Nitidine chloride (NC) is a compound with prominent anti-tumor activity. To determine potential cardiotoxicity of NC, this study was designed to investigate the distribution of NC in rat heart and the underlying mechanism. The animal studies were approved by Institutional Animal Care and Use Committee of Zhejiang University Medical Center (2015-380-01) and complied with the standards of animal welfare in China. At 0.25, 0.5 and 2 h after a single intravenous injection (iv) of 5 mg·kg^-1 NC, the concentrations of NC in rat heart were 47.7, 71.1 and 63.2 μg·g^-1 respectively, which were 576, 1 352 and 1 212 folds of that in plasma. This study also revealed that the NC concentration in heart was 458.5 μg·g^-1 (7 336 folds of that in plasma) at 2 h after the last dose in rats, after daily iv administration of NC at 5 mg·kg^-1·day^-1 for successive 20 days. Further studies showed that the accumulations of NC in MDCK-hOCT1 and MDCK-hOCT3 cells were 16.1 and 4.99 folds higher than that of the mock cells, respectively. There is no significant difference between the accumulations of NC in MDCK cells transfected with hOCTN1, hOCTN2 or hPMAT and the mock cells. Additionally, quinidine, L-tetrahydropalmatine and Decynium 22, the inhibitors of OCTs, clearly reduced the accumulations of NC in primary cardiomyocytes and cardiac fibroblasts from neonatal rats. MTT assay showed that the LC₅₀ of NC on cardiomyocytes and cardiac fibroblasts were 10.9 and 10.4 μmol·L^-1, respectively. Moreover, treatment of the primary cardiomyocytes and cardiac fibroblasts with NC (1~15 μmol·L^-1) for 48 h resulted in significantly increased LDH enzyme leakage. These results indicated that NC can be highly accumulated in the heart, and accumulation is mediated by OCT1 and OCT3, but not by OCTN1, OCTN2 and PMAT. The accumulated NC has potential cytotoxicity as shown in the results from primary cardiomyocytes and cardiac fibroblasts.

Based on the concept of network pharmacology, the main nephroprotective components in Erzhi Pill reported in previous studies, were used to predict the targets through the PharmMapper method. Molecular docking was applied to screen for potential targets and biological information annotation databases (DAVID) was used to analyze the molecular function and biological process of the action targets. The Cytoscape software was used to construct the "ingredient-target-pathway" network of Erzhi Pill for renal injury treatment. TTD and GAD database were then applied to screen for the targets of renal disease for building "ingredient-core target" network. We found that 17 major active ingredients of Erzhi Pill regulated 32 targets (including ESR1, ESR2, GCK, MMP3) and affected 6 pathways, such as PI3K-Akt signaling pathway, estrogen signaling pathway and purine metabolism. This study reflected the nature of traditional Chinese medicine as multi-ingredients, multi-targets and multi-path ways, providing new clues for basic science research on the nephroprotective pharmacological mechanism of Erzhi Pill.

Based on special scientific facts demonstrated in traditional Chinese medicine (TCM) complex system, this paper proposes a hypothesis of "one output multi-source", discussing the concept, features, structures and the scope. The law of interaction between the integrity and multiple components of TCM complex system was examined. Feasibility, technical methods and evidence supporting the hypothesis have been presented here. We present a basic model of the hypothesis, i.e. artificial neural network (ANN) model. This hypothesis promotes a deeper modern scientific understanding towards the TCM complex system and advancement in research of the material basis. TCM compatibility and quality control will serve as the theoretical foundation for guiding the research on drug combination including chemical, biological and herbal medicines.

A highly sensitive and selective bioluminescent probe for hydrazine (BPH) was designed, synthe sized and evaluated for detection of hydrazine in vitro and in vivo. BPH was designed to include a specific recogni tion group (acetyl) of hydrazine at an appropriate modification site of the optical reporter hydroxyluciferin (Dluciferin), which showed excellent performance both in selectivity and sensitivity to hydrazine. The results showed that the bioluminescent probe BPH developed in this study is an innovative and widely applicable tool for detecting hydrazine in complex natural environment or in animals.

Photodynamic therapy (PDT) is one of the new approaches for cancer treatment with high efficacy. However, applications of current photosensitizers are restricted to skin and superficial tumor due to poor in vivo targeting ability, poor water solubility and short wavelength excitement, which limits penetration therefore thera peutic depth. Here, a biodegradable polymeric micelle, methoxy poly(ethylene glycol)-polylactide copolymer (mPEG-PDLLA), is employed as drug delivery system to co-encapsulate strong two-photon absorption compound (L_TPA) and photosensitizers. This delivery system is designed to target tumor passively, resulting in near infrared light with an approximately 808 nm wavelength becoming able to indirectly excite photosensitizers through fluores cence resonance energy transfer. Tumor cells and microvessels could be damaged by the generated singlet oxygen. The average size of drug loaded micelles was approximately 55 nm and showed a spherical shape. Both com pounds could be released simultaneously from micelles under either weak acid and neutral pH conditions. Reactive oxygen species was produced intracellularly during two-photon PDT process and induced cell apoptosis/necrosis, which was quantified by Annexin-V/FITC assays. Time-dependent ex vivo organ distribution and in vivo anticancer efficacy results suggested that the drug carriers could accumulate in tumors and suppress tumor growth by twophoton PDT. All animals experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of College of Pharmaceutical Sciences, Southwest University. In summary, we have employed two-photon PDT for breast cancer treatment successfully in a mouse model and have demonstrated the significance of delivery system in such therapeutics.

The roots and flowers of Gentiana waltonii and Gentiana robusta are used as Tibetan herb Jie-Ji in traditional Tibetan medicine, with iridoids as the main active ingredient and index components. To study the pathway of iridoid biosynthesis, roots, stems, leaves and flowers of G. waltonii and G. robusta were subjected to a high-throughput transcriptomic sequencing analysis by Illumina HiseqXTen. After removing insignificant reads and de novo splicing, 79 455 and 78 466 unigenes were obtained from G. waltonii and G. robusta respectively, with average length as 834 bp and 862 bp. The unigene GO functions could be divided into three categories of 65 branches. The unigenes were aligned in KOG database and were classified into 25 classes according to function. In KEGG database, 315 and 340 unigenes of G. waltonii and G. robusta were implicated in 20 standard secondary metabolic pathways, respectively. Furthermore, 80 and 57 unigenes of the two species were analyzed to encode 24 key enzymes in the pathway related to iridoid biosynthesis. There were differences in gene expression among different organs. Based on sequence data, significant amounts of SSRs, SNPs and InDels were detected in each dataset. This study provides a platform for further development of molecular markers, excavation of functional genes, and research into metabolic pathways and their regulatory mechanism within G. waltonii and G. robusta.

Protein acetylation is a process of adding an acetyl group to a protein lysine residue with the help of acetyltransferase, which is a pivotal protein post-translational modification linking acetyl-CoA metabolism and cell signal transduction. Recently, the development of mass spectrometry has deepened our understanding of lysine acetylation. Lysine acetylation is involved in many processes such as gene transcription, protein degradation, cellular metabolism, and stress response, which affects biological processes by regulating protein interactions, activity, stability and localization. Protein acetylation is widely happened and plays important regulatory roles in a diversity of human diseases such as metabolic diseases, tumors and cardiovascular diseases. Besides, deacetylase inhibitors have displayed a great potential in the treatment of various diseases especially tumors and metabolic associated diseases. In this review, we summarized the advances and application of acetylation, and discussed the remaining problems in this area.

Adaptation to hypoxia of the plateau environment has been a focus of scientific research in decades. The geographical distributions of such living environment include the Qinghai-Tibet Plateau, Andean Plateau in South America and Ethiopian Plateau. Over the past century, the unique features of physiological adaptation to high-altitude chronic hypoxia have been documented scientifically. The genetic studies of hypoxic adaptation in the past decade have revealed genetic bases of human high-altitude adaptation, with a close relationship to the hypoxia inducible factor (HIF) pathway and hypoxia response elements (HREs). Interestingly, the genetic pattern of adaptation to hypoxia is not the same among the three plateau populations. Tibetan has developed the best high-altitude adaptation, with modification of the HIF pathway as the key genetic element. Due to the wide range of HIF pathways, HIFs could regulate hundreds of downstream genes and are closely related to various diseases such as cancer, inflammation, ischemia, acute organ damage and infection, etc. The treatment researches of these diseases through HIFs-related regulations have led to the development of stabilizers and inhibitors of HIF pathway. We review here the adaptive responses of the three plateau populations to the hypoxic environment, and the genetic mechanism of HIF and HREs in the different ethnic high-altitude populations. Classes of HIF inhibitors, such as PI3K and/or mammalian target of rapamycin (mTOR) inhibitors, DNA-binding inhibitors, histone deacetylase inhibitors, heat-shock protein 90 inhibitors, cardiac glycosides, transcription inhibitors, topoisomerase inhibitors, and HIF activators including 2-OG mimics, Fe²⁺ chelators, prolyl hydroxylase (PHD) active-site blockers and CUL2 deneddylators have been presented with the drug examples. In addition, the top 3 chemical-disease and chemical-gene (protein) co-occurrences have been presented from the Pubmed literature search. The review could serve as references for research of hypoxia adaptation and HIF-related diseases.

Protein-protein interaction (PPI) plays an important role in many steps of the human immunodeficiency virus (HIV) life cycle. Targeting these protein-protein interactions, especially the interaction between the virus with host cells, can provide new insights into the development of HIV inhibitors with novel mechanisms of action. Herein, we review the latest discoveries of PPI inhibitors based on the mechanisms of action of various protein-protein interactions with specific research examples.

Using the idiosyncratic lipopolysaccharide (LPS)-mediated hepatotoxicity model as a positive control, liver injury induced by Cortex Dictamni aqueous extract (AE) or Cortex Dictamni ethanol extracts (EE) was evaluated. Idiosyncratic hepatotoxicity model was established in rats[Institutional Animal Care and Use Committee (IACUC)-2018-008] by injecting LPS at a dosage of 2.8 mg·kg^-1. Rats were randomly divided into 10 groups. The plasma levels of liver function biomarkers such as alanine transaminase (ALT), aspartate aminotransferase (AST) were measured. Histological changes (HE staining), hepatocellular apoptosis and the content of cytokines of liver were measured. Network pharmacology was used to analyze the relationship between chemical components and immunity in Cortex Dictamni. Compared with the control group, the doses (25, 50 g·kg^-1) of AE or EE had no significant changes in ALT, AST and liver pathology (P>0.05). The doses of 4.2 g·kg^-1 of AE or EE+LPS groups exhibited an elevation in ALT, AST and serum cytokines (P < 0.01). Disorder of liver lobular arrangement and irregular island-like or massive necrosis of liver cells were observed in these groups. Network pharmacology shows that Cortex Dictamni may directly or indirectly participate in the process of immunomodulation. We found that Cortex Dictamni regulated 15 core targets and affected 19 pathways, including apoptosis, TNF-α, NF-kappa B signaling pathways. These results suggest that Cortex Dictamni can induce idiosyncratic hepatotoxicity and the water extract can induce more serious liver injury then ethanol extract of Cortex Dictamni. These findings provide a reference for elucidating the idiosyncratic hepatotoxicity induced by Cortex Dictamni.