Skullcapflavone II, a novel NQO1 inhibitor, alleviates aristolochic acid I-induced liver and kidney injury in mice.

Aristolochic acid I (AAI) is a well established nephrotoxin and human carcinogen. Cytosolic NAD(P)H quinone oxidoreductase 1 (NQO1) plays an important role in the nitro reduction of aristolochic acids, leading to production of aristoloactam and AA-DNA adduct. Application of a potent NQO1 inhibitor dicoumarol is limited by its life-threatening side effect as an anticoagulant and the subsequent hemorrhagic complications. As traditional medicines containing AAI remain available in the market, novel NQO1 inhibitors are urgently needed to attenuate the toxicity of AAI exposure. In this study, we employed comprehensive 2D NQO1 biochromatography to screen candidate compounds that could bind with NQO1 protein. Four compounds, i.e., skullcapflavone II (SFII), oroxylin A, wogonin and tectochrysin were screened out from Scutellaria baicalensis. Among them, SFII was the most promising NQO1 inhibitor with a binding affinity (KD = 4.198 µmol/L) and inhibitory activity (IC50 = 2.87 µmol/L). In human normal liver cell line (L02) and human renal proximal tubular epithelial cell line (HK-2), SFII significantly alleviated AAI-induced DNA damage and apoptosis. In adult mice, oral administration of SFII dose-dependently ameliorated AAI-induced renal fibrosis and dysfunction. In infant mice, oral administration of SFII suppressed AAI-induced hepatocellular carcinoma initiation. Moreover, administration of SFII did not affect the coagulation function in short term in adult mice. In conclusion, SFII has been identified as a novel NQO1 inhibitor that might impede the risk of AAI to kidney and liver without obvious side effect.

Early argatroban and antiplatelet combination therapy in acute non-lacunar single subcortical infarct associated with mild intracranial atherosclerosis.

BACKGROUND: Patients with acute non-lacunar single subcortical infarct (SSI) associated with mild intracranial atherosclerosis (ICAS) have a relatively high incidence of early neurological deterioration (END), resulting in unfavorable functional outcomes. Whether the early administration of argatroban and aspirin or clopidogrel within 6-12 h after symptom onset is effective and safe in these patients is unknown. METHODS: A review of the stroke database of Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University and Qingdao Center Hospital, Qingdao University Medical College in China was undertaken from May 2017 to January 2020 to identify all patients with non-lacunar SSI caused by ICAS within 6-12 h of symptom onset based on MRI screening. Patients were divided into two groups, one comprising those who received argatroban and mono antiplatelet therapy with aspirin or clopidogrel on admission (argatroban group), and the other those who received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel during hospitalization (DAPT group). The primary outcome was recovery by 90 days after stroke based on a modified Rankin scale (mRS) score (0 to 1). The secondary outcome was END incidence within 120 h of admission. Safety outcomes were intracranial hemorrhage (ICH) and major extracranial bleeding. The probability of clinical benefit (mRS score 0-1 at 90 days) was estimated using multivariable logistic regression analysis. RESULTS: A total of 304 acute non-lacunar SSI associated with mild ICAS patients were analyzed. At 90 days, 101 (74.2%) patients in the argatroban group and 80 (47.6%) in the DAPT group had an mRS score that improved from 0 to 1 (P < 0.001). The relative risk (95% credible interval) for an mRS score improving from 0 to 1 in the argatroban group was 1.50 (1.05-2.70). END occurred in 10 (7.3%) patients in the argatroban group compared with 37 (22.0%) in the DAPT group (P < 0.001). No patients experienced symptomatic hemorrhagic transformation. CONCLUSIONS: Early combined administration of argatroban and an antiplatelet agent (aspirin or clopidogrel) may be beneficial for patients with non-lacunar SSI associated with mild ICAS identified by MRI screening and may attenuate progressive neurological deficits. TRIAL REGISTRATION: Our study is a retrospectively registered trial.

Analysis of Spino-pelvic Sagittal Alignment in Young Chinese Patients with Lumbar Disc Herniation.

OBJECTIVE: Few studies have concentrated on the sagittal alignment of lumbar disc herniation (LDH), especially the parameters of the pelvis, and controversy exists about whether pelvic morphology is involved in the pathogenesis of LDH. The present study analyzed the characteristics of the sagittal alignment in young Chinese LDH patients and explored the impact of pelvic morphology on the pathogenesis of LDH. METHODS: A retrospective analysis was conducted on 100 young patients with LDH (69 men and 31 women, aged 18-35 years), and the clinical and imaging findings met the criteria for the diagnosis of LDH. The control group included 100 asymptomatic volunteers with matching age and gender. Coronal and sagittal parameters were measured on the anteroposterior and lateral radiographs of the whole spine, including lumbar lordosis (LL), pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), thoracic kyphosis (TK), and sagittal balance (SVA). The cases were classified into four types by the apex position of lumbar lordosis (type I, L5 or the L4-5 intervertebral space; type II, bottom or middle of L4 ; type III, upper part of L4 or the intervertebral space between L3 and L4 ; type IV, L3 or more high level), and divided into three groups by PI; namely, a low PI group (PI < 40°), a medium PI group (40° ≤ PI < 50°), and a high PI group (PI ≥ 50°). The sagittal parameters, especially PI, were compared between the LDH group and the control group. Correlations between the parameters in the LDH group were analyzed. RESULTS: The PI value of the LDH group was not different from that of the control group (46.1° ± 10.0° vs 47.2° ± 8.8°, P > 0.05). The LDH group showed lower average LL, SS, and TK (P < 0.01), as well as higher PT and SVA compared with the control group (P < 0.01). The LL (34.4° ± 15.3° vs 50.8° ± 10.2°) and SVA (21.6 ± 53.6 mm vs - 18.4 ± 32.8 mm) showed a significant difference (P < 0.01); LL was correlated with PI, SS, PT, TK and SVA (P < 0.01); and SVA was also correlated with the parameters above (P < 0.01) except PI (P > 0.05), and the lordosis apex tended to be higher. The distributions of PI groups between the LDH group and the control group were not different. Pairwise correlations were found among LL, PI, SS, and PT. In addition, TK and SVA were correlated with LL, SS, and PT. CONCLUSIONS: There is no difference in PI between young Chinese patients with lumbar disc herniation and the normal population. Young LDH patients may present flat lumbar and thoracic curves, as well as lower sacral slope. The anteversion sagittal imbalance is regulated by both the spine and the pelvis.

Effect of patient position on the lordosis and scoliosis of patients with degenerative lumbar scoliosis.

This study aimed to analyze the effect of patient positions on the lordosis and scoliosis of patients with degenerative lumbar scoliosis (DLS).Seventy-seven patients with DLS were retrospectively analyzed. We measured lordosis and Cobb's angle on preoperative upright x-rays and magnetic resonance imagings in supine position. The lordosis and scoliosis of surgical segments in intraoperative prone position were measured on intraoperative radiographs of 20 patients to compare with that in standing position. Paired t tests were performed to investigate the parameters of the sample.From standing to supine position the whole lordosis increased (29.2 ±â€Š15.7 degree vs. 34.9 ±â€Š11.2 degree), and the whole scoliosis decreased (24.3 ±â€Š11.8 degree vs. 19.0 ±â€Š10.5 degree); 53 of 77 (68.8%) cases had increased lordosis, and 67 of 77 (87%) cases had decreased scoliosis. The lordosis of surgical segments in standing position had no difference with that in intraoprerative prone position. But in changing from supine/standing position to intraoprerative prone position, the scoliosis of surgical segments decreased (14.7 ±â€Š9.4 degree vs. 11.4 ±â€Š7.0 degree; 19.0 ±â€Š11.8 degree vs. 11.4 ±â€Š7.0 degree, respectively), and 18 of 20 (90%) cases had decreased scoliosis in intraoperative prone position than that in standing position.Compared with standing position in DLS patients, supine position increased lordosis and reduced scoliosis, and intraoperative prone position reduced scoliosis significantly. When evaluating the severity of DLS and making preoperative surgical plans, lumbar lordosis in supine position should also be evaluated in addition to upright x-ray, and the effects of different positions should be taken into consideration to reduce deviation.