To explore the protective effects of metformin plus berberine against diabetes-induced cognitive dysfunction in db/db mice.

Mice were randomly divided into model, metformin, berberine, and metformin plus berberine (MB) groups. Db/m mice born in the same litter were used as the control group. Metformin (300 mg·kg^-1) and berberine (135 mg·kg^-1), either alone or in combination, were administered orally for 10 weeks. Body weight, blood glucose and related indices, and behavioral, oxidative stress-related, and inflammatory factor-related indexes of db/db mice were measured. Brain tissue sections were subjected to hematoxylin-eosin (HE) staining, and pathological changes were observed via light microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to observe changes in the levels of small molecules in the brain tissue.

Fasting blood glucose levels were significantly lower in the MB group than in the model, metformin, and berberine groups after 8 and 10 weeks of dosing. In the Morris water maze test, escape latency and time to find the platform from the contralateral quadrant were significantly shorter in the MB group than in the model group. The number of target crossings in 90 s and residence time in the target quadrant significantly increased in the metformin plus berberine group. According to ELISA, glycated hemoglobin, 8-hydroxydeoxyguanosine, protein carbonyl, tumor necrosis factor-α, NLRP3, and interleukin-1β levels were significantly lower in the MB group than in the model group, whereas interleukin-6 levels significantly increased. In HE staining experiments, compared with the model group, the neurons in the hippocampal region in the metformin plus berberine group were arranged neatly, with more complete shape, clear nuclear staining, and clear cell boundaries. In mass spectrometry imaging experiments, brain aspartate, N-acetyl-aspartate, and glutamate levels were significantly higher in the MB group than in the model group, whereas taurine and glucose levels significantly decreased.

Oral administration of MB has protective effects on diabetes-induced cognitive dysfunction and stronger effects than using either drug alone. The mechanism of action may be related to anti-inflammatory and antioxidative stress effects and increase in excitatory amino acids levels.

To analyze the correlation between blood drug concentration and kidney injury in children with medulloblastoma treated with high-dose methotrexate (HD-MTX) chemotherapy.

A total of 139 children with medulloblastoma treated with high-dose methotrexate chemotherapy were selected and their 782 blood drug concentrations, basic data, and laboratory examination results before and after treatment were retrospectively collected to analyze the correlation between changes in kidney function indicators and blood drug concentration.

Serum MTX concentrations at 24 h post medication were positively correlated with uric acid level, negatively correlated with creatinine clearance, but not with serum creatinine and blood urea nitrogen levels. Serum concentrations of MTX at 42 h post medication were positively correlated with serum creatinine and blood urea nitrogen levels, negatively correlated with creatinine clearance and blood urea nitrogen level.

Monitoring of MTX serum concentration can predict the kidney damage caused by MTX chemotherapy.

To demonstrate equivalent clinical efficacy of all biosimilars of adalimumab (ADA), etanercept (ETA), infliximab (INF), and rituximab (RIT) with their reference drugs as well as to evaluate the relative safety and immunogenicity of biosimilars in the treatment of rheumatoid arthritis (RA).

Pubmed, Embase, Cochrane Library, Web of Science, Sinomed, ClinicalTrial.gov, CNKI and Wanfang database were searched to collect the randomized controlled trials (RCTs) about the comparisons between biosimilars and their reference drugs for the treatments of RA published from inception to December 17, 2019. Two researchers screened literature, extracted data and assessed risk of bias independently. STATA 15.0 software was used to perform data analysis. To reduce heterogeneity, subgroup analysis in accordance with the drug treatment duration was conducted.

A total of 27 RCTs were included (ADA: 10, ETA: 6, INF: 7, RIT: 4), involving 10 405 RA patients with inadequate response to the first-line treatment regimen. The clinical efficacy and safety of the four biosimilar drugs were comparable with their reference drugs. In terms of immunogenicity, no statistically significant differences were found between the other three groups except for ETA. It should be noted that the quality rating of the evidence related to the immunogenicity outcome was low, so the results of the immunogenicity need to be further verified by subsequent relevant studies.

This study supports the similarity of the four biosimilars to their respective reference drugs, which may serve as evidence for related clinical practice, guideline development, and policy making.

To investigate the activation mechanism of glucagon-like peptide-1 receptor (GLP-1R) by molecular dynamics method.

The active and inactive states of GLP-1R were constructed and embedded in a palmitoyl oleoyl phosphatidyl choline (POPC) bilayer. Molecular dynamics simulations were carried out on each system for 50 ns. Conformations of active and inactive states were compared, and hydrogen bond analysis, energy analysis and principal component analysis etc. were performed.

Conformation analysis showed that the N-terminal ectodomain of GLP-1R moved to the transmembrane domain in inactive state. The third intracellular loop (ICL3) was different between active and inactive states of GLP-1R, suggesting that ICL3 played a significant role in the activation of GLP-1R. The outcomes of hydrogen bond analysis and energy analysis indicated that His7*, Glu9* and Asp15* of GLP-1 were important in the binding of GLP-1R.

Molecular dynamics method can be used as a supplementary tool to study the effects of GLP-1R conformational changes on its own activation and the activation mechanism of GLP-1 binding to receptors, providing theoretical guidance for the development of drugs targeting GLP-1R.

To study the neurotoxicity of DH-004, a derivative of harmine (HM).

IL-1β, TNF-α, IL-12 and IL-6 in the brain of mice were determined by enzyme-linked immunosorbent assay (ELISA). Morphological changes of neurons in cerebral cortex of mice were detected by Nissl staining. Real-time fluorescence quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect ionized calcium binding adaptor molecule-1 (Iba-1) mRNA expression in brain tissue. Iba-1 protein expression in brain tissue was detected by Western-Blot.

ELISA results showed that except for the insignificant changes of IL-6 in each dose group, the expression levels of the other three inflammatory factors with HM-treated mice in the brain tissues were the highest. After the same dose of DH-004 was given, the expression levels of inflammatory factors in the cerebellum tissues were significantly decreased compared with HM-treated mice (P<0.01). The results of Nisier staining, qRT-PCR and Western-Blot showed that compared with the blank control group, HM group had serious and dose-dependent damage to the cortical nerve cells of mice. The expression levels of Iba-1 mRNA and Iba-1 protein in HM group were up-regulated compared with the corresponding blank control group (P<0.01), after the same dose of DH-004 was given, the expression levels of Iba-1 mRNA and Iba-1 protein in cerebellum tissues were significantly down-regulated compared with HM group (P<0.01).

HM can induce the activation of microglia cells in mice, then the activated microglia cells promote the release of inflammatory factors, leading to nerve tissue damage. While DH-004 can inhibit the activation of microglia cells, thus reducing the release of inflammatory factors and reducing neurotoxicity.

To observe the expression of endoplasmic reticulum related protein in hippocampus of VD model rats, determine whether endoplasmic reticulum stress (ERS) plays an important role in the progress of VD, and observe whether different doses of butylphthalide (NBP) has protective effect by regulating the expressions of markers related to ERS.

Grouping and model preparation were carried out in accordance. A Morris water maze experiment was conducted after giving NBP intervention. Western Blot and real time-PCR assay were used for evaluating the expression of endoplasmic reticulum related protein after bilateral common carotid artery occlusion among sham group, model group and different doses of NBP-treated groups.

The escape latency of model group was significantly longer than the sham group and NBP-treated groups on day 2 (P<0.05). Compared with the sham group, the escape latency of the model group was significantly longer on days 3~5 (P<0.05). We detected the protein expression of endoplasmic reticulum related protein. Except for GRP78 in 30 mg·kg^-1 NBP group, the expressions of other proteins in rats treated with NBP significantly decreased compared with the model group (P<0.05). NBP of 120 mg·kg^-1 significantly down-regulated the expression of all the proteins except for XPB1 and elF2α (P<0.05). Except for proteins, we also detected the mRNA expression of endoplasmic reticulum related protein. The mRNA levels of CHOP and elF2α were significantly increased in NBP₃₀ group compared with the model group (P<0.01) and there was no significant difference between NBP₆₀ group and the model group. Besides CHOP and elF2α, all the other markers were significantly decreased in NBP₁₂₀ group compared with the model group (P<0.01). The NBP₁₂₀ group exhibited the most significant differences among the treated groups except for caspase-12 (equal in NBP₁₂₀ and NBP₆₀ groups) (P<0.01).

The markers of ERS in hippocampal tissue were activated in the VD model rats. After giving NBP, the expressions of endoplasmic reticulum related protein were down-regulated. NBP played neuroprotective effects by inhibiting apoptosis of neurons and promoting cell survival by down-regulating the markers related with ERS.

To synthesize a series of Bola type nonionic surfactants using 1, 12-dodecanediol and undecenoic acid as raw materials, characterize the products and evaluate the safety.

Dodecyl Di-10-undecenoate was prepared by esterification, epoxidation was conducted on the product followed by ring opening to prepare disubstituted polyoxyethylene undecanoate dodecyl with different degrees of polymerization glycol ester, and the products were compared with the nonionic surfactant Tween 80 in terms of surface activity, solubilization, hemolysis, etc.

The safe and effective index of PUDD-800 was 10 times that of Tween 80.

PUDD-800 can replace the commercially available surfactants and has the potential for further application in the development of injection formulations.

To compare the rabbit method and dynamic turbidity method for pyrogen detection in heat-clearing Xingnaojing injection.

Three batches of heat-clearing type Chinese medicine injection, Xingnaojing injection, were selected as the research object. Animals were divided into seven groups, including endotoxin, 3 groups of endotoxin+endotoxin test samples, 3 groups of endotoxin test samples. Pyrogen was tested using rabbit pyrogen examination. At the same time, the endotoxin in Xingnaojing Injection was quantitatively detected by dynamic turbidimetry.

No pyrogen reaction was found in 3 batches of test sample groups by rabbit method. The body temperature of rabbits in endotoxin group increased by 0.6 ℃, and the pyrogen reaction occurred. Compared with the endotoxin group, the pyrogen test in endotoxin+test group was false negative. The contents of bacterial endotoxin in 3 batches of Xingnaojing Injection groups were determined by dynamic turbidimetric method, the content of endotoxin was <0.01 EU·mL^-1.

Rabbit pyrogen test is easy to produce false negative results for pyrogen test of heat-clearing Xingnaojing Injection, and dynamic turbidimetry can quantitatively detect the contents of bacterial endotoxin.

To analyze the characteristics of serious adverse reactions (ADRs) caused by rituximab in order to provide reference for rational clinical use of rituximab.

A total of 35 serious ADR reports associated with rituximab were collected in Beijing from 2003 to 2019 and further analyzed.

Among the 35 cases of serious ADRs, there were 18 males and 17 females involved. The average age of the patients was 60±17. Systemic symptoms and respiratory system damage ranked the first, and the occurrence time varied from 30 min to 7 mo after treatment. As a result of serious ADRs, 1 case died, 4 cases aggravated, 12 cases prolonged the course of disease, and 18 cases had no obvious effect on the original disease.

The monitoring over middle-aged and elderly patients and serious ADR patients should be strengthened. If serious ADRs occur, the drug should be stopped in time, and the treatment and rescue should be actively taken so as to ensure the safety of the drug application.