ABSTRACT
Objective: Deep venous thrombosis (DVT) refers to a clot in a deep vein caused by various reasons. If such a clot becomes dislodged, it can return to the vein and lead to pulmonary embolism (PE), which can cause death in severe cases. Therefore, we aimed to evaluate the efficacy and safety of Safflower yellow combined with low molecular weight heparin (LMWH) for the prevention of DVT after orthopedic surgery. Methods: A comprehensive search of randomized controlled studies (RCTs) of Safflower yellow combined with LMWH for the prevention of DVT after orthopedic surgery was performed in PubMed, Embase, Cochrane Library, CNKI, VIP, and Wanfang databases from January 2000 to June 2021. Data were extracted for quality evaluation and meta-analysis was performed using RevMan 5.3 software. Results: A total of 8 RCTs including 624 patients were included. The combination treatment reduced the incidence of DVT compared with the control group; the combination treatment improved the activated partial thromboplastin time (APTT) and prothrombin time (PT). There was no statistically significant difference in the incidence of adverse effects. Conclusion: Safflower yellow combined with LMWH can reduce postoperative blood hypercoagulability and prevent DVT formation in lower extremities in orthopedic patients, and achieves better outcomes than LMWH alone in terms of postoperative bleeding tendency.
ABSTRACT
BACKGROUND: Spinal cord injury (SCI) is a life-threatening traumatic disorder. Paeonol has been confirmed to be involved in a variety of diseases. The purpose of this study is to investigate the role of paeonol on SCI progression. METHODS: Sprague Dawley (SD) rat was used for the establishment of SCI model to explore the anti-inflammation, anti-oxidation, and neuroprotective effects of paeonol (60 mg/kg) on SCI in vivo. For in vitro study, mouse primary microglial cells (BV-2) were induced by lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment. The effect of paeonol on the polarization of LPS/ATP-induced BV-2 cells was determined by detection the expression inducible nitric oxide synthase (iNOS), tumour necrosis factor alpha (TNF-α), arginase-1 (Arg-1), and interleukin (IL)-10 using qRT-PCR. ELISA was used to assess the levels of IL-1ß, IL-18, TNF-α, malondialdehyde (MDA), and glutathione (GSH). Western blotting was conducted to determine the levels of NLRP3 inflammasomes and TLR4/MyD88/NF-κB (p65) pathway proteins. RESULTS: Paeonol promoted the recovery of locomotion function and spinal cord structure, and decreased spinal cord water content in rats following SCI. Meanwhile, paeonol reduced the levels of apoptosis-associated speck-like protein (ASC), NLRP3, active caspase 1 and N-gasdermin D (N-GSDMD), repressed the contents of IL-1ß, IL-18, TNF-α and MDA, and elevated GSH level. In vitro, paeonol exerted similarly inhibiting effects on pyroptosis and inflammation. Meanwhile, paeonol promoted BV-2 cells M2 polarization. In addition, paeonol also inactivated the expression of TLR4/MyD88/NF-κB (p65) pathway. CONCLUSION: Paeonol may regulate NLRP3 inflammasomes and pyroptosis to alleviate SCI, pointing out the potential for treating SCI in clinic.
Subject(s)
Inflammasomes , Spinal Cord Injuries , Acetophenones , Adaptor Proteins, Signal Transducing/metabolism , Adenosine Triphosphate , Animals , Inflammasomes/metabolism , Inflammasomes/pharmacology , Interleukin-18/metabolism , Interleukin-18/pharmacology , Lipopolysaccharides/pharmacology , Mice , Myeloid Differentiation Factor 88/metabolism , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis/physiology , Rats , Rats, Sprague-Dawley , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Development of multi-target drugs is becoming increasingly attractive in the repertoire of protein kinase inhibitors discovery. In this study, we carried out molecular docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, principal component analysis (PCA), and dynamical cross-correlation matrices (DCCM) to dissect the molecular mechanism for the valmerin-19 acting as a dual inhibitor for glycogen synthase kinase 3ß (GSK3ß) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3ß/CDK5 were calculated to be -12.60 ± 2.28 kcal mol(-1) and -11.85 ± 2.54 kcal mol(-1), respectively, indicating that valmerin-19 has the potential to act as a dual inhibitor of GSK3ß/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3ß/CDK5 and the valmerin-19 bound to GSK3ß/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3ß/CDK5 inhibitors.
Subject(s)
Computer-Aided Design , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Drug Design , Glycogen Synthase Kinase 3/antagonists & inhibitors , Indolizidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Urea/analogs & derivatives , Binding Sites , Cluster Analysis , Cyclin-Dependent Kinase 5/chemistry , Cyclin-Dependent Kinase 5/metabolism , Drug Stability , Energy Transfer , Enzyme Stability , Glycogen Synthase Kinase 3/chemistry , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Indolizidines/chemistry , Indolizidines/metabolism , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Targeted Therapy , Principal Component Analysis , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Structure-Activity Relationship , Surface Properties , Urea/chemistry , Urea/metabolism , Urea/pharmacologyABSTRACT
OBJECTIVE: To investigate the role of Wnt5a in the mechanism of radiculopathy and the relation between Wnt5a and tumor necrosis factor α (TNF-α) by observing the change of the expression of Wnt5a in the rat model of chronic compression of dorsal root ganglia (CCD). METHODS: A total of 192 adult male Sprague Dawley rats were allocated into 4 groups: shame group (group A, n = 48), CCD group (group B, n = 48), CCD + saline group (group C, n = 48), and CCD + etanercept group (group D, n = 48). An L-shaped needle (about 3.5 mm in length, 0.6 mm in diameter) was inserted into the L5 intervertebral foramen, and the dorsal root ganglia (DRG) was compressed by the needle to prepare the CCD model in groups B, C, and D, and then normal saline (5.5 mg/kg) or etanercept was injected intraperitoneally in groups C and D. The intervertebral foramen was exposed in group A. The mechanical pain threshold of the posterior paw was tested by the von Frey filaments at 1, 3, 5, and 7 days after operation; the expressions of Wnt5a protein and mRNA were detected at 3 and 7 days after operation by immunohistochemical staining and RT-PCR, respectively. RESULTS: The mechanical pain threshold of groups B and C was significantly lower than that of groups A and D, and in group D than in group A (P < 0.05), but no significant difference was found between groups B and C (P > 0.05). The Wnt5a positive cells and the mRNA expression of Wnt5a at 7 days were significantly more than those at 3 days in groups B, C, and D (P < 0.05). The Wnt5a positive cells and the mRNA expression of Wnt5a in groups B and C were significantly more than in groups A and D, and in group D than in group A (P < 0.05), but no significant difference was shown between groups B and C (P > 0.05). CONCLUSION: The expression of Wnt5a in the DRG is increased after CCD. The expression of Wnt5a in the DRG is decreased after the administration of the inhibitor of TNF-α.
