Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in tumors, which generally exhibit anti-inflammatory M2 phenotypes, and are the key inducers of tumor development, metastasis and drug resistance, and thus becoming a popular target in the field of antitumor immunotherapy.The study and application of nanocarriers optimize TAMs-targeted antitumor therapy.According to the characteristics and functions of TAMs, modulation strategies based on TAMs are elaborated, including TAMs depletion, inhibition of TAMs recruitment and TAMs repolarization.At the same time, in order to apply the above strategies more efficiently and overcome the general off-target problems in treatment, specific TAMs-targeted therapies based on nanocarriers are reviewed and analyzed, including passive targeting to TAMs, active targeting to macrophages and specifically active targeting to M2-TAMs. Finally, based on the limitations of targeting TAMs alone, new therapeutic strategies of targeting both TAMs and tumor cells via nanocarrier based delivery systems are introduced to provide new ideas for the application of these strategies in the field of tumor immunotherapy and combination therapy with other antitumor strategies.

Bromodomain-containing protein 4 (BRD4), a new target for tumor therapy, is the most important member of the bromodomain and extra-terminal family. The overexpression of BRD4 is associated with genesis and development of various cancers.Used either alone or in combination with other treatments such as chemotherapy, photothermal therapy and immunotherapy, the BRD4 inhibitors or degraders exhibited excellent antitumor effects, providing a new direction in tumor treatment. In this review, the structure and function of BRD4, the inhibition strategies of BRD4, the application in tumor combination therapy and drug resistance are introduced, which provides reference for targeting BRD4 in tumor therapy.

Non-coding RNA (ncRNA) is a type of RNA that has no or limited protein-coding ability. It mainly includes microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), transfer RNA (tRNA), PIWI-interacting RNA (piRNA), and small nucleolar RNA (snoRNA).At present, research has found that ncRNA plays a central role in regulating the function of pancreatic β cells, and that defects of insulin signaling is an important cause of diabetes.This article reviews the relationship between ncRNA and insulin signaling pathway in recent years, and discusses the possibility of ncRNA as a potential therapeutic target and clinical diagnostic marker for diabetes, hoping to provide some reference for the treatment and diagnosis of diabetes.

Eleven alkaloids were isolated from the twigs and leaves of Ervatamia pandacaqui using chromatographic methods of silica gel, Sephadex LH-20, ODS, and HPLC.Their structures were elucidated by physical,chemical and spectroscopic methods and determined as voacristine 7-hydroxyindolenine (1),iboxygaine (2), 19S-hydroxyibogamine (3), 3-oxotabersonine (4), perivine (5), pericyclivine (6), rhazinalinol (7), geissoschizol (8), 3, 14-dihydroolivacine (9), vallesamine (10), and conolobine A (11), respectively.All compounds were isolated from this plant for the first time.

Polyethylene glycol (PEG) of different lengths were prepared to investigate their effects on oral absorption of nanostructured lipid carrier (NLCs).Three kinds of PEG-modified NLCs with different chain lengths, including polyethylene glycol (100) monostearate (S100), polyethylene glycol (55) monostearate (S55), polyethylene glycol (40) monostearate (S40), were prepared by film dispersion method.Coumarin 6 was chosen as a fluorescent probe to characterize the physicochemical properties of NLCs with different lengths.Meanwhile, the stability of NLCs in simulate buffer, the release behavior, cytotoxicity of NLCs, the uptake kinetics and cellular uptake mechanisms were evaluated. This work demonstrated that the thickness of the hydrated layer increased with the increase of PEG length. Of note, S100-modified NLCs (pNLC-EG100) exhibited higher cellular uptake efficiency compared with other formulations. Thus, S100 was optimized as the best molecular weight for PEG-modified NLCs on oral drug delivery system.

To construct PTEN/PLGA-(HE)10-MAP nanoparticles, which encapsulated PTEN plasmid DNA and combined with the pH-responsive cell-penetrating peptides (CPPs), and to investigate their effects of gene delivery and anti-tumor targets in vitro. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with PTEN plasmid DNA were prepared by double emulsification-solvent evaporation method. PTEN/PLGA-(HE)10-MAP nanoparticles were prepared by coupling the histidine-glutamic acid-model amphipathic peptide nanocomplex [(HE)10-MAP] to the surface through amide condensation reaction. Particle size, Zeta potential, encapsulation rate and drug loading were tested to characterize the nanoparticles. By analyzing the cytotoxicity, cellular uptake, targeted transfection of eukaryotic expression plasmids and anti-tumor cell proliferation, the feasibility as a targeted gene delivery system were evaluated. The particle size of PTEN/PLGA-(HE)10-MAP nanoparticles was (266.5 ± 2.86) nm, with the encapsulation efficiency (80.6 ± 6.11)%. Zeta potentials were -(6.7 ± 0.26) mV, +(0.7 ± 0.22) mV and +(37.5 ± 0.85) mV at pH 7.4, 7.0 and 6.5, respectively. In the cytotoxicity test, the cell survival rates of tumor and normal cells were above 80%.Non-loading PLGA-(HE)10-MAP nanoparticles showed no obvious cytotoxicity. The results of cellular uptake experiments showed that PTEN/PLGA-(HE)10-MAP nanoparticles were more readily taken up by cells.The results of CCK-8 showed that the nanoparticles could pH-specifically inhibit proliferation of tumor cell in vitro.And PTEN/PLGA-(HE)10-MAP nanoparticles may be applied in tumor gene therapy.

In this study, ivabradine hydrochloride (IVB) was prepared as elementary osmotic pump tablets whose administration frequency was reduced to once daily. The dissolution method was developed, and effects on drug release profiles were evaluated by single factor analysis involving suspending agents, osmotic active agents and aging process. Orthogonal test was carried out at 3 levels on 3 factors including the amount of polyoxyethylene (PEO) in the core, polyethylene glycol (PEG) percentage and weight increase of controlled-release film coatings. The final formulation consisted of IVB (16.25 mg), PEO N80 (60 mg), hypromellose E5 (10 mg), lactose (111.75 mg), magnesium stearate (2 mg); and the film coatings consisted of PEG (15%), cellulose acetate (85%), with a weight increase of 7.5%. In vitro drug release behaviors were investigated. Prepared tablets exhibited similar release profiles in different pH dissolution media, with no risk of dose dumping in 40% ethanol solutions. The osmotic pressure differences inside and outside the membrane drove drug release. IVB osmotic pump tablets could reduce the frequency of administration and improve patients'' compliance, thus with better application values.

PLZ-NPs (PNS-lipid-zein nanoparticles) prepared by co-assembly of Panax notoginseng saponins, lecithin, β-sitosterol and zein were applied for in vitro cell experiment and oral gavage to study the protective effect of cerebral ischemia-reperfusion rats.PLZ-NPs were characterized by Malvin-particle size analyzer and transmission electron microscope (TEM), respectively. The toxicity of PLZ-NPs and free carrier were evaluated by MTT, and the uptake of nanoparticles in Caco-2 cells was analyzed by laser confocal and flow cytometry. The cerebral ischemia reperfusion rat model was established by MCAO method and then be given samples by gavage for 3 days. The brain tissues were taken to stain by 2, 3, 5-triphenyltetrazole chloride (TTC) and the biochemical indicators of MDA, inflammatory cytokines IL-1β and TNF-α, apoptosis-related proteins Bax and Bcl-2 from the harvested brain tissues were detected to evaluate the protective effect of PNS in PLZ-NPs on cerebral ischemia reperfusion. The particle size, PDI, and zeta potential of formed PLZ-NPs were (116.4 ± 0.81) nm, 0.048 and -(31.5 ± 0.31) mV, respectively. The results of MTT showed that the zein lipoprotein carrier was non-toxic to Caco-2 cells. The results of laser confocal and flow cytometry showed that FITC uptake of nanoparticles could be significantly improved in Caco-2 cells.The uptake from the nanoparticles at 4h was 1.76 times of that of the free FITC group.Compared with the model group, the TTC staining images of free drug PNS group and PLZ-NPs group showed certain reduction in the white infarct area.The contents of MDA, IL-1β, TNF-α and Bax were significantly decreased, while the content of Bcl-2 was significantly increased. Furthermore, all parameters of PLZ-NPs group showed better results than those of PNS group, and there was a significant difference (P < 0.05). All results indicated that the prepared PLZ-NPs had good stability and biological safety, and could significantly increase the uptake in intestinal epithelial cells, and effectively protect against the damage caused by cerebral ischemia reperfusion in rats.

To investigate the in situ intestinal absorption characteristics and pharmacokinetic behavior of metformin-resveratrol compound water-in-oil nanoemulsion (MRCE) in rats, the in situ intestinal perfusion model was constructed in rats to study the intestinal absorption characteristics of MRCE in different intestinal segments. Male Sprague-Dawley rats were randomly divided into two groups. After intragastric administration of metformin and MRCE, blood was taken at a preset time point. The content of metformin in intestinal perfusion samples and blood samples at various time points was determined by HPLC. Plasma concentration-time profiles of free metformin and MRCE were calculated, and the main pharmacokinetic data were processed and analyzed by DAS 2.1.1 software. The absorption rate constant (Ka), the effective permeability (Peff) and the percentage of absorption (PA) of MRCE in each intestinal segment were significantly higher than those of metformin (P < 0.05). The area under the drug-time curve (AUC0-72 h), the half-life (t1/2) and mean residence time (MRT0-72 h) of MRCE were 1.68, 11.25 and 6.97 times of metformin, respectively (P < 0.01).The relative bioavailability of MRCE was 167.6%. The 90% confidence interval of AUC0-72 h was 156.9%-187.4%, which was not within the standard interval of bioequivalence. The intestinal absorption of MRCE was significantly better than that of free metformin; MRCE improved the oral bioavailability of metformin and was not bioequivalent to metformin.

To establish a method for the determination of formaldehyde and glyoxal simultaneously in varenicline tartrate active pharmaceutical ingredient (API) and its intermediate, formaldehyde and glyoxal were derivatized by 2, 4-dinitrophenylhydrazine (2,4-DNPH) to improve the HPLC retention and UV detection sensitivity. Separation was performed on a C8 (150 mm × 4.6 mm, 5 μm) column by linear gradient elution using acetonitrile and water as the mobile phase; the detective wavelength was set at 380 nm.Formaldehyde and glyoxal were quantitatively determined by an external reference method.Linear calibration was established for both formaldehyde and glyoxal in the range from 0.094 to 1.88 μg/mL.The detection and the quantification limits were 0.047 μg/mL (19 μg/g) and 0.094 μg/mL (38 μg/g), respectively.The recoveries were (95.0±1.1)% and (99.4 ± 2.6)% for formaldehyde and glyoxal, respectively.This method has been fully validated to be applicable to quantitative analysis of trace amount of formaldehyde and glyoxal in varenicline tartrate API and its intermediate.Test results demonstrated that the contents of both formaldehyde and glyoxal met the permitted daily exposure (PDE) limits for the finished products of varenicline tartrate API as well as its intermediate, though the glyoxal contents in the crude intermediates were likely to exceed the limit.The established method is valuable for the manufacturing process and quality control of varenicline tartrate.