Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

Objective:To investigate the clinical and imaging characteristics of cervical spine hyperextension injury plus multilevel disco-ligamentous complex (MDLC) injury and the therapeutic effectiveness of their treatment.Methods:A total of 456 patients with cervical hyperextension injury were hospitalized between January 2010 and October 2020 at Department of Orthopaedics, The 909th Hospital, Dongnan Hospital Affiliated to Xiamen University. A retrospective study was conducted to analyze the clinical data of the 43 patients among them who had been diagnosed with MDLC injury and undergone surgical treatment and been fully followed up. They were 37 males and 6 females with an age of (50.6±10.7) years. According to the American Spinal Injury Association (ASIA) grading, there were 1 case of grade A, 8 cases of grade B, 18 cases of grade C, and 16 cases of grade D. The Japanese Orthopaedic Association (JOA) score was (7.9±1.6) points. Anterior cervical decompression, fusion and internal fixation were conducted for 42 patients, and posterior total laminectomy and internal fixation for 1 patient. The clinical and imaging manifestations of the patients, and the consistency between preoperative and intraoperative diagnosis of disco-ligamentous complex (DLC) injury were analyzed. ASIA grading and JOA score were used to assess the outcomes of surgical treatment and comparisons were made between preoperation and postoperation.Results:DLC injury existed at 99 levels (43 cases), with a high incidence at level C 5-6 (30 cases), and high-signal manifestations of cervical cord injury existed at 48 levels, with a high incidence at level C 3-4 (16 cases). Two-segment DLC injury was the most common [74.4% (32/43)], while three-segment DLC injury existed in 9 cases and four-segment DLC injury in 2 cases. There were 21 cases of jumping MDLC injury and 22 cases of continuous MDLC injury. At preoperation, DLC injury was suspected in 10 patients (at 11 levels), of whom 8 (at 9 levels) were diagnosed intraoperatively with DLC injury, and 2 (at 2 levels) were excluded from the DLC injury. All the 43 patients were followed up for (54.7±10.7) months. By the ASIA grading at the last follow-up, 3 cases were grade C, 13 cases grade D, and 27 cases grade E. The JOA score at the last follow-up was (15.1±2.2) points. Both the 2 outcomes showed significant improvements compared with the preoperative values ( P<0.05). Conclusions:The clinical incidence of cervical hyperextension injury combined with MDLC injury is low, but relatively higher in the middle-aged and elderly patients. As the level of DLC injury is often inconsistent with the likely level of cervical spinal cord injury, surgical exploration of the DLC structure with suspected injury can reduce the rate of missed diagnosis and misdiagnosis.

OBJECTIVE: To explore the potential molecular mechanism of tetrahydropalmatine (THP) on acute myocardial ischemia (AMI). METHODS: First, the target genes of THP and AMI were collected from SymMap Database, Traditional Chinese Medicine Database and Analysis Platform, and Swiss Target Prediction, respectively. Then, the overlapping target genes between THP and AMI were evaluated for Grene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction network analysis. The binding affinity between the protein and THP was assessed by molecular docking. Finally, the protective effects of THP on AMI model and oxygen and glucose deprivation (OGD) model of H9C2 cardiomyocyte were explored and the expression levels of target genes were detected by RT-qPCR in vivo and in vitro. RESULTS: MMP9, PPARG, PTGS2, SLC6A4, ESR1, JAK2, GSK3B, NOS2 and AR were recognized as hub genes. The KEGG enrichment analysis results revealed that the potential target genes of THP were involved in the regulation of PPAR and hormone pathways. THP improved the cardiac function, as well as alleviated myocardial cell damage. Furthermore, THP significantly decreased the RNA expression levels of MMP9, PTGS2, SLC6A4, GSK3B and ESR1 (P<0.05, P<0.01) after AMI. In vitro, THP significantly increased H9C2 cardiomyocyte viability (P<0.05, P<0.01) and inhibited the RNA expression levels of PPARG, ESR1 and AR (P<0.05, P<0.01) in OGD model. CONCLUSIONS THP could improve cardiac function and alleviate myocardial injury in AMI. The underlying mechanism may be inhibition of inflammation, the improvement of energy metabolism and the regulation of hormones.
Humans ; Matrix Metalloproteinase 9 ; Network Pharmacology ; Cyclooxygenase 2 ; Molecular Docking Simulation ; PPAR gamma ; Myocardial Ischemia/genetics* ; Glucose ; RNA ; Drugs, Chinese Herbal/therapeutic use* ; Serotonin Plasma Membrane Transport Proteins

Bivalent platinum drugs [Pt(II)] represented by cisplatin are the first-line drugs in clinical application, but they have defects such as severe side-effects, poor bioavailability and drug resistance.Tetravalent platinum [Pt(IV)] complexes, derivatives of Pt(II) with different substitutions in axial positions, can be reduced to Pt(II) under the action of reductants in tumor, and can therefore act as a prodrug of Pt(II).Axial substituents can improve platinum drugs'' pharmacokinetics, selectivity and bioactivity, as well as achieve anti-tumor effect by additional cytotoxic mechanisms other than DNA damage, which can overcome the drug resistance to Pt(II).This review outlines the resistance mechanisms of platinum drugs, including platinum transport, detoxification, autophagy, and DNA repair, etc.It also summarizes the structure-activity relationship, main types and advances of tetravalent platinum prodrugs, as well as possible approach to solve platinum drug resistance.

Objective:To investigate the effects of titanium dioxide nanoparticles (TiO 2 NPs) on urine metabolites in occupationally exposure people based on metabolomics technology, and to explore the mechanism of early health effects of TiO 2 NPs on occupational exposure. Methods:In October 2019, the TiO 2 NPs occupational exposure population was selected as the research object, of which 64 people were in the exposure group who had been engaged in TiO 2 NPs exposure positions for more than 1 year; the control group was 62 people, who were logistics administrative staff of the same company. The urine of the research subjects before class was collected, using the ultra-high performance liquid chromatography time-of-flight mass spectrometer to collect the metabolism data of the urine, Progenesis QI software for data preprocessing and metabolite identification, SIMCA-P software for the principal component analysis of the data and potential biomarkers screening, MetaboAnalyst 4.0 software for metabolic pathway enrichment analysis. Results:The urine metabolism profile of workers in the exposure group was different from the control group, and 44 potential biomarkers were screened and identified. These potential biomarkers were significantly enriched in three pathways ( P<0.05) , namely D-arginine and D-ornithine metabolism pathway, nitrogen metabolism pathway and D-glutamine and D-glutamate metabolism pathways. Conclusion:The occupational exposure of TiO 2 NPs can affect the concentration of metabolites in people urine and metabolic pathways, which provides a direction for the study of occupational hazard mechanisms of TiO 2 NPs and the monitoring of health risks.

Nanoparticle is a kind of material with at least one dimension in Nanometer scale, which has unique physical and chemical properties and is widely used in the fields of food and engineering. Intestinal Flora is involved in the regulation of human circulation and metabolism. The disturbance of Intestinal Flora may cause inflammatory reaction and chronic metabolic diseases. Nano titanium dioxide, Nano silver, Nano zinc oxide, Nano carbon nanoparticles and other nanoparticles have been proven to have good antibacterial properties, and can affect the intestinal flora of experimental animals. In this paper, the effects and mechanisms of various nanoparticles on intestinal microflora are summarized, which is helpful to provide a new idea for the safety study of nanoparticles.

Objective:To investigate the effects of titanium dioxide nanoparticles (TiO 2 NPs) on urine metabolites in occupationally exposure people based on metabolomics technology, and to explore the mechanism of early health effects of TiO 2 NPs on occupational exposure. Methods:In October 2019, the TiO 2 NPs occupational exposure population was selected as the research object, of which 64 people were in the exposure group who had been engaged in TiO 2 NPs exposure positions for more than 1 year; the control group was 62 people, who were logistics administrative staff of the same company. The urine of the research subjects before class was collected, using the ultra-high performance liquid chromatography time-of-flight mass spectrometer to collect the metabolism data of the urine, Progenesis QI software for data preprocessing and metabolite identification, SIMCA-P software for the principal component analysis of the data and potential biomarkers screening, MetaboAnalyst 4.0 software for metabolic pathway enrichment analysis. Results:The urine metabolism profile of workers in the exposure group was different from the control group, and 44 potential biomarkers were screened and identified. These potential biomarkers were significantly enriched in three pathways ( P<0.05) , namely D-arginine and D-ornithine metabolism pathway, nitrogen metabolism pathway and D-glutamine and D-glutamate metabolism pathways. Conclusion:The occupational exposure of TiO 2 NPs can affect the concentration of metabolites in people urine and metabolic pathways, which provides a direction for the study of occupational hazard mechanisms of TiO 2 NPs and the monitoring of health risks.

Nanoparticle is a kind of material with at least one dimension in Nanometer scale, which has unique physical and chemical properties and is widely used in the fields of food and engineering. Intestinal Flora is involved in the regulation of human circulation and metabolism. The disturbance of Intestinal Flora may cause inflammatory reaction and chronic metabolic diseases. Nano titanium dioxide, Nano silver, Nano zinc oxide, Nano carbon nanoparticles and other nanoparticles have been proven to have good antibacterial properties, and can affect the intestinal flora of experimental animals. In this paper, the effects and mechanisms of various nanoparticles on intestinal microflora are summarized, which is helpful to provide a new idea for the safety study of nanoparticles.

OBJECTIVE: To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening. METHODS: The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper. RESULTS: It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score. CONCLUSIONS A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.
China ; Computer Simulation ; Coronavirus Infections ; diagnosis ; drug therapy ; Drug Repositioning ; methods ; Drugs, Chinese Herbal ; pharmacology ; Glycoproteins ; drug effects ; metabolism ; Humans ; Imaging, Three-Dimensional ; Mass Screening ; methods ; Molecular Docking Simulation ; methods ; Pandemics ; Peptidyl-Dipeptidase A ; drug effects ; Pneumonia, Viral ; diagnosis ; drug therapy ; Protein Binding ; United States ; United States Food and Drug Administration