Berberine improves cognitive impairment by alleviating brain atrophy and promoting white matter reorganization in diabetic db/db mice: a magnetic resonance imaging-based study.

Diabetic cognitive impairment is a common complication in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid that has been shown to have neuroprotective effects against diabetes. This study aimed to investigate the effect of BBR on the gray and white matter of the brain by using magnetic resonance imaging (MRI) and to explore the underlying mechanisms. The study used diabetic db/db mice and administered BBR (50 and 100 mg/kg) intragastrically for twelve weeks. Morris water maze was applied to examine cognitive function. T2-weighted imaging (T2WI) was performed to assess brain atrophy, and diffusion tensor imaging (DTI) combined with fiber tracking was conducted to monitor the structural integrity of the white matter, followed by histological immunostaining. Furthermore, the protein expressions of the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3ß (GSK-3ß) were detected. The results revealed that BBR significantly improved the spatial learning and memory of the db/db mice. T2WI exhibited ameliorated brain atrophy in the BBR-treated db/db mice, as evidenced by reduced ventricular volume accompanied by increased hippocampal volumes. DTI combined with fiber tracking revealed that BBR increased FA, fiber density and length in the corpus callosum/external capsule of the db/db mice. These imaging findings were confirmed by histological immunostaining. Notably, BBR significantly enhanced the protein levels of phosphorylated AKT at Ser473 and GSK-3ß at Ser9. Collectively, this study demonstrated that BBR significantly improved the cognitive function of the diabetic db/db mice through ameliorating brain atrophy and promoting white matter reorganization via AKT/GSK-3ß pathway.

Magnetic resonance imaging detects cerebral gray and white matter injury correlated with cognitive impairments in diabetic db/db mice.

Type-2 diabetes not only causes gray matter injury but also induces widespread white matter damages, which may contribute the cognitive impairments. This study aimed to assess the structural alterations of the gray and white matter in 20-week-old diabetic db/db mice using magnetic resonance imaging including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), and to correlate them with the cognitive performance detected by Morris water maze (MWM). The results revealed impaired spatial learning and memory in db/db mice. T2WI detected severe brain atrophy involving the hippocampus and cortex after diabetes. DTI showed reduced fractional anisotropy (FA) in the cortex, hippocampus, corpus callosum/external capsule, and increased radial diffusivity in the corpus callosum/external capsule of the db/db mice. The immunostaining confirmed the MRI findings showing decreased cell density in the cortex, hippocampus, and reduced integrated optical density of Luxol fast blue staining in the corpus callosum/external capsule. The correlational analysis revealed that the T2WI-derived tissue atrophy and DTI-derived FA in the relevant gray matter and white matter significantly correlated with the behavior performance in the MWM test. Collectively, the present in vivo MRI detected varying degrees of structural abnormalities in the gray and white matter of db/db mice, which might be favorable predictors of diabetic cognitive dysfunction. Our findings might provide new clues for identifying gray and white matter damages associated with cognitive decline, which is imperative for the evaluation of potential pharmacological therapies in preclinical phase.

Population pharmacokinetics of high-dose methotrexate in Chinese pediatric patients with medulloblastoma.

Methotrexate (MTX) pharmacokinetics has substantial inter-individual variability and toxicity. In children with medulloblastoma treated with high-dose methotrexate (HD-MTX), the pharmacokinetic properties of methotrexate have not been established. A total of 660 serum samples from 105 pediatric patients with medulloblastoma were included in a population pharmacokinetic (PPK) analysis of methotrexate by using the nonlinear mixed-effects modeling method. The basic one-compartment population pharmacokinetic model was established by NONMEM software and the first-order conditional estimation (FOCE) method, and the final covariate model was obtained by the stepwise regression method. Weight (WT), creatinine clearance (CrCL), and whether the treatment was combined with dexamethasone (DEX) were covariates that had significant effects on the clearance rate (CL) of the model. The pharmacokinetic equation of CL in the final covariate model was as follows: CLi = 9.23× (1 + 0.0005× (θCrCL -105.78)) × (1 + 0.0017× (θWT -16)) × eηcl,i (L/h), IF (θDEX ) CLi = 1.19× CLi (L/h). The estimation accuracy of all pharmacokinetic parameters were acceptable (relative standard error < 14.74%). The goodness-of-fit diagram and bootstrap tests indicated that the final PPK model was stable with acceptable predictive ability. The PPK model may be useful for determining personalized medication levels in pediatric medulloblastoma patients undergoing HD-MTX therapy.

Application of lower limb nerve block combined with slow induction of light general anesthesia and tracheal induction in elderly hip surgery.

BACKGROUND: This study aims to evaluate the effectiveness and safety of lower limb nerve block combined with slow induction of light general anesthesia and tracheal intubation in hip surgery in the elderly. METHODS: Thirty elderly patients who underwent hip surgery under the lower limb nerve block were randomly divided into 2 groups: slow induction of light general anesthesia and tracheal intubation group (group M), and laryngeal mask light general anesthesia group (group H). After undergoing total intravenous anesthesia without muscle relaxants, all patients received sciatic nerve, lumbar plexus, and paravertebral nerve blocks. The hemodynamic situations, dosage of anesthetics, time for awakening and extubation (or laryngeal mask removal), and incidence of respiratory adverse reactions in the induction period were recorded. RESULTS: Compared with baseline levels, the difference in mean arterial pressure (MAP) value at each time point after intubation/laryngeal mask removal in both groups was not statistically significant (P > .05). Furthermore, the time for awakening and extubation/laryngeal mask removal, and anesthetic dosage were significantly decreased in group M, when compared with group H (P < .05). For the incidence of adverse reactions, the incidence of poor sealing and hypoxia was significantly lower in group M than in group H (P < .05), and the incidence of sore throat was significantly lower in group H than in group M (P < .05). CONCLUSION: Lower limb nerve block combined with slow induction of light general anesthesia and tracheal intubation was associated with smaller anesthetic dosage, and shorter duration of anesthesia induction and extubation/laryngeal mask after surgery.

UPLC-QTOF/MSE and Bioassay Are Available Approaches for Identifying Quality Fluctuation of Xueshuantong Lyophilized Powder in Clinic.

Xueshuantong Lyophilized Powder (XST), consisting of a series of saponins extracted from Panax notoginseng, is widely applied to treat acute cerebral infarction, stroke, and coronary heart disease in China. However, most adverse drug reactions (ADR) in clinic are caused by quality problems of XST. In this study, six batches of certainly abnormal, four batches of possibly abnormal XST, and eight batches of normal XST were obtained from the clinical practice. Their quality fluctuations were identified by ultra-performance liquid chromatography coupled with an electrospray ionization quadrupole time-of-flight mass spectrometry operating in MSE mode (UPLC-QTOF/MSE) and bioassays including antithrombin and proplasmin assay. Fourteen potential components responsible for clinical ADR were identified by UPLC-QTOF/MSE, especially ginsenoside Rg1, Rg3, Rb1 and notoginsenoside R1. In addition, 83.3% (5/6) and 50.0% (3/6) certainly abnormal samples could be identified by UPLC-QTOF/MSE and bioassay, respectively. Interestingly, further integration of the two methods could entirely identify all the certainly abnormal samples and inferred that all the possibly abnormal samples were closely related to their quality fluctuation. It indicates that it is advisable to combine UPLC-QTOF/MSE and bioassay for identifying quality fluctuation of XST, and thus reduce its ADR in clinic.

Simultaneous determination of 13 bioactive compounds in Herba Artemisiae Scopariae (Yin Chen) from different harvest seasons by HPLC-DAD.

Herba Artemisiae Scopariae is a Chinese herbal medicine widely used for the remedy of liver diseases. A high performance liquid chromatography method coupled with diode array detection was developed to simultaneously determine 13 different bioactive compounds in Herba Artemisiae Scopariae (Yin Chen) including chlorogenic acid (1), 6,7-dihydroxycoumarin (2), caffeic acid (3), 4-hydroxyacetophenone (4), scopoletin (5), rutin (6), hyperoside (7), isoquercitrin (8), scoparone (11), 7-methoxycoumarine (12) and quercetin (13). By using four different wavelengths in the HPLC analysis, the developed method was able to determine the bioactive compounds with excellent resolution, precision and recovery. The method was applied to determine the amounts of the bioactive compounds in nine samples from different cultivated regions and harvest seasons in China, and significant variations were revealed. Chlorogenic acid was the most abundant among the analyzed compounds. The samples harvested in the spring contained higher contents of chlorogenic acid than those collected in other seasons. Other phenolic acids as caffeic acid, 3,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid and 4-hydroxyacetophenone accumulated at much higher amounts in about May to July. The samples analyzed contained a much lower level of the amount of other flavonoids and coumarins as rutin, hyperoside, isoquercitrin and scoparone.