Rotor-based image-guided therapy of glioblastoma.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.

Gut Microbiota and Its Metabolite Deoxycholic Acid Contribute to Sucralose Consumption-Induced Nonalcoholic Fatty Liver Disease.

As important signal metabolites within enterohepatic circulation, bile acids (BAs) play a pivotal role during the occurrence and development of diet-induced nonalcoholic fatty liver disease (NAFLD). Here, we evaluated the functional effects of BAs and gut microbiota contributing to sucralose consumption-induced NAFLD of mice. The results showed that sucralose consumption significantly upregulated the abundance of intestinal genera Bacteroides and Clostridium, which produced deoxycholic acid (DCA) accumulating in multiple biological matrixes including feces, serum, and liver of mice. Subsequently, elevated hepatic DCA, one of the endogenous antagonists of the farnesol X receptor (Fxr), inhibited hepatic gene expression including a small heterodimer partner (Shp) and Fxr leading to sucralose-induced NAFLD in mice. Dietary supplements with fructo-oligosaccharide or metformin markedly restored genera Bacteroides and Clostridium abundance and the DCA level of sucralose-consuming mice, which eventually ameliorated NAFLD. These findings highlighted the effects of gut microbiota and its metabolite DCA on sucralose-induced NAFLD of mice.

The study of citrus-derived flavonoids as effective bitter taste inhibitors.

BACKGROUND: The pericarp of citrus in rutaceae is rich in flavonoids that may possess diverse biological activities. Some citrus flavonoids have been used as natural bitterness inhibitors; however, many citrus flavonoid analogues that possess merit taste amelioration functions have not been reported with respect to utilization in food industry. RESULTS: The effects of 12 citrus flavonoids on the inhibition of the bitter taste of naringin, quinine hydrochloride and stevioside were evaluated both by a sensory panel and electronic tongue analysis. Among the flavonoid compounds evaluated, both neohesperidin dihydrochalcone (NHDC) and neodiosmin were identified to show an excellent bitterness inhibition effect on all three bitterness vehicles tested. The results of the electronic tongue evaluation also showed that the addition of neodiosmin, NHDC or hesperidin dihydrochalcone-7-o-glucoside (HDC-7-G) was able to reduce significantly the bitterness response value of quinine hydrochloride, which is consistent with the sensory panel evaluation. Structure-activity relationship analysis found that the 7-linked neohesperidosyloxy group in the A-ring of the citrus flavonoid skeleton has the best bitterness inhibition effect. In addition, a ternary mixture of NHDC, neodiosmin and naringin, and neodiosmin/ß-cyclodextrin was formulated and it demonstrated, for the first time in the flavor improvement of citrus fruit wine, an enhancement of sweetness and a reduction of bitter taste. CONCLUSION: Twelve citrus flavonoids were found to inhibit the bitter taste of naringin, quinine hydrochloride and stevioside. With respect to the structure-activity relationship analysis, it was found that the 7-linked neohesperidosyloxy group in the A-ring of the citrus flavonoid skeleton possessed the best bitterness inhibition effect. © 2021 Society of Chemical Industry.

Network pharmacology, molecular docking integrated surface plasmon resonance technology reveals the mechanism of Toujie Quwen Granules against coronavirus disease 2019 pneumonia.

BACKGROUND: The Coronavirus disease 2019 pneumonia broke out in 2019 (COVID-19) and spread rapidly, which causes serious harm to the health of people and a huge economic burden around the world. PURPOSE: In this study, the network pharmacology, molecular docking and surface plasmon resonance technology (SPR) were used to explore the potential compounds and interaction mechanism in the Toujie Quwen Granules (TQG) for the treatment of coronavirus pneumonia 2019. STUDY DESIGN: The chemical constituents and compound targets of Lonicerae Japonicae Flos, Pseudostellariae Radix, Artemisia Annua L, Peucedani Radix, Forsythiae Fructus, Scutellariae Radix, Hedysarum Multijugum Maxim, Isatidis Folium, Radix Bupleuri, Fritiliariae Irrhosae Bulbus, Cicadae Periostracum, Poria Cocos Wolf, Pseudobulbus Cremastrae Seu Pleiones, Mume Fructus, Figwort Root and Fritillariae Thunbrgii Bulbus in TQG were searched. The target name was translated to gene name using the UniProt database and then the Chinese medicine-compound-target network was constructed. Protein-protein interaction network (PPI), Gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the core targets were performed in the Metascape to predict its mechanism. The top 34 compounds in the Chinese medicine-compound-target network were docked with SARS-CoV-2 3CL enzyme and SARS--CoV--2 RNA-dependent RNA polymerase (RdRp) and then the 13 compounds with lowest affinity score were docked with angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 Spike protein and interleukin 6 to explore its interaction mechanism. Lastly, SPR experiments were done using the quercetin, astragaloside IV, rutin and isoquercitrin, which were screened from the Chinese medicine-compound-target network and molecular docking. RESULTS: The Chinese medicine-compound-target network includes 16 medicinal materials, 111 compounds and 298 targets, in which the degree of PTGS2, TNF and IL-6 is higher compared with other targets and which are the disease target exactly. The result of GO function enrichment analysis included the response to the molecule of bacterial origin, positive regulation of cell death, apoptotic signaling pathway, cytokine-mediated signaling pathway, cytokine receptor binding and so on. KEGG pathway analysis enrichment revealed two pathways: signaling pathway- IL-17 and signaling pathway- TNF. The result of molecular docking showed that the affinity score of compounds including quercetin, isoquercitrin, astragaloside IV and rutin is higher than other compounds. In addition, the SPR experiments revealed that the quercetin and isoquercitrin were combined with SARS-CoV-2 Spike protein rather than Angiotensin-converting enzyme 2, while astragaloside IV and rutin were combined with ACE2 rather than SARS-CoV-2 Spike protein. CONCLUSION: TQG may have therapeutic effects on COVID-19 by regulating viral infection, immune and inflammation related targets and pathways, in the way of multi-component, multi-target and multi-pathway.

Synthesis and biological evaluation of curcumin derivatives containing NSAIDs for their anti-inflammatory activity.

Oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) was frequently associated with serious adverse effects. Inspired by curcumin-a naturally traditional Chinese medicine, a series of curcumin derivatives containing NSAIDs, used for transdermal application, were synthesized and screened for their anti-inflammatory activities in vitro and in vivo. Compared with curcumin and parent NSAID (salicylic acid and salsalate), topical application of A11 and B13 onto mouse ear edema, prior to TPA treatment markedly suppressed the expression of IL-1ß, IL-6 and TNF-α, respectively. Mechanistically, A11 and B13 blocked the phosphorylation of IκBα and suppressed the activation of p65 and IκBα. It was found that A11 and B13 may be potent anti-inflammatory agents for the treatment of inflammatory diseases.

Anticancer activity of Acanthopanax trifoliatus (L) Merr extracts is associated with inhibition of NF-kB activity and decreased Erk1/2 and Akt phosphorylation.

Acanthopanax trifoliatus (L) Merr (AT) is commonly used as an herbal medicine and edible plant in some areas of China and other Asian countries. AT is thought to have anticancer effects, but potential mechanisms remain unknown. To assess the anticancer properties of AT, we exposed prostate cancer cells to AT extracts and assessed cell proliferation and signaling pathways. An ethanol extract of AT was suspended in water followed by sequential extraction with petroleum ether, ethyl acetate and n-butanol. PC-3 cells were treated with different concentrations of each extract and cell viability was determined by the MTT and trypan blue exclusion assays. The ethyl acetate extract of the ethanol extract had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than any of the other extracts. Mechanistic studies demonstrated that the ethyl acetate extract suppressed the transcriptional activity of NF-kB, increased the level of caspase-3, and decreased the levels of phospho-Erk1/2 and phospho-Akt. This is the first report on the anticancer activity of AT in cultured human prostate cancer cells. The results suggest that AT can provide a plant-based medicine for the treatment or prevention of prostate cancer.

Effects of ursolic acid derivatives on Caco-2 cells and their alleviating role in streptozocin-induced type 2 diabetic rats.

In this study, the effect and mechanism of a series of ursolic acid (UA) derivatives on glucose uptake were investigated in a Caco-2 cells model. Their effect on hyperglycemia, hyperlipidemia and oxidative stress were also demonstrated in streptozocin (STZ)-induced diabetic rats. 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-glucose (2-NBDG) was used as a fluorescein in Caco-2 cells model to screen UA derivatives by glucose uptake and expression of glucose transporter protein (SGLT-1, GLUT-2). Moreover, STZ-induced diabetic rats were administered with these derivatives for 4 weeks of treatment. The fasting blood glucose (FBG), insulin levels, biochemical parameters, lipid levels, and oxidative stress markers were finally evaluated. The results of this study indicated that compounds 10 and 11 significantly inhibited 2-NBDG uptake under both Na+-dependent and Na+-independent conditions by decreasing SGLT-1 and GLUT-2 expression in the Caco-2 cells model. Further in vivo studies revealed that compound 10 significantly reduced hyperglycemia by increasing levels of serum insulin, total protein, and albumin, while the fasting blood glucose, body weight and food intake were restored much closer to those of normal rats. Compounds 10 and 11 showed hypolipidemic activity by decreasing the total amounts of cholesterol (TC) and triglycerides (TG). Furthermore, compound 10 showed antioxidant potential which was confirmed by elevation of glutathione (GSH) and superoxide dismutase (SOD) and reduction of malondialdehyde (MDA) levels in the liver and kidney of diabetic rats. It was concluded that compound 10 caused an apparent inhibition of intestinal glucose uptake in Caco-2 cells and hypoglycemia, hypolipidemia and augmented oxidative stress in STZ-induced diabetic rats. Thus, compound 10 could be developed as a potentially complementary therapeutic or prophylactic agent for diabetics mellitus and its complications.

Biotransformation and pharmacokinetics of the novel anticancer drug, SYUIQ-5, in the rat.

SYUIQ-5, a novel telomerase inhibitor, has demonstrated antitumor activity in nude mouse studies. The objective of the present study was to examine the metabolism and pharmacokinetics of SYUIQ-5 in rats. The plasma pharmacokinetics of SYUIQ-5 was nonlinear following i.p. administration at 15, 30 and 60 mg/kg. SYUIQ-5 metabolism in rat liver microsomes followed Michaelis-Menten kinetics, with Km and Vmax values of 12.3 microM and 2.01 nmol/min/mg protein, respectively. Ketoconazole significantly inhibited the metabolism of SYUIQ-5 in liver microsomes from rats pretreated with control vehicle or various inducers, whereas sulphaphenazole, ticlopidine, quinidine, and methylpyrazole had no inhibitory effects on SYUIQ-5 metabolism. Dexamethasone and beta-naphthoflavone (BNF), but not phenobarbital and ethanol, significantly induced SYUIQ-5 metabolism in rats. Alpha-naphthoflavone significantly inhibited SYUIQ-5 metabolism in liver microsomes from BNF-pretreated rats. Similar to other secondary amines, SYUIQ-5 underwent N-demethylation and O-oxygenation to at least two metabolites by rat liver microsomes. Pretreatment of rats with SYUIQ-5 at 0.1, 5 or 10 mg/kg for 5 days significantly induced the expression and activity of rat Cyp1A1/2, and induced Cyp3A1/2 expression at 10 mg/kg, but not Cyp2E1 and 2B1/2. These results indicate that that SYUIQ-5 exhibits dose-dependent pharmacokinetics in rats and it is mainly metabolized by Cyp3A1/2.