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Ginkgo biloba L. leaf (GBL) has been reported to protect against ischemic stroke (IS), one of the leading causes of death and longterm disability worldwide, while there is a lack of systematic study on the exact mechanism. Here, network pharmacology and bioinformatics were used to predict the active components, important targets, and potential mechanisms of GBL in the treatment of IS. Active compounds of GBL were screened based on drug-like index and oral bioavailability, key target genes were screened based on network pharmacology and gene chip, downstream pathways for the regulation of key target genes were predicted based on gene set enrichment analysis, and the interaction between key targets and active compounds was verified based on molecular docking. The results showed that GBL played a protective role in cerebral ischemia with mainly 14 active compounds, such as isoquercitrin, luteolin-4'-glucoside, beta-sitosterol, campesterol, diosmetin, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M, isogoycyrol, laricitrin, luteolin, sesamin, and stigmasterol. Further studies revealed that GBL played important role in immunomodulation and inflammation inhibition after cerebral ischemia by acting on its peripheral targets ARG1 and MMP9 to regulate Toll-like receptor, Chemokine and Notch signaling pathway. Meanwhile, GBL played important role in reducing neuroinflammation and blood-brain barrier damage after cerebral ischemia by acting on its central targets, CCL2, PTGS2, IL6, IL1B and MMP9 to regulate the Cytokine-cytokine receptor interaction, Jak-STAT, and Toll-like receptor signaling pathway. Additionally, molecular docking verified that the active compounds mentioned above could bind to ARG1, MMP9, CCL2, PTGS2, IL6, and IL1B. The present study shows the multicomponent, multitarget and multichannel pharmacological effects of GBL on cerebral ischemia and provides a new strategy for the treatment of IS. [ABSTRACT FROM AUTHOR]

To improve the bioavailability oforally administered drugs, we synthesized a pH-sensitive polymer (poly(ethyleneglycol)–poly(2-methyl-2-carboxyl-propylene carbonate)–vitaminE, mPEG–PCC–VE) attempting to integrate the advantages of enteric coating and P-glycoprotein(P-gp) inhibition. The aliphatic polycarbonate chain was functionalizedwith carboxyl groups and vitamin E via postpolymerization modification.Optimized by comparison and central composite design, mPEG113–PCC32–VE4exhibited low criticalmicelle concentration of 1.7 × 10–6mg/mL andhigh drug loading ability for tacrolimus (21.2% ± 2.7%, w/w).The pH-responsive profile was demonstrated by pH-dependent swellingand in vitrodrug release. Less than 4.0% tacrolimuswas released under simulated gastric fluid after 2.5 h, whereas animmediate release was observed under simulated intestinal fluid. ThemPEG113–PCC32–VE4micellessignificantly increased the absorption of P-gp substrate tacrolimusin the whole intestine. The oral bioavailability of tacrolimus micelleswas 6-fold higher than that of tacrolimus solution in rats. This entericpolymer therefore has the potential to become a useful nanoscale carrierfor oral delivery of drugs. [ABSTRACT FROM AUTHOR]

Uridine, a potential endogenous neuromodulator, has been demonstrated to interact with the dopaminergic system and to regulate dopamine-related behaviors. The present study investigated the effects of uridine on morphine-induced hyperactivity and behavioral sensitization and on modulating dopaminergic neurotransmission in mice, which may help to understand how uridine and its metabolites act as modulators of the GABAA receptors. The results showed that either systemic (30 or 100 mg/kg) or central (30, 100 or 300 nM) uridine administration significantly attenuated the hyperactivity induced by acute morphine treatment in mice. Intracerebroventricular administration of uracil and β-alanine also inhibited morphine-induced hyperactivity. Uridine, a known modulator of the GABA receptors, increased the extracellular levels of GABA in the brain. In addition, the GABAA receptors antagonist bicuculline significantly attenuated the effects of uridine on morphine-induced hyperactivity, suggesting that the GABAA receptors potentially mediate the effects of uridine and its metabolites on morphine-related activity. It was also observed that morphine-induced locomotor sensitization was abolished after chronic uridine treatment. In vivo microdialysis demonstrated that uridine reversed morphine-induced dopamine release in the dorsal striatum of morphine-sensitized mice. In conclusion, these data suggest that the therapeutic effects of uridine and its metabolites on morphine-induced hyperactivity and established behavioral sensitization may be mediated in part by interfering with the dopaminergic system possibly via agonistic effects at GABAA receptors. [ABSTRACT FROM AUTHOR]