QSAR Study, Molecular Docking and Molecular Dynamic Simulation of Aurora Kinase Inhibitors Derived from Imidazo[4,5-b]pyridine Derivatives.

Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules.

WDR5a functions in cadmium-inhibited root meristem growth by regulating nitric oxide accumulation in Arabidopsis.

MAIN CONCLUSION: Cadmium stress induces WDR5a expression to promote NO accumulation to repress root meristem growth via suppressing auxin transport and synthesis in Arabidopsis. Nitric oxide (NO) synthase (NOS)-like activity plays a vital role in toxic cadmium (Cd)-induced NO production and inhibition of root meristem growth, while factor(s) regulating NOS-like activity and root meristem growth in plant response to Cd has not been identified yet. Here, we report that WD40 repeat 5a (WDR5a) functions in Cd-induced NOS-like activity, NO accumulation and root meristem growth suppression. We found that wdr5a-1 mutant root has increased root meristem growth with lower NOS-like activity and NO accumulation than wild type upon Cd exposure, and exogenous NO donors sodium nitroprusside or nitrosoglutathione can restore its reduced Cd sensitivity. In addition, Cd activates WDR5a expression in roots, and overexpressing WDR5a results in increased NO accumulation and suppressed root meristem growth similar to Cd-stressed wild-type roots, while scavenging NO or inhibiting NOS-like activity significantly reverts these effects of Cd. Furthermore, WDR5a acts in Cd-repressed auxin accumulation through reducing the levels of auxin efflux carriers PIN1/3/7 and biosynthetic enzyme TAA1, and reduced sensitivity of wdr5a-1 root meristem to Cd can be partially reverted by inhibiting TAA1 activity pharmaceutically or mutating TAA1 genetically. This study identified WDR5a as a key factor modulating NO accumulation and root meristem growth in plant response to Cd.

Preliminary outcomes of endovascular treatment of moyamoya disease.

PURPOSE: This study aimed to investigate the effectiveness and safety of endovascular revascularisation of intracranial artery occlusion and stenosis in moyamoya disease using stent angioplasty. MATERIALS AND METHODS: We recruited 12 patients (8 women and 4 men) with occlusion and stenosis of intracranial arteries in the context of moyamoya disease who underwent endovascular stent angioplasty. Clinical data, baseline conditions, lesion location, treatment outcomes, periprocedural complications, and follow-up outcomes were analysed. RESULTS: The occlusion was located at the M1 segment of the middle cerebral artery in 8 patients, at both the M1 and A2 segments in one patient, and at the C7 segment of the internal carotid artery in 3. Thirteen stents were deployed at the occlusion site, including the low-profile visualized intraluminal support (LVIS) device in 8 patients, an LVIS device and a Solitaire AB stent in one, and a Leo stent in 3, with a success rate of 100% and no intraprocedural complications. Plain CT imaging after stenting revealed leakage of contrast agent, which disappeared on the second day, resulting in no clinical symptoms or neurological sequelae. Follow-up angiography studies were performed in all patients for 6-12 months (mean, 8.8). Slight asymptomatic in-stent stenosis was observed in 2 patients (16.7%), and no neurological deficits were observed in the other patients. All preoperative ischaemic symptoms completely disappeared at follow-up. CONCLUSION: Stent angioplasty is a safe and effective treatment for occlusion and stenosis of intracranial arteries in moyamoya disease.

Jasmonic acid promotes leaf senescence through MYC2-mediated repression of CATALASE2 expression in Arabidopsis.

Plants relocate nutrients and energy from aging leaves to developing tissues during leaf senescence, which is important for plant growth, development, and responses to various environmental stimuli. Both jasmonic acid (JA) and H2O2 are two crucial signalling molecules positively regulating leaf senescence, whereas whether and how they are coordinated in leaf senescence remains elusive. Here, we report that H2O2 accumulates in JA-treated leaves, while scavenging the increased H2O2 can significantly suppresses JA-induced leaf senescence and the expression of senescence-associated genes (SAGs). The mutant myc2 with a mutation of MYC2, a master transcription factor in JA signalling pathway, exhibits delayed leaf senescence with increased catalase activity and decreased H2O2 accumulation compared with the wild type upon JA treatment. Further study showed that MYC2 downregulates CATALASE 2 (CAT2) expression by binding to its promoter, thus promoting JA-induced H2O2 accumulation and leaf senescence. Moreover, the delayed leaf senescence with reduced H2O2 accumulation and SAGs expression of the myc2 mutant is significantly reverted by the cat2-1 mutation in myc2 cat2-1 double mutant. Thus, our study reveals that JA represses CAT2 expression to increase H2O2 accumulation, thus promoting leaf senescence in a MYC2 dependent manner in Arabidopsis.

Safety and efficacy of endovascular treatment of ruptured tiny cerebral aneurysms compared with ruptured larger aneurysms.

PURPOSE: To investigate the effect and safety of endovascular embolization of tiny aneurysms (≤3 mm) within 72 h of subarachnoid hemorrhage compared with larger ones. MATERIALS AND METHODS: Patients with intracranial aneurysms treated with endovascular embolization within 72 h were retrospectively enrolled and divided into group A (n = 33) with ruptured tiny aneurysms (≤3 mm) and group B (n = 244) with ruptured larger aneurysms (>3 mm). The clinical and angiographic data before and after embolization were analyzed. RESULTS: Most tiny aneurysms were located at the posterior communicating artery (36.4%) followed by anterior communicating artery (18.2%). The stent-assisted coiling technique was used mostly in group A with 18 stents deployed (51.5%), but only 24 (9.8%) patients had stent-assisted coiling in group B, with the stent-assisted coiling technique more significantly (P < 0.001) frequently used in group A. No significant (P > 0.05) difference existed in the total, subtotal and incomplete occlusion of aneurysms in two groups. The procedure-related complication rate was not significantly (P > 0.05) different between groups A (24.2%) and B (17.0%). At discharge, no significant (P > 0.05) difference existed in the neurological abnormality between the two groups. Follow-up was performed in 64.5% (20/31) in group A and 75.6% (177/234) in group B. No significant (P > 0.05) difference existed in the aneurysm recurrence rate, deaths, and prognosis. CONCLUSION: Early embolization of tiny cerebral aneurysms within 72 h of subarachnoid hemorrhage is safe and effective compared with ruptured large aneurysms treated in the same manner.

Successful Thrombectomy Using Sofia (6F) PLUS Catheter in Acute Stroke Patient with Coincident Proximal Unruptured Aneurysm.

BACKGROUND: Little literature is available on mechanical thrombus aspiration in acute ischemic stroke with coincident ipsilateral unruptured aneurysm, especially with aneurysm proximal to the occlusion site. In this report, we describe a case of ischemic stroke in a patient with acute occlusion of M1 segment of the middle cerebral artery with coincident ipsilateral internal carotid artery-posterior communicating artery aneurysm who was successfully treated by mechanical clot retrieval using the Sofia (6F) PLUS technique (MicroVention Terumo, Tustin, California, USA). CASE DESCRIPTION: A 52-year-old woman presented at our hospital 6 hours after sudden onset of dysarthria and right limb hemiplegia on waking up in the morning. She was managed using a direct aspiration first pass technique for distal middle cerebral artery mechanical aspiration using the Sofia (6F) PLUS catheter. The thrombus was manually aspirated in 2 minutes, and Thrombolysis in Cerebral Infarction scale 3 flow was restored. Next, LVIS (MicroVention Terumo, Tustin, California, USA) stent-assisted coiling of the aneurysm of the posterior communicating segment of the left internal carotid artery was immediately undertaken. The National Institutes of Health Stroke Scale score was 4 at day 1 and 0 at day 7 postoperatively. No device-related or catheter-related complications occurred. CONCLUSIONS: Ischemic stroke patients with coincident aneurysm are at increased risk of aneurysmal rupture and should be managed with tailored endovascular strategies. Our case shows that a direct aspiration first pass technique using the Sofia (6F) PLUS catheter provides a safe, effective approach for thrombus aspiration in stroke patients.

Purinergic P2X7 receptor blockade mitigates alcohol-induced steatohepatitis and intestinal injury by regulating MEK1/2-ERK1/2 signaling and egr-1 activity.

The P2X7 receptor is an ATP-binding cation channel involved in a broad range of inflammatory diseases. However, little is known about the potential role of P2X7R in alcohol-induced steatohepatitis and intestinal injury. In our study, C57BL/6 mice were intraperitoneally injected with P2X7R antagonists Brilliant Blue G and A438079 from the 4th day to the 10th day during the induction of chronic plus binge alcohol feeding model. Our results showed that alcohol feeding induced significant steatohepatitis and liver injury, which were mitigated by P2X7R blockade as evidenced by decreased serum levels of ALT, AST, T-CHO and TG, reduced lipid accumulation, and less inflammation. The increased intestinal inflammatory cytokines production and the prominent intestinal barrier disruption caused by alcohol were also modulated by P2X7R antagonism. Interestingly, alcohol feeding increased the relative abundance of phylum Bacteroidetes while decreased the number of phylum Verrucomicrobia and genus Akkermansia in the cecal content, which were reversed by P2X7R antagonist. Importantly, the improvement of intestinal barrier function and the restoration of partial taxonomic alterations in the gut microbiota might contribute to protect the liver from gut microbiota dysbiosis-induced second hit. Furthermore, P2X7R blockade inhibited MEK1/2-ERK1/2 phosphorylation and egr-1 expression in both liver and intestine from alcohol-fed mice. Collectively, P2X7R blockade mitigates alcohol-induced steatohepatitis and intestinal injury by inhibiting MEK1/2-ERK1/2 signaling and egr-1 expression. These studies strongly suggest that P2X7R blockade may be a promising therapeutic approach for treating alcoholic liver disease.