Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy.

Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

Synchronous microencapsulation of multiple components in silymarin into PLGA nanoparticles by an emulsification/solvent evaporation method.

The development of polymeric carriers loaded with extracts suffers from the drawback not to be able to incorporate simultaneously various pharmacological compounds into the formulation. The aim of this study was therefore to achieve synchronous microencapsulation of multiple components of silymarin into poly (lactic-co-glycolic acid) nanoparticle, the most commonly used polymeric carrier with biodegradability and safety. The main strategy taken was to improve the overall entrapment efficiency and to reduce the escaping ratio of the components of different physicochemical properties. The optimized nanoparticles were spherical in morphology with a mean particle size of 150 ± 5 nm. Under common preparative conditions, silybin and isosilybin were entrapped in high efficiency, whereas taxifolin, silychristin and silydianin, especially taxifolin, showed less entrapment because they were more hydrophilic. By changing the pH of the outer aqueous phase and saturating it with silymarin, the entrapment efficiency of taxifolin, silychristin and silydianin could be significantly improved to over 90%, the level similar to silybin and isosilybin, thereby achieving synchronous encapsulation. It could be concluded that synchronous encapsulation of multiple components of silymarin was achieved by optimizing the preparative variables.

The construction of puerarin nanocrystals and its pharmacokinetic and in vivo-in vitro correlation (IVIVC) studies on beagle dog.

Puerarin is widely used in clinics in China as a therapeutic agent for cardiovascular diseases by intravenous administration. Adverse drug reactions caused by cosolvents often increase the patients' treatment burden (high drug costs and low compliance). The development of oral formulation is urgently needed and nanocrystal technique has become a preferred way to develop oral dosage form, nowadays. In this study, high pressure homogenization (HPH) was employed to prepare puerarin nanocrystals by employing SDS as the stabilizer, and redispersibility of the nanocrystals powder was also studied. The nanocrystals prepared was characterized using DLS, DSC, XRD and SEM. A preferred in vivo-in vitro correlation was also established in this study. Pharmacokinetic studies on beagle dog showed that comparing to raw puerarin powder, both of the Cmax and AUC of puerarin nanocrystals were enhanced. From the above results, we can conclude that nanocrystal technique is an efficient technology to improve the oral bioavailability of puerarin.

Effects of particle size on the pharmacokinetics of puerarin nanocrystals and microcrystals after oral administration to rat.

Puerarin, which is extracted from traditional Chinese medicine, is widely used in clinic in China and mainly used as a therapeutic agent to cardiovascular diseases. Owing to its poor water solubility and adverse drug reactions caused by cosolvents after intravenous administration, the development of oral formulation is urgently needed. Nowadays, nanocrystals technique has become a preferred way to develop oral dosage form. In this study, we used high pressure homogenization (HPH) to prepare puerarin nanocrystals and microcrystals with different sizes ranged from 525.8 nm to 1875.6 nm and investigated the influence of particle size on pharmacokinetics. The nanocrystals and microcrystals prepared were characterized using DLS, DSC, XRD and SEM, and we found that the crystalline state of puerarin was changed during the preparation process and the drug was dispersed into HPMC. In the pharmacokinetic study, we observed an increasing of Cmax and AUC and a decreasing of CL/F with the decreasing of particle size. The AUC of the puerarin nanocrystals (525.8 nm) was 7.6-fold of that of raw puerarin suspension, with an absolute bioavailability of 21.44%. From the above results, we can conclude that nanocrystal technique is an efficient technology to improve the oral bioavailability of puerarin.

Controlled release of cyclosporine A self-nanoemulsifying systems from osmotic pump tablets: near zero-order release and pharmacokinetics in dogs.

It is very important to enhance the absorption simultaneously while designing controlled release delivery systems for poorly water-soluble and poorly permeable drugs (BCS IV). In this study, controlled release of cyclosporine (CyA) was achieved by the osmotic release strategy taking advantage of the absorption-enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDSs). The liquid SNEDDS consisting of Labrafil M 1944CS, Transcutol P and Cremophor EL was absorbed by the osmotic tablet core excipients (sucrose, lactose monohydrate, polyethylene oxide, and partly pregelatinized starch) and then transformed into osmotic tablets. Near zero-order release could be achieved for CyA-loaded nanoemulsions reconstituted from the SNEDDS. In general, the influencing factor study indicated that the release rate increased with increase of inner osmotic pressure, ratio of osmotic agent to suspending agent, content of pore-forming agent, and size of release orifice, whereas the thickness of the membrane impeded the release of CyA nanoemulsion. Pharmacokinetic study showed steady blood CyA profiles with prolonged Tmax and MRT, and significantly reduced Cmax for self-nanoemulsifying osmotic pump tablet (SNEOPT) in comparison with highly fluctuating profiles of the core tablet and Sandimmune Neoral(®). However, similar oral bioavailability was observed for either controlled release or non-controlled release formulations. It was concluded that simultaneous controlling on CyA release and absorption-enhancing had been achieved by a combination of osmotic tablet and SNEDDS.

Simultaneous determination of synephrine, arecoline, and norisoboldine in Chinese patent medicine Si-Mo-Tang oral liquid preparation by strong cation exchange high performance liquid chromatography.

CONTEXT: Chinese patent medicine Si-Mo-Tang oral liquid preparation (SMT) is composed of Aucklandia luppa Decne (Compositae), Citrus aurantium Linn (Rutaceae), Lindera aggregata (Sims) Kosterm (Lauraceae), and Areca catechu Linn (Arecaceae). Studies of SMT have been impeded due to the lack of quality control methods. OBJECTIVE: This study aimed to simultaneously determine three alkaloids including synephrine, arecoline, and norisoboldine in SMT for the first time. MATERIALS AND METHODS: A strong cation exchange (SCX) high performance liquid chromatography (HPLC) method was developed to simultaneously determine synephrine, arecoline, and norisoboldine in SMT, and was compared with ion-pairing chromatography using regular reversed-phase chromatography columns. System suitability parameters of synephrine, arecoline, and norisoboldine using the SCX chromatography column were investigated. RESULTS: Results demonstrated that good separations were achieved on an Agilent SCX (250 × 4.6 mm, 5 µm) column at 35 °C. The mobile phase consisting of methanol-0.2% phosphoric acid was delivered at a constant flow of 1.0 mL min(-1) and the eluent was monitored at 215 nm. The HPLC method showed good linearity for the examined concentration ranges of 2.55-255.0, 1.30-208.0, and 2.06-201.6 µg mL(-1) for synephrine, arecoline, and norisoboldine, respectively. The limits of quantification (S/N = 10) were 2.55, 1.30, and 2.06 µg mL(-1), the limits of detection (S/N = 3) were 1.53, 0.78, and 1.21 µg mL(-1), and average recoveries were 98.99, 95.63 and 99.04%, respectively, for synephrine, arecoline, and norisoboldine. DISCUSSION AND CONCLUSION: This method has been successfully applied to determine synephrine, arecoline, and norisoboldine in Chinese patent medicine SMT.

[Extracting flavonoids from Choerospondias axillaris by percolation].

OBJECTIVE: To study the technology of extracting flavonoids from Choerospondias axillaris by percolation. METHOD: The optimum extraction process was selected by orthogonal design, and the factors of concentration amount of ethanol and soaking time were investigated. Total flavonoids was determined by spectrophotometer to compare the effect of extraction. RESULT: The optimum extraction process was that added 8 times 60% ethanol and then impregnated for 48 h. CONCLUSION: The technology is stable and feasible, it's suitable for industrial production.