TCGA (The Cancer Genome Atlas) database and divided into MALT1_H (MALT1_High) and MALT1_L (MALT1_Low) groups based on MALT1’s expression level. First, the enrichment levels of the 29-immune signature were quantified in every GBM patient of MALT1_H and MALT1_L. Next, DEIGs (differentially expressed immune genes) were identified and used to establish an IPS (immune prognostic signature) by the LASSO (Least Absolute Shrinkage and Selection Operator) Cox regression analysis. PDYN was first found to be associated with GBM prognosis and was identified as a potential target of GBM. Based on three-gene IPS, we developed a predictive nomogram model to assess the prognosis of GBM patients. Additionally, MALT1 were proved to be a potential ideal therapeutic target for GBM. So, series of computer-aided technology were applied to screen favorable inhibitors of MALT1. In summary, we explored role of MALT1 in the suppressive immune microenvironment of GBM, established a novel MALT1-related nomogram model for prognostic prediction, and developed the targeted therapy for GBM in this study.