Evaluation of a flavonoid library for inhibition of interaction of HIV-1 integrase with human LEDGF/p75 towards a structure-activity relationship.

Background: Proteinsprotein interaction (PPI) between lens epithelium-derived growth factor (LEDGF/p75) and human immunodeficiency virus (HIV) integrase (IN) becomes an attractive target for anti-HIV drug development.Methods: The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. In this study, a panel of 99 structurally related flavonoids were was tested, concerning their ability to inhibit IN-LEDGF/p75 interaction, using a homogeneous time time-resolved fluorescence (HTRF) assay. Results: From the obtained results, it was possible to observe that the flavonoid with hydroxyl group in C3-, C4-, C5- and C7-position on the A-ring, C4'- and C5'-position of the B-ring, a carbonyl group of the C-ring, was more active against IN-LEDGF/p75 interaction, through competitive inhibition. Moreover, the binding modes of representative compounds, including myricetin, luteolin, dihydrorobinetin, naringenin, epicatechin, genistein and helichrysetin, were analyzedanalysed by molecular docking. Biolayer interferometry assay confirmed that these representative compounds disrupted the PPI by binding to IN with KD values ranging from 1.0 to 3.6 µM.Conclusion: This study presents the first to quantitative comparation of the effect of flavonoids with different structural subclasses on IN-LEDGF/p75 interaction. Our findings provide new insights into the development of inhibitors targeting IN-LEDGF/p75 interaction using flavonoids. Key MessagesHIV-1 integrase (IN)-LEDGF/p75 interaction is an attractive target for antiviral drug development.For the first time, the structure-activity relationship of flavonoids belonging to seven flavonoidic subclasses on IN-LEDGF/p75 interaction was determined.This study comprehends an HTRF-based screening system, biolayer interferometry and an in silico molecular docking analysis.

The selenium-containing drug ebselen potently disrupts LEDGF/p75-HIV-1 integrase interaction by targeting LEDGF/p75.

Lens-epithelium-derived growth-factor (LEDGF/p75)-binding site on HIV-1 integrase (IN), is an attractive target for antiviral chemotherapy. Small-molecule compounds binding to this site are referred as LEDGF-IN inhibitors (LEDGINs). In this study, compound libraries were screened to identify new inhibitors of LEDGF/p75-IN interaction. Ebselen (2-phenyl-1,2-benzisoselenazol-3-one), a reported anti-HIV-1 agent, was identified as a moderate micromolar inhibitor of LEDGF/p75-IN interaction. Ebselen inhibited the interaction by binding to LEDGF/p75 and the ability of ebselen to inhibit the interaction could be reversed by dithiothreitol (DTT). BLI experiment showed that ebselen probably formed selenium-sulphur bonds with reduced thiols in LEDGF/p75. To the best of our knowledge, we showed for the first time that small-molecule compound, ebselen inhibited LEDGF/p75-IN interaction by directly binding to LEDGF/p75. The compound discovered here could be used as probe compounds to design and develop new disrupter of LEDGF/p75-IN interaction.

Effect of covered stent length in portal and hepatic veins on long-term clinical efficacy of transjugular intrahepatic portosystemic shunt / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the effect of the length of covered stents in the portal and hepatic veins on long-term clinical efficacy of transjugular intrahepatic portosystemic shunt (TIPS).</p><p><b>METHODS</b>We retrospectively reviewed 53 cases receiving TIPSs between January, 2008 and December, 2011. All the shunts were created with Fluency stents (8 mm in diameter). Bare metal grafts of the same diameter were implanted to extend the length in the portal and hepatic veins as deemed necessary according to angiographic images. The primary patency, hepatic encephalopathy and patient survival were evaluated during the follow up. The length of the covered stents within the hepatic vein (X1) and in the portal vein (X2), and the total length of stents placed in the hepatic vein (X3) and the portal vein (X4) were measured and their effects on primary patency and the patients'outcomes were evaluated.</p><p><b>RESULTS</b>The procedures were completed successfully in all the patients and the mean portosystemic pressure decreased from 29.80∓4.83 mmHg to 19.00∓3.92 mmHg (t=13.44, P<0.01) after the procedure. The patients were followed up for a median of 64 months (3 to 89 months, 39 months on average). Hepatic encephalopathy occurred in 23% (12/53) of the patients after TIPS. Shunt dysfunction occurred in 16 cases, and the cumulative primary patency rates at 1 to 5 years were 83%, 75%, 63%, 62%, and 54%, respectively. The cumulative survival rates of the patients at 1 to 5 years were 79%, 72%, 72%, 69%, and 69%, respectively. Cox proportional regression analysis showed a significant association between the length of covered-stent in the hepatic vein and the primary patency (OR=0.42, P<0.01), and there was a significant association between the length of stent in the portal vein and the patient survival. No significant correlation was found between these parameters and hepatic encephalopathy.</p><p><b>CONCLUSION</b>Increasing the length of the covered stent in the hepatic vein and decreasing the stent length in the portal vein can improve the primary patency and the patient survival receiving TIPS.</p>

Percutaneous intratumoral injection with pingyangmycin lipiodol emulsion for treatment of recurrent sacrococcygeal chordomas / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the effectiveness and safety of fluoroscopy-guided percutaneous intratumor injection of pingyangmycin lipiodol emulsion (PLE) in the management of recurrent sacrococcygeal chordomas.</p><p><b>METHODS</b>Seven patients with recurrent sacrococcygeal chordomas presenting with severe local pain with visual analogue score (VAS)≥8 received treatment sessions of fluoroscopy-guided percutaneous intratumor injection of PLE. The patients were followed up every 3 months after the last session to assess their clinical responses and observe the changes in the tumor size measured by computed tomography. The changes in the VAS, tumor necrosis and pain relief as well as the adverse events were recorded.</p><p><b>RESULTS</b>A total of 22 sessions of fluoroscopy-guided percutaneous intratumoral PLE injection was performed in these cases (3 or 4 sessions in each case). The total average pingyangmycin dose delivered was 48.0 mg and the average lipiodol dose was 40.0 ml in each case. Five patients showed low fever and vomiting 48 after the injection. During the follow-up (median time of 21.7 months, range 10-26 months), all the patients showed obviously reduced tumor size and VAS, and partial remission was achieved in 6 patients and stable disease (SD) in 1 patient. None of the patients had complications during the follow-up.</p><p><b>CONCLUSION</b>Fluoroscopy-guided percutaneous intratumoral injection of PLE can be effective and safe and may serve as a alternative for treatment of recurrent sacrococcygeal chordomas.</p>

Effect of percutaneous intratumoral injection of lipiodol emulsion of chemotherapie agents on implanted VX2 tumor in rabbits / 南方医科大学学报

<p><b>OBJECTIVE</b>To assess the therapeutic effect of percutaneous intratumoral injection with lipiodol emulsion of chemotherapie agents (CALE) on implanted VX2 tumor in rabbits.</p><p><b>METHODS</b>Twelve New Zealand rabbits with implanted VX2 tumor (24 models) were divided into lipiodol group, chemotherapeutic agent group and CALE group with intratumoral injections of the corresponding agents. The pathological changes of all the lesions were observed and the expression of proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) were evaluated 7 days after the operation.</p><p><b>RESULTS</b>Compared with the lipiodol group and chemotherapie agent group, intratumoral injection of CALE resulted in the highest tumor necrosis rate and greatest tumor necrosis (P<0.01). The labeling indices of PCNA and VEGF expressions in CALE group were markedly lower than those in the other two groups (P<0.01).</p><p><b>CONCLUSION</b>Percutaneous intratumoral injection of CALE is an effective ablation approach for treatment of malignant solid tumors.</p>

Removal of metallic foreign body in the soft tissue under fluoroscopy: 10 years of experiences / 南方医科大学学报

<p><b>OBJECTIVE</b>To summarize our 10-year experience with percutaneous fluoroscopically guided removal (PFGR) of metallic foreign body (MFB) in the soft tissue.</p><p><b>METHODS</b>PFGR was performed in 65 patients for removing a total of 368 MFBs from the soft tissues. The MFBs ranged from 0.2 to 0.3 cm in length embedded in the soft tissue for 7 days to 8 years. For superficial MFBs, the MFBs were removed directly with curved forceps under real time fluoroscopy. For deep MFBs, trocar technique was applied using the instruments for percutaneous diskectomy, with the outer cannula inserted toward the foreign body under real-time fluoroscopy followed by MFB removal by grasping forceps.</p><p><b>RESULTS</b>A total of 346 MFBs were successfully removed without any serious complications (success rate 94.0%), including 154 removed directly and 192 MFBs with trocal technique. The time of the procedures and radiation exposure for MFB removal was 30 s to 20 min and 1-6 min, respectively.</p><p><b>CONCLUSION</b>PGFR of MFBs in the soft tissue under fluoroscope is safe and effective. Direct removal using curved forceps is suitable for MFBs in superficial soft tissues, while trocal techniques needs to be utilized for deep MFBs.</p>

Endovascular graft exclusion with digital subtraction angiography for treatment of Stanford type B aortic dissection / 南方医科大学学报

<p><b>OBJECTIVE</b>To assess value of endovascular graft exclusion (EVGE) with digital subtraction angiography (DSA) in the treatment of Stanford type B aortic dissection (AD).</p><p><b>METHODS</b>On the basis of diagnosis with multi-slice spiral CT (MSCT), DSA was performed in 20 Stanford B AD cases for further diagnostic confirmation and EVGE was conducted for treatment. The DSA findings of the cases and the therapeutic effect of EVGE were evaluated.</p><p><b>RESULTS</b>In the 20 cases of Stanford type B AD, altogether 22 stents were implanted during EVGF with a stent release success rate of 100%. Postoperative examination revealed no obvious leakage or false lumen in 15 cases, and death occurred in 1 case 6 days after the operation due to right renal hemorrhage and infection, and the rest 19 patients were cured and discharged. Follow-up of the patients demonstrated improvement in the clinical symptoms, and MSCT showed that all the dissections were sealed successfully. No severe complications were observed 3 months after the treatment in these patients.</p><p><b>CONCLUSION</b>DSA can identify the fine anatomy of AD and allowed intraoperative monitoring in EVGE, which is an effective and safe means for treatment of Stanford type B AD.</p>

Effects of granulocyte colony-stimulating factor on repair of injured canine arteries / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Endothelial progenitor cells (EPCs) derived from bone marrow may differentiate into endothelial cells and participate in endothelial repair. These cells can be mobilized into peripheral blood by cytokines, including granulocyte colony-stimulating factor (G-CSF). In the present study, we investigated the effects of G-CSF on neointimal formation and restenosis in a canine model of arterial balloon injury.</p><p><b>METHODS</b>Sixteen male beagle dogs were injected subcutaneously with 20 microg x kg(-1) x d(-1) recombinant human G-CSF (n = 8) or normal saline (n = 8) for 1 week. On the fifth day of treatment, the dogs underwent renal arterial angioplasty. At 8 weeks after arterial balloon injury, angiographic observations were made and injured arteries were processed for morphometric analysis of neointimal formation.</p><p><b>RESULTS</b>Peripheral white blood cell counts were increased by 3.34-fold compared to baseline on the fifth day of administration of G-CSF. Angiographies revealed that one stenosis had occurred among the eight injured renal arteries from dogs treated with G-CSF, whereas all injured renal arteries from dogs treated with normal saline remained patent. The mean extent of stenosis among injured arteries was 18.3% +/- 17.9% in the G-CSF treated group compared to 12.5% +/- 7.6% in the saline treated control group (P = 0.10). G-CSF treatment slightly increased neointimal thickness (0.42 +/- 0.15 mm vs 0.25 +/- 0.06 mm, P = 0.08) with an intima to media ratio of 0.83 +/- 0.49 vs 0.54 +/- 0.18 (P = 0.11).</p><p><b>CONCLUSIONS</b>G-CSF treatment does not attenuate neointimal hyperplasia and restenosis formation in a canine model of renal arterial injury, suggesting that the therapeutic strategy for preventing restenosis by stem cell mobilization should be investigated further.</p>

Percutaneous intradiscal oxygen-ozone injection for lumbar disc herniation: no need of perioperative antibiotic prophylaxis / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the feasibility of no antibiotic administration to prevent infection during the perioperative period of percutaneous intradiscal ozone-injection for treatment of lumbar disc herniation.</p><p><b>METHODS</b>Seventy-two patients with lumbar disc herniation but normal body temperature as well as normal results of three routine tests (blood, urine, stool) and C-reactive protein (CRP) level were randomly divided into two groups. The patients in prophylaxis group were given cephalothin V(2.0 g) intravenous 30 min before the operation, and the control group did not use any antibiotics. All the patients were injected with 6-10 ml ozone (40 microg/ml) for medical use into the discs with 21G needles under fluoroscopic guidance, followed by 10 ml ozone into the paravertebral space. Three days later the general examinations and CRP measurement were repeated.</p><p><b>RESULTS</b>No infection was found in these patients, nor were any significant differences noted in the results of the examinations between the two groups after controlling in patients with above-normal white blood cell count, neutrophil percentage and CRP level.</p><p><b>CONCLUSION</b>Prophylaxis antibiotics is not necessary during the perioperative period of percutaneous intradiscal ozone injection for lumbar disc herniation.</p>

Treatment of orbital venous malformations with intralesional injection of bleomycin lipiodol emulsion / 中华放射学杂志

5 mm and ≤8 mm in 4 cases.The mean value was 4.2 mm. Four patients noticed reduction in their vision and two had diplopia.Those patients were examined by CT or MR.Direct venography was performed in each patient.After the diagnosis of OVM was confirmed, intralesional injection of BLE was performed.The efficacy of the treatment and complications were observed during the following 8 to 42 months(mean 23 months).Results The BLE were successfully injected in all the patients.All patients had resolution of proptosis and diplopia.Three patients gained improvement of visual acuity.The periorbital swelling occurred in all patients after operation and resolved within 1 week without special treatment.Other complications,such as orbital hemorrhage and periorbital scar,were not observed during following-up.Conclusion Intralesional injection with BLE is convenient,safe and efficient for the treatment of OVM.