The chemical constituents of Cydonia oblonga (Quince) seeds were investigated using chromatographic methods, including silica gel, Sephadex LH-20 and semi-preparative-HPLC. Eleven compounds were isolated and their structures were elucidated on 1D or 2D NMR, and HR-ESI-MS. These analyses have lead to identification of 5, 7-dihydroxy-2-n-pentacosanyl chromen-4-one (1), ursolic acid (2), tormentic acid (3), oleanolic acid (4), β-daucosterol (5), β-sitosterol (6), amygdalin (7), rutin (8), kaempferol (9), quercetin (10) and isoquercitrin (11). Among these, compound 1 is a new compound, and compounds 3, 5 were isolated from this plant for the first time. Compounds 1-4 and 8 showed significant PTP1B inhibitory activities with IC₅₀ value of 0.465, 16.14, 28.96, 23.78 and 11.70 μmol·L^-1, respectively.

Ferroptosis is a novel type of regulated cell death with morphology, biochemistry and mechanisms differing from traditional cell death types such as apoptosis, necrosis and pyroptosis. The regulatory mechanisms of ferroptosis mainly involve iron metabolism, amino acid metabolism and lipid metabolism. It has been found that ferroptosis plays a key role in the pathogenesis of diseases including neurodegenerative diseases, malignant tumors and ischemic reperfusion injury. Parkinson's disease (PD) is one of the most common neurodegenerative diseases and its etiology and pathogenesis remains unclear. Recent studies revealed that ferroptosis might be involved in the pathogenesis of PD, as evidenced by high iron content, depletion of reduced form of glutathione and elevated levels of lipid peroxides detectable in the midbrain of PD patients. Both in vitro and in vivo models of PD have shown that some ferroptosis inhibitors have the ability of attenuating the symptoms and one iron chelator is undergoing a clinic trial. We here summarize the mechanisms of ferroptosis and its association with PD, in an effort to suggest potential novel targets for therapies of PD.

Lipid droplets (LDs) are ubiquitous dynamic organelles that store and supply lipids in all eukaryotic and some prokaryotic cells for energy metabolism, membrane synthesis and production of essential lipid-derived molecules. There is increasing evidence that hepatitis C virus (HCV) has co-evolved due to its lack of lipid biosynthetic pathways to utilize host lipid metabolic pathways to establish a suitable environment for virus proliferation and obtain the necessary components, eventually promote the assembly and transportation of virus. In this review, we outline the relationship between HCV life cycle and lipid droplet biosynthesis and metabolism, with the aim to discover potential antiviral targets for development of new therapeutic interventions.

This study was designed to explore the interventional mechanism involving "multi-components, multi-targets and multi-pathways" of Gu-Chang-Zhi-Xie pills (GCZX) for treatment of irritable bowel syndrome (IBS) using pharmacological network technology. Firstly, 96 active ingredients from GCZX pills were screened by ADME parameter filtration and chemical space principal component analysis, and the targets of anti-IBS function were predicted using PharmMapper online database. Secondly, AutoDock Vina was used to validate the docking between the active ingredients and predicted disease targets, and to establish the corresponding relationship between "pharmacodynamic molecules and target proteins". Finally, the target elements were mapped into the KEGG biological pathway by CluoGO plug-in, which further elucidates the potential relationship between the key targets and the mechanism of action of Gu-Chang-Zhi-Xie pills for treatment of IBS. The results showed that most of the top 11 key pharmacodynamic molecules were isoquinoline alkaloids, which mainly acted on inflammatory or pain targets, with different degrees of anti-inflammatory and analgesic effects. A total of 39 key targets were identified, including TPH1, TNF-α, IL-6, IFN-γ, MAO-A and IL-10. These targets were mapped to 29 KEGG pathways, of which the P-value of 5-HT signaling pathway was the smallest. Therefore, the pharmacodynamic molecules mainly act on 6 core targets and may play a major role in the regulation of 5-HT signal synthesis or transport pathway. This study sets an example for drug development and mechanistic investigation using innovative technology.

As a part of novel drug delivery carriers, peptides have diverse biological activities, low immunogenicity and good biocompatibility. In recent years, studies on the delivery carriers modified by peptides have attracted much attention. Among them, the peptides with acid sensitivity can change their secondary structures under slightly acidic microenvironment of the tumor or in lysosome. Therefore, the carriers made or modified by acid-sensitive peptides can specifically release the loaded drug in the tumor tissue, enhance the cell internalization of drugs and improve its therapeutic effects. In accordance with acid-sensitive peptides studied, the side chains, number of polar residues, sequence and secondary structure of the peptides might be involved in the acid sensitivity. In this review, we summarize the acid-sensitive peptides from recent literatures, analyze the connection between the structure and the acid sensitivity, and focus on the mechanism and application of acid-sensitive peptides in drug delivery. This provides the basis for further development and utilization for acid-sensitive peptides for efficient drug delivery.

Hemorrhagic transformation (HT) is a frequent complication of ischemic stroke, especially after thrombolytic therapy. This event is associated with increased morbidity and mortality. Tissue plasminogen activator (t-PA), the only FDA proved drug for breaking blood clots, is underutilized in ischemic stroke, because of its limited therapeutic window and hemorrhagic complications. Due to the lack of clear understanding of the pathological mechanism, there are no effective drugs to decrease the incidence of HT. Pinocembrin is a natural flavonoid compound and has neuroprotective effects in animal ischemic stroke models. In this study, we investigated the role of pinocembrin in t-PA thrombolysis-induced HT in rat thromboembolic stroke model. t-PA was administrated 6 h after ischemia and pinocembrin (5, 10 and 20 mg·kg^-1) was given 5 min before t-PA administration. Infarct volume, neurological score and hemoglobin content were evaluated at 24 h after ischemia. Evans blue leakage was used to detect blood-brain barrier (BBB) permeability. All procedures were approved by the Institutional Animal Care and Use Committee of the Peking Union Medical College. The results showed that treatment with t-PA at 6 h after ischemia aggravated brain injury and increased the risk of HT, with infarct volume and brain water content reached 39% and 83.4%, respectively. Pretreatment with pinocembrin decreased the infarct volume and brain water content to 28.5% and 80.3%, and improved neurological function. In addition, the combined application of pinocembrin with t-PA reduced hemoglobin content and Evans blue content in brain tissue by 50% and 40%, indicating that pinocembrin could protect the BBB permeability and reduce the occurrence of HT. Among these doses, 10 mg·kg^-1 is most effective. In conclusion, our results demonstrate that the combination of pinocembrin with t-PA protects against cerebral ischemia, reduces the occurrence of HT induced by t-PA thrombolysis. Thus, pinocembrin may be a potential therapeutic drug for t-PA induced HT.

Melatonin (MLT) is an endogenous chemical that has antitumor effects at high doses. However, it shows low oral bioavailability and short in vivo half-life, leading to drug resistance. Here, liposomal melatonin dry powder inhalers (LMD) were prepared, and were used for treatment of primary rat lung cancer by pulmonary delivery. Liposomal melatonin (LM) was prepared by the ethanol injection method to achieve an entrapment efficiency of 98.89%. LMD was obtained by freeze-drying after LM was mixed with mannitol. LMD appeared as spherical particles under a scanning electron microscope. The rehydrated liposomes had a small size of 65.15 nm and the zeta potential of -14.2 mV without change inentrapment efficiency. LMD had an aerodynamic particle size of 6.73 ±0.012 μm and a fine particle fraction (FPF < 8.06 μm) of 22.2%, suitable for pulmonary delivery. When administered with the same dose, LMD showed much higher inhibition on A549 lung cancer cells than MLT and gemcitabine. LMD of a large dose had no effect on the growth of normal lung epithelial cells (BEAS-2B). Rat lung cancer models were established after 45 days by instilling 3-methylcholanthrene (MCA) and N, N-dimethylnitrosamine (DEN) into the rat lungs once (the experiments had been approved by the ethics committee and carried out in accordance with relevant guidelines and regulations). Decreases of tumor nodules and inflammatory cells in the tumor-bearing rat lungs were observed after treatment of MLT, gemcitabine and LMD by pulmonary delivery compared with the models, wherein LMD was most effective. The efficiencies of inhibition of NF-κB p65, increase of Tunel detection (indicating enhancement of apoptosis), and decrease of malondialdehyde corresponded to LMD being most effective. Therefore, given the fact that LMD can deliver the drug into the tumor tissues of lungs, and it presents as a promising pulmonary inhalable regiment for treatment of lung cancer.

Alterations of mitochondrial structure and function in tumor cells allow cell survival and proliferation under hypoxic and acidic microenvironment. The effect of normal mitochondria on tumor initiation and development remains unknown. In this study, mice were euthanized by rapid cervical dislocation for isolation of hepatic mitochondria, which were injected intravenously to melanoma-bearing mice. This animal experiment had been approved by Southwest University Experiment Animal Ethics Review Committee. The results showed that exogenous mitochondria can significantly inhibit the growth of melanoma. Mitochondria isolated from the liver of young mice had more potent anti-melanoma effect than those isolated from aging mice. The average volume of tumors decreased significantly from 1.35 cm³ to 0.34 cm³, and the average mass of tumors decreased significantly from 0.63 g to 0.22 g. This anti-tumor mechanism might be associated with induction of mitophagy and cell necrosis after the exogenous mitochondria entering the melanoma cells. As mitotherapy can clinically improve somatic cell survival for treatment of pediatric patients with myocardial ischemia, the observed anti-tumor effect of exogenous mitochondria provides a hope for selective tumor treatment.

A sensitive and efficient liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitative determination of diflucortolone in rabbit plasma after dermal administration of diflucortolone valerate cream to rabbits. After extraction with ethyl acetate, the chromatographic separation was performed on Zorbax Eclipse XDB-C18 (50 mm×4.6 mm, 5 μm) with a gradient mobile phase consisting of 50% acetonitrile-50% methanol and 0.1% formic acid-5% methanol-5 mmol·L^-1 ammonium formate at a flow rate of 0.35 mL·min^-1. The quantitative analysis was carried out using multiple reaction monitoring (MRM) at specific ion transitions of m/z[M+H]⁺ 395.2→m/z 355.2 for diflucortolone and m/z[M+H]⁺ 258.1→m/z 120.9 for ethoxyphenylethylamine (internal standard) in positive ion mode with electrospray ionization (ESI) source. This validated LC-MS/MS method had a linearity over the concentration range of 0.01-10 ng·mL^-1 with the lower limit of quantification (LLOQ) at 0.01 ng·mL^-1. At level of LLOQ, the inter and intra-assay precision (RSD) were no greater than 9.82% and 11.0%, respectively. The main pharmacokinetic parameters of the diflucortolone including t_max, C_max, AUC_{0-72 h}, and t_1/2 were as follows:(6.33±1.21) h, (0.168±0.080 0) ng·mL^-1, (3.15±0.834) h·ng·mL^-1, (32.0±17.4) h. The method was validated in the pharmacokinetic study of diflucortolone in rabbit following dermal administration of diflucortolone valerate cream at dose of 0.01 g·cm^-2. In this study, the program of animal testing had been approved by Committee on the management and usage of experimental animal in the Evaluation Company of Innovative Drug, Tianjin Institute of Pharmaceutical Research.

To screen the antithrombotic effective components group of Trichosanthes extract, and to verify its pharmacodynamics and analyze its mechanism, the HPLC fingerprint of Trichosanthes extract (0.09, 0.45, 0.9 g·kg^-1) was established, and the pharmacodynamic indexes of antithrombosis in rats with aspirin (0.01 g·kg^-1) as positive control group were determined (the animals used in this experiment were approved by the Medical Ethics Committee of Wannan Medical College). The antithrombotic spectrum-activity relationship of Trichosanthes extract was studied and the effective antithrombotic ingredients group was screened by grey relational analysis. The monomer compound mixed solution (0.006, 0.03, 0.06 g·kg^-1) was prepared according to the content of each component in the active component group, and the pharmacodynamics and action mechanism were studied to verify the correctness of the spectrum-effect relationship. The correlation between the 22 components of Trichosanthes extract and antithrombotic efficacy was different and showed dose-effect relationship. Cytosine, uracil, guanine, hypoxanthine, xanthine, adenine, guanosine, and adenosine are the main antithrombotic components of Trichosanthes extract. The ratio of cytosine, uracil, guanine, hypoxanthine, xanthine, adenine, guanosine and adenosine was 3:12:10:5:2:8:13:14. Compared with the model group, the thrombus dry weight of each effective components group could be effectively reduced (P < 0.01 or P < 0.05), but there was no significant difference between each effective components group and the Trichosanthes extract group. Compared with the model group, the TXB₂ content in group (0.06 g·kg^-1, 0.03 g·kg^-1) could be effectively reduced (P < 0.01 or P < 0.05), and the content of 6-keto-PGF_1α could be increased in each group (P < 0.01), and the TXB₂/6-keto-PGF_1α tended to be normal and showed a dose-effect relationship. The effect was better than that in the Trichosanthes extract group (0.45 g·kg^-1) (P < 0.01). The effective ingredients group has a good antithrombotic effect, its mechanism is to inhibit platelet aggregation and improve vascular endothelial function.