Progress on the application of artificial intelligence technology in ligand-based and receptor structure-based drug screening / 药学学报

Artificial intelligence technology is being widely applied in drug screening. This paper introduces the characteristics of artificial intelligence, and summarizes the application and progress of artificial intelligence technology especially deep learning in drug screening, from ligand-based and receptor structure-based aspects. This paper also introduces how to apply artificial intelligence to drug design from these two aspects. Finally, we discuss the main limitations, challenges, and prospects of artificial intelligence technology in the field of drug screening.

Research progress on the neurorestorative benefits of mesenchymal stem cell exosomes for the treatment of ischemic stroke / 药学学报

Ischemic stroke is one of the leading causes of death and disability worldwide. A large number of preclinical studies have demonstrated that exogenous cell-based therapies such as mesenchymal stem cell transplantation can promote brain function recovery in the subacute phase of stroke. Emerging data indicate that mesenchymal stem cell-derived exosomes play a key role in mediating tissue repair by participating in intercellular signal transduction and transferring biological information especially microRNA to recipient cells, which affects endo-genous recovery in ischemic brain tissue after injury. In this review we briefly describe the characteristics and biological functions of exosomes and exosomal microRNA, and discuss the therapeutic effects of mesenchymal stem cell-derived exosomes on ischemic stroke from different perspectives. Finally, we outline the potential clinical value of exosomes and challenges of translating these therapies into clinical trials.

Preparation of a co-amorphous form of bexarotene-PVP-K30 and evaluation in rats / 药学学报

Bexarotene is a synthetic analogue of retinoic acid and exerts protective effects on the nervous system. However, low bioavailability and poor solubility of the crystal type I form severely limits the application of bexarotene in the clinic. A co-amorphous sample of bexarotene-PVP-K30 was prepared and the structure was characterized by X-ray diffraction and infrared spectroscopy. To determine the pharmacokinetics and tissue distribution of bexarotene, an LC-MS method was established to profile and quantify bexarotene in plasma and tissues of SD rats. In vitro dissolution indicated that the co-amorphous form improved the dissolution of bexarotene in pure water 4.17-fold. After rats were orally administered bexarotene or bexarotene-PVP-K30 co-amorphous (equivalent to 30 mg·kg-1 bexarotene) the AUC of bexarotene was 7 034.89 and 10 174.03 μg·L-1·h respectively, the peak time was advanced from 7.33 h to 0.9 h with the amorphous form, and Cmax was enhanced from 627.76 to 3 011.88 μg·L-1. The co-amorphous form yielded higher concentrations of bexarotene in various tissues, especially brain, liver and kidney. Animal welfare and experimental procedures complied with the rules of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. The results indicate that bexarotene-PVP-K30 co-amorphous improves the pharmacokinetic characteristics of bexarotene and provides preclinical data in support of bexarotene-PVP-K30 for the treatment of brain diseases.

Isorhamnetin activates Sirt1/PGC-1α signaling pathway to inhibit MPP+-induced SH-SY5Y cell injury / 药学学报

We studied the protective effect and mechanism of isorhamnetin (ISO) on 1-methyl-4-phenylpyridiniumion (MPP+)-induced SH-SY5Y cells injury. MPP+-induced SH-SY5Y cell injury model was established, and cell viability was measured by MTT and LDH methods. The activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in cells were determined to investigate the level of oxidative stress. DCFH-DA and MitoSOX fluorescence probes were used to detect the levels of intracellular reactive oxygen species (ROS) and mitochondria superoxide, respectively. JC-1 fluorescence probe was used to detect the changes of mitochondrial membrane potential. Western blot and immunofluorescence methods were used to determine the expressions of Sirt1 and PGC-1 proteins, as well as the expression levels of apoptosis-related proteins Bax and Bcl-2. MPP+ at the dose of 500 μmol·L-1 significantly reduced SH-SY5Y cells viability to 52.46% and increased LDH release to 417.63%. ISO at 5 and 15 μmol·L-1 significantly increased the expression of Sirt1 and PGC-1α, inhibited LDH release, reduced intracellular ROS and mitochondria superoxide, inhibited the decline of mitochondrial membrane potential and increased cell viability to 61.61% and 67.55%. In addition, ISO could downregulate the expression of Bax and upregulate the expression of Bcl-2 to reduce cell apoptosis. ISO-mediated inhibition of apoptosis could be reversed by Sirt1 specific inhibitor Sirtinol. Through activating Sirt1/PGC-1α signaling pathway, ISO could reduce oxidative stress injury and inhibit cell apoptosis to protect cells from MPP+ injury.

Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation / 中国天然药物

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.

Effects of salvianolic acid D on mitochondrial function and biosynthesis in SH-SY5Y cells after MPP+injury / 中国药理学通报

Aim To investigate the effects of salvianol-ic acid D ( SalD) on mitochondrial function and bio- synthesis in SH-SY5Y cells after MPP+injury and the possible mechanisms. Methods The cell model was established by MPP+injury in SH-SY5Y cells. The cytotoxicity of MPP+was detected by MTT assay. The effects of SalD on viability of SH-SY5Y cells were ex-amined by MTT and LDH assay. The apoptosis of SH-SY5Y cells was detected by AO/EB assay. The levels of ROS and mitochondrial superoxide were determined using DCFH-DA and MitoSOX probes, respectively. Mitochondrial function was examined by measuring ATP level and mitochondrial membrane potential. The levels of PGC-1α and its downstream regulatory genes NRF1 and TFAM mRNA were detected by qPCR. The protein levels of PGC-1α, NRF1 and TFAM in cells were detected by Western blot and immunofluorescence assays. Results MPP+injury resulted in a significant reduction of cell viability to 51.34%. 0.1, 1, 5 μmol ·L-1SalD and 5 mmol·L-1NAC could reduce MPP+-induced SH-SY5Y cell injury and LDH release. The cell viability increased to 67.98% , 71.79% , 76.91% and 77.55% , respectively. Moreover, SalD could reduce the increase of intracellular ROS and mi-tochondrial superoxide induced by MPP+, decrease mitochondrial membrane potential and improve mito-chondrial function. SalD also significantly increased both the transcription and expression levels of PGC-1α, NRF1 and TFAM. Conclusion SalD could in-hibit MPP+-induced SH-SY5Y cell injury and improve mitochondrial function and mitochondrial biosynthesis.

Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation / 中国天然药物

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.

Pharmacokinetics of two kinds of nimodipine crystal tablets in rhesus monkey / 药学学报

Nimodipine is a selective calcium channel antagonist of cerebral vessels smooth muscle and also has polymorphs. It hasn't been reported that different crystal forms influence the metabolism process in huge animals like rhesus monkeys in vivo. This article may provide reference in the control of the quality of nimodipine and quality consistency evaluation. The powder X-ray diffraction (PXRD) method was used to identify different crystal forms and the dissolution test in vitro was used to detect the dissolution. The LC-MS method of assay nimodipine in rhesus monkey plasm was established to determine pharmacokinetics characters of different tablets from different crystal forms in rhesus monkey in vivo. As a result, the tablets inherit difference crystal forms and the dissolution of reference tablets is 1.3% higher than crystal tablets. However, the maximal blood concentration (Cmax) of crystal tablet was 37.3% higher than reference tablet and AUC of crystal tablet was 29.8% higher than reference tablet. After administrated 2.5 mg·kg-1 orally, calculated pharmacokinetics characters were observed as following:Cmax was 381.4 ±327.3 and 178.0 ±214.8 μg·L-1; AUC0-t was 853.1 ±500.7 and 646.5 ±430.3 μg·L-1·h respectively. The serum concentration result of different nimodipine tablets in rhesus monkeys in vivo suggests that polymorphs has a significantly distinction, which points out that controlling the crystal forms of nimodipine is essential to ensure the therapeutic efficacy. It is essential to execute quality consistency evaluation.

Salvianolic acid A alleviate the brain damage in rats after cerebral ischemia-reperfusion through Nrf2/HO-1 pathway / 药学学报

The aim of present study is to investigate the protective effects and mechanism of salvianolic acid A (SAA) on cerebral ischemia-reperfusion injury in rats. The model was established with middle cerebral artery occlusion and reperfusion (MCAO/R) with ischemia for 1.5 h and reperfusion for 24 h in adult male SD rats. After the behavior assessment, TTC assay was used to calculate the infarct volume of rat brain; the distribution of Nrf2 in nuclear and cytoplasm and expression of HO-1 were detected by Western blot. The PC12 cells injury model was established with oxygen-glucose deprivation for 6 h and reintroduction for 24 h. Cell viability was determined with MTT assay, and the expression of Nrf2 and HO-1 were detected through immunofluorescence staining. The mechanisms were investigated in PC12 cells with Nrf2 knocking down by siRNA. SAA (10 and 20 mg·kg-1) significantly reduced the neuronal damage in MCAO/R model, and SAA (0.5 and 5 μmol·L-1) increased cell viability in PC12 cells injury model. Meanwhile, the nuclear translocation of Nrf-2 and the expression of HO-1 were increased in PC12 cell and rats brain. SAA exhibited anti-cerebral ischemia-reperfusion effects. The mechanism may be related to activation of Nrf2/HO-1 signaling pathway, which promotes the synthesis and nuclear translocation of Nrf2 to enhance the expression of the antioxidant protein HO-1.

Pharmacokinetic comparison of two ozagrel polymorph forms in SD rats / 药学学报

To enhance the quality and efficiency of ozagrel by investigating the differences between the ozagrel polymorphs in bioavailability. Solid ozagrel in different polymorph forms were orally administered to SD rats. An HPLC method was established to determinate plasma level of ozagrel. The bioavailabilities of two polymorph forms were calculated and compared. The pharmacokinetic parameters of ozagrel, were as follows: Cmax was 32.72 ± 17.04 and 34.01 ± 19.13 mg · L(-1), respectively; AUC0-t was 61.14 ± 14.76 and 85.56 ± 18.08 mg · L(-1) · h, respectively; t½ was 1.53 ± 0.51 and 4.73 ± 3.00 h, respectively. There was no significant difference in pharmacokinetic parameters between form I and II polymorphs of ozagrel while the t½ of form II is longer, which indicates that the use of form II polymorph as pharmaceutical product may prolong the effective action time in clinics. This would help the polymorph quality control in drug production.

Pharmacokinetics of salvianolic acid A after single intravenous administration in Rhesus monkey / 药学学报

Salvianolic acid A (Sal A) is one of the most effective compounds isolated from the root of Salvia miltiorrhiza. Up to now, several studies regarding the pharmacokinetic profiles of Sal A have been reported, however there is no such study reported in monkeys, the species which is more similar to human. The aim of this study is to develop a LC-MS method for the determination of Sal A in monkey plasma and apply it to the pharmacokinetic studies of monkeys. After single intravenous administration of Sal A, the plasma concentration-time curves were observed and the main pharmacokinetic parameters were calculated. The plasma concentration at 2 min (C2 (min)) values were (28.343 ± 6.426), (45.679 ± 12.301) and (113.293 ± 24.360) mg x L(-1) for Rhesus monkeys treated with Sal A at 2.5, 5 and 10 mg x kg(-1). The area under the concentration-time curve (AUC(0-∞)) values were (3.316 ± 0.871), (5.754 ± 2.150) and (13.761 ± 2.825) μg x L(-1) x h, respectively. Furthermore, this method was improved and applied to the simultaneous determination of Sal A, Sal B and Sal C, which provided useful information for preclinical studies and clinical trials of Sal A, Sal B and Sal C.