The Nrf2-Keap1-ARE pathway is an important signaling axis that functions to protect cells against oxidative stress and harmful chemicals through the induction of cytoprotective genes. The maintenance and protective role of Nrf2 pathway has been recognized as a means for chemoprevention. On the other hand, constitutive activation of Nrf2, due to somatic mutations of genes that control Nrf2 degradation, promotes carcinogenesis and imparts chemoresistance to cancer cells. Autophagy is another tightly regulated complex cellular process that functions as a cellular quality control system to remove damaged proteins or organelles. Recently, these two cellular pathways were shown to intersect through the direct interaction between p62 (an autophagy adaptor protein) and Keap1. Dysregulation of autophagy was shown to result in prolonged activation of Nrf2 in a p62-dependent manner, which is associated with the pathogenesis and therapies of several human diseases including cancer. In this review, we discuss the molecular mechanisms of p62-mediated Nrf2 signaling pathway, with a special emphasis on their impact on nervous system disease, cardiovascular disease and cancer.

Eighty percent of bacterial infections are related to the formation of bacterial biofilm. Compared with planktonic bacteria, bacterial biofilm is 10-1 000 times more resistant to antibiotics, which is the main cause of current bacterial drug resistance. A comprehensive understanding of the characteristics and resistance mechanisms of bacteria biofilm will help us treat the stubborn infections caused by the bacterial biofilm better and solve the problem of bacterial drug resistance. In this review, the composition and quorum sensing of bacterial biofilm, two major patterns of biofilm formation and drug resistance mechanisms were presented. Furthermore, representative compounds with anti-biofilm activity and compounds synergistic with antibiotics in anti-biofilm actions were introduced. Nano drug delivery strategies used for anti-biofilm in recent years as well as a novel drug delivery system-molecularly imprinted polymer was also introduced.

The development and metabolism of medicinal plant is affected by many factors, among which the effect from endophytic fungi has been noticed recently and has become one of hot fields. In order to explore the effect of endophytic fungi on gene expression in R. crenulata, RNA-sequencing was used to find genes involved in metabolic pathways, and the differential genes were verified by real-time fluorescent quantitative PCR. The method of 2^-△△Ct was used to analyze the relative expression levels of genes in related metabolic pathways, which was used to verify the result of transcriptomics sequencing. The results showed that the endophytic fungus, P. fortinii, could up-regulate the gene expression in lipid metabolic pathway of R. crenulata. In signal transduction pathway, the genes were influenced at different level but the gene expressions were significantly increased under control of Notch signaling pathway, which was 34 times of that in control. The gene expressions of environmental adaption pathway were up-regulated in R. crenulata after inoculation of P. fortinii. This study could provide help for further understanding on mechanism of plant-fungus interaction, root cause of geoherbalism of medicinal plant and exploring bio-function of endophytic fungi.

Annonaceous acetogenins (ACGs) are effective part extracted and separated from Annona squamosa seeds, they have good antitumor activity against a variety of tumor cells. However, the solubility of ACGs is poor with serious toxic and side effects, which greatly limits their application in clinical practice. In this study poloxamer 188 (P188) was selected as a drug carrier or a stabilizer to prepare ACGs nanosuspensions (ACGs-NSps) using anti-solvent precipitation. The nanosuspensions were examined via dynamic light scattering (DLS) method to examine size of the nanosuspensions. Transmission electron microscopy was used to observe their morphology. HPLC assay was used to measure their drug loading content and the in vitro drug release. The stability of ACGs-NSps at room temperature, in various physiological media and plasma, and the hemolytic test and lyophilization were all investigated. MTT assay was performed to study the cytotoxocity of ACGs-NSps against four tumor cell lines. 4T1 bearing tumor model was used to assess their in vivo antitumor therapeutic efficacy. The obtained ACGs-NSps were spherical, the average particle size was 169.4±1.25 nm, the polydispersity index (PDI) value was 0.130±0.020, the zeta potential was -19.8 mV and the drug loading content was 48.18%. ACGs-NSps were stable at room temperature for at least 15 days. They could be lyophilized in the presence of 0.5% glucose and 2.0% P188. ACGs-NSps showed sustained in vitro drug release, and the cumulative drug release reached 80.82% within 144 hours. ACGs-NSps maintained their particle size in various physiological media, and plasma with no hemolysis and then met demands of both oral and intravenous administration. In contrast to free ACGs, ACGs-NSps displayed significantly higher cytotoxicity against 4T1 (IC₅₀, 0.892±0.124 μg·mL^-1 vs 2.495±0.108 μg·mL^-1, P < 0.05), HeLa (IC₅₀, 0.747±0.051 μg·mL^-1 vs 2.204±0.064 μg·mL^-1, P < 0.01), HepG2 (IC₅₀, 2.265±0.081 μg·mL^-1 vs 4.159±0.071 μg·mL^-1, P < 0.01), and MCF-7 (IC₅₀, 0.473±0.024 μg·mL^-1 vs 1.196±0.022 μg·mL^-1, P < 0.05). The in vivo study demonstrated that the daily oral administration of ACGs-NSps (3 mg·kg^-1) resulted in higher tumor inhibition rate compared to ACGs/oil solution (67.23% vs 53.11%), comparable to the intravenous injection of 0.5 mg·kg^-1 ACGs-NSps every other day (70.34%). Nanosuspensions effectively solved the problem of ACGs insolubility and difficulty in drug delivery. Using P188, a pharmaceutic adjuvant approved by FDA for iv injection, the resultant ACGs-NSps appear promising as an anti-tumor drug that can be used in clinic.

The discovery and verification of components are prerequisites for developing of component preparations. The molecular docking technique and pharmacodynamic activity evaluation provide effective methods for the discovery and verification of the representative components of Chishao terpene glucoside components (CSTGC_S) against ischemia and hypoxia injury. The chemical constituents of CSTGC_S were analyzed qualitatively by UPLC-TOF/MS/MS. Main chemical constituents were docked with key receptor proteins of myocardial ischemia to preliminarily screen anti-ischemia active ingredients, and screening for main active ingredients with Libdockscore. Then a H9c2 cell hypoxia injury model was established, and creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA) were determined to screen the representative combinations in CSTGC_S. In addition, apoptosis index, apoptotic protein expression and mitochondria-associated mRNA levels were determined to verify the inhibition of the representative components (RC_S) on the apoptosis of hypoxic cells. Eventually, the representative components of CSTGC_S were determined. The results showed that paeoniflorin, albiflorin, benzoyl paeoniflorin and oxypaeoniflorin were considered to be the main active components because of their high matching with target proteins (4TWT, 3O4O, 4KZN, 1M9J) in space and energy. There was no statistical difference in regulating CK, LDH, SOD, MDA levels and maintaining mitochondrial function as well as inhibiting cell apoptosis between CSTGC_S group and RC_S group (paeoniflorin + albiflorin + benzoyl paeoniflorin combination). Therefore, paeoniflorin, albiflorin and benzoyl paeoniflorin were selected as the most representative ingredients of CSTGC_S against ischemia and hypoxia injury, providing a basis for the overall properties of the components and formulation of CSTGC_S.

Based on the charge repulsion and solution-diffusion effect in nanofiltration separation, the correlation among mass transfer behavior, solution environment and molecular structure of three typical alkaloids from medicine was analyzed by nanofiltration mass mathematical model. The experiment revealed a linear relationship between ln[(1-R_o)·J_v/R_o] and J_v, and the regression coefficients were all greater than 0.9. Compared with the ultrafiltration separation behavior conforming to molecular sieve, the mass transfer coefficient of three alkaloids under different pH was pH 3.00 < pH 7.00 < pH 10.00. As the pH changed, the state of alkaloid transit from ionic state to a free state, the alkaloid could easily approach the membrane surface and pass through the nanofiltration membrane with charge repulsion and solution-diffusion effects, and the results were verified by the membrane adsorption tendency. The nanofiltration mass transfer of alkaloids is related to the state and molecular weight. In the ionic state, the charge effect produces separation behavior, and the molecular state is related to the molecular weight. The separation mechanism of nanofiltration for alkaloids was clarified further by analyzing the correlation of nanofiltration mass transfer behavior and molecular structure. The results of nanofiltration technology provide references for separation of alkaloids at room temperature with fast separation and low energy consumption.

Tribbles homologous protein 3 (TRB3) has a wide range of biological functions, such as involvement in tumor regulation, the occurrence of insulin resistance, endoplasmic reticulum stress response, inflammation regulation and the regulation of cell growth and differentiation. TRB3, as a key "pressure regulating switch", is involved in the regulation of numerous diseases and serves as a biomarker and potential therapeutic target for many diseases. This paper gives an overview of the research on the biological function of TRB3 in recent years, in order to provide a theoretical basis for further research on TRB3 function.

Based on the integrity and systematicness of Chinese medicine, the components preparation simplifies the complex problems of multi-components of Chinese medicine, provides an effective and feasible model for the development of Chinese medicine preparation. It has become a hot topic in the research of prep-aration, and is also considered as one of the effective ways to realize the modernization of Chinese medicine. Based on the previous research on multi-components and the work of our research group, the research frontiers of multi-components are elucidated, including the properties and characterization techniques of components, the construction of components release unit, and the multiple drug delivery system. The purpose of this paper is to explore the technical basis and key problem of components preparation, and then bring some inspiration and thought to the relevant researchers.

Traditional Chinese medicine (TCM) formula is one of the unique cultural treasures of Chinese. However, only a few studies have been carried out to deliver TCM formula with utilization of nanocarriers. The purpose of this study was to prepare the hydroxypropyl-β-cyclodextrin complex-over-a-poly(lactic-co-glycolic acid) nanoparticle (HP-β-CD-PLGA NP) for co-delivery and sequential release of five main effective ingredients of Danshen and Sanqi to a specific target, which can provide strategies for design of intelligent drug delivery system of TCM formula. PLGA can be employed as scaffolds for sustained release of both hydrophobic and hydrophilic drugs. HP-β-CD could encapsulate the hydrophobic drugs by forming inclusion complexes. Superparamagnetic iron oxide nanoparticles (SPION) embedded inside PLGA nanoparticles that allow a spatio-specific targeting. HP-β-CD inclusion complex was prepared by an unsaturated alcohol solution method. PLGA NP loaded with SPION was obtained through double emulsion-organic solvents evaporation. Then core-shell PLGA nanosystem was formed by co-incubation of the above two materials. The nanoparticulate system was characterized by confocal laser scanning microscopy (CLSM), laser particle size instrument and transmission electron microscope. Magnetic property was determined by magnet adsorption and vibrating sample magnetometer (VSM). Targeted distribution was investigated by cell uptake and sequential release of multiple components was observed by intracellular distribution of fluorescent probes. Release difference of five components between core and shell of HP-β-CD-PLGA NP was measured by high performance liquid chromatography. The results demonstrated that NP had a unique core-shell structure and possessed superpara-magnetism. Magnetic NP could be ingested site-specifically by L929 cells with the aid of magnetic field, and coumarin-6 and rhodamine B were released from NP sequentially in the L929 cells. In vitro release of multiple components of Danshen and Sanqi from NP exhibited double phase time-controlled release kinetics of quick-release shell and sustained-release core. Therefore, the spatio-temporal nanoplatform has a great capacity for unlocking the full therapeutic potential of displaying synergistic efficacy of TCM formula in the formulation design.

The multiple drug delivery system of components of traditional Chinese medicine is a system composed of multiple components and multiple units. According to the characteristics of each component, different drug delivery units are designed and combined to achieve the purpose of improving bioavailability and enhancing drug efficacy. In this study, supercritical extracts, phenolic acids, and polysaccharides derived from Angelica sinensis were examined as research objects, and a pellet-based vehicle was applied to construct a multiple drug delivery system for the treatment and chemoprevention of colitis and colorectal cancer. The extrusion-spheronization method was used to prepare pellets of Angelica polysaccharides which should be released in the stomach. The yield in 18-24 mesh and plane critical angle served as the index. The Box-Behnken design and the orthogonal design were used to optimize the formulation and parameters of pellets. According to a previous study, the colon specific pellets loading supercritical extracts and phenolic acid extracts were prepared by the optimized process. These two units of pellets were combined into the multiple drug delivery system of effective components of Angelica sinensis, and the quality evaluation and in vitro release study were conducted. The dynamic observation of pellets in mice was evaluated using small animal in vivo imaging system. The prescription of the Angelica polysaccharides gastric releasing pellets was:microcrystalline cellulose 6.5 g, polysaccharide 3.3 g, silica 0.2 g and 7 mL of 60% ethanol as wetting agent. The process parameters were as follows:extrusion rate at 75 r·min^-1, rounding rate at 1 800 r·min^-1, and rounding time for 3 min. Both in vivo and in vitro studies indicate that the prepared multiple drug delivery system of effective components of Angelica sinensis produced good release properties. The polysaccharide pellets could be rapidly released in the artificial gastric fluid and in the stomach. The colon specific pellets showed good targeting. They released little in the artificial gastric fluid within 2 hours, released less than 20% in the artificial intestinal fluid for 4 hours, and released more than 90% in artificial colon fluid for 6 hours.