Selectivity of drug action is a determinant for wide therapeutic window and less adverse response. From the viewpoint of molecular structure the conception and strategy of drug design are mainly embodied in raising selectivity. For the target-based drug discovery it is crucial to precisely obliterate detrimental targets in dimension of time and space, so as to efficaciously translate the in vitro active compounds into in vivo therapeutic medicines. To realize this translation drug molecules must be accurately transported to and destroy the harmful targets. To this end, chemical structures of drugs must be manipulated in multiple dimensions. This article attempts to concisely describe several kinds of bifunctional molecules for raising selectivity from the standpoint of medicinal chemistry. The bifunctionality of antibody-drug conjugates (ADCs) involves in the guidance and carrier of the antibody to guide ADC and reach to target cells, and simultaneously injury quality of the toxin moiety of ADC interacts with and destroys targets. Based upon target 3D structures design of irreversible inhibitors consist in connecting an appropriate electrophilic moiety to a well-defined ligand to endow the molecule with an additional ability to covalently bond to a specific amino acid residue. Hydrophobic tag (HyT), proteosis-targeting chimera (PROTAC), and degradation tag (dTAG) are new developed technologies, which are structurally characterized by bifunctionality, and mechanistically these compounds are capable of recruiting protein of interest (POI), inducing protein-protein interaction (PPI), and cleaving POI. In spite of large molecular size and the bottleneck of pharmacokinetic and physicochemical properties these technologies still have broad development prospect owing to high selectivity and wide adaptations.

As a post-translational modification, protein acetylation plays an important role in the regulation of apoptosis, mitochondriopoiesis, lipid metabolism and cellular stress response. The imbalance of acetylation and deacetylation has been blamed for the tumorigenesis and malignant progression, which is gradually considered as a promising therapeutic target. Mammalian sirtuins, a NAD⁺ dependent class Ⅲ HDACs, are closely related to the development of aging, tumor, diabetes, obesity and neurodegenerative diseases. To provide a theoretical basis for the development of new anti-tumor drugs and the treatment of malignant tumors, this paper is prepared to focus on the irreplaceable role of sirtuins in tumor evolution:maintaining genomic stability, regulating energy metabolism, and facilitating tumor cells stemness. The modulator and pathways of sirtuins family and the research progress of agonists and inhibitors are also reviewed. The functions of SIRT2 in resistance, proliferation and metastasis have been highlighted.

Voltage-dependent anion channels (VDACs), which are located at the mitochondrial outer membrane, playing an important role in the regulation of mitochondrial energy metabolism and mitochondria- mediated apoptotic events, are considered as potential targets for tumor therapy. Studies have indicated that neurodegenerative diseases such as Alzheimer's disease (AD) generally lead to mitochondrial dysfunction. During this process, VDAC1, changing in expression, interacting with disease-related molecules, was involved in the occurrence and development of diseases. This review summarizes the characteristics and physiological functions of VDAC1, common important structural units and its role in apoptosis. The focus is on the research progress of VDAC1 in AD, as well as the effects in learning and memory related functions by modulating VDAC1 expression or function.

Phage display technology utilizes filamentous phage display proteins and polypeptides to extract a desired polypeptide or protein from a large number of variants. The antibody fragments screened and obtained by phage display library technology play an important role in disease diagnosis and treatment. This article briefly introduces the principles of phage display technology, summarizes the development of monoclonal antibodies, the development of antigenic microbial vaccines, and the application of peptide drugs. This review highlights the importance of phage display technology in the diagnosis and treatment of various human diseases such as cancer and autoimmune diseases etc.

A new polyketide:3R, 5R-(-)-talaroflavone (2), along with 15 known compounds were isolated from a EtOAc extract of a sponge-derived fungus Alternaria sp. F49. Compounds 1-2 and 3-4 were separated as two pairs of enantiomers by chiral HPLC from Ⅰ and Ⅱ. The structures of compounds 1-16 were elucidated by means of NMR and MS. Furthermore, the absolute configurations of compounds 1-2 were determined by single crystal X-ray diffraction experiment and CD analyses. Compounds 6, 8-10 were isolated from this genus (Alternaria sp.) for the first time. Compound 16 showed moderate COX-2 enzyme inhibitory activity with IC₅₀ of 7.3 μmol·L^-1.

ABC transporters (ATP-binding cassette transporters) are a family of trans-membrane transport proteins, which are ubiquitous in prokaryotes and eukaryotes. They are functionallyinvolved in the transport and accumulation of plant secondary metabolites, phytohormone transport, lipid metabolism, exogenous toxins detoxification, plant disease and other aspects. Based on the genome and transcriptome data of Dendrobium officinale, 88ABC transporters were preliminarily identified in D. officinale and their functions and subcellular localization were predicted. These proteins are divided into seven subfamilies, ABCA-ABCI, including 4 ABCA, 19 ABCB, 12 ABCC, 3ABCD, 9 ABCF, 37ABCG and 4 ABCI, which are mainly located in plasma membrane, vacuole and Golgi apparatus. Comparative transcriptomic analysis of ABC protein expression profile between asymbiotic and symbiotic germination of D. officinale show that some members of ABCB and ABCG proteins are highly expressed during seed germination inoculated fungi. qPCR validated that 2 ABCB11 and 2 ABCG-PDR are significantly up-regulated in symbiotic assay compared to asymbiotic germination (fold change ≥ 10.0). These proteins are mainly involved in abscisic acid and auxin transport, suggesting that these proteins play an important role in the germination of D. officinale seed and in the interaction with microorganisms.

A simple, sensitive and reliable method was developed for simultaneous quantification of IMM-H007 and its major active metabolites-M1 and MP in the blood of rhesus monkey using HPLC-MS/MS analysis. The analytes and internal standard (IS) WS070119 were separated using a Capcell PAK ADME Column (2.1 mm×100 mm, 3 μm, Shiseido, Japan) with a gradient mobile phase of methanol/water containing 0.1% formic acid. The detection was performed in positive selected reaction monitoring (SRM) mode with electrospray ionization (ESI) source. Satisfactory linearity was obtained while the inter- and intra-assay precision and accuracy differences were no more than 15% with high recovery and good stability for the quantification, indicating the present method was specific, accurate and reliable. The method was successfully applied to the pharmacokinetic study of IMM-H007 in rhesus monkey. After single oral administration of IMM-H007 (70, 210, 630 mg·kg^-1), M1 and MP were detected in blood, while the concentration of IMM-H007 was much lower than its metabolites. The active metabolite MP with linear kinetics had a higher exposure than other analytes in vivo. The results provide an useful and reliable model for pharmacological and toxicological studies of IMM-H007 as well as its clinical application.

Focusing on the TCM-related adverse drug reactions, especially those conventionally non-toxic TCM induced hepatotoxicity, this paper has proposed and established the disease-syndrome-based toxicology evaluation pattern and approach for TCM, not only the normal rats, but the hepatic fibrosis model rat were studied hepatotoxic or hepatoprotective effects of rhubarb, meanwhile liver histopathology changes by histological tests such as HE and TUNEL staining. The metabolomics analysis method will be employed to screen the key metabolites and possible metabolic pathway of the dual effects of rhubarb in rats. The results showed that rhubarb could result in significant liver injury in normal rats, indicated by the elevation of plasma serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities (P < 0.01), as well as liver histopathology changes by histological tests such as HE and TUNEL staining; whereas the levels of ALT and AST were significantly decreased in the model group of rhubarb, and the histopathology of liver was significantly improved. The UPLC-QTOF/MS methods were used to characterize the differences metabolites in contrast group plasma of rats. Eventually, seven potential biomarkers such as taurine, L-arginine, creatine, L-valine, retinyl ester, and prostaglandin F2α were confirmed by multivariate statistical analysis and metabolic pathways enrichment analysis linked to six metabolic pathways, including taurine and hypotaurine metabolism, primary bile acid biosynthesis, arginine and proline metabolism, arachidonic acid metabolism, retinol metabolism and valine, leucine and isoleucine biosynthesis. In summary, the results suggested the dual effects of rhubarb screened by taurine and hypotaurine metabolism, primary bile acid biosynthesis and arginine and proline metabolism may be the key metabolic pathway related to You Gu Wu Yun phenomenon of rhubarb. This study will provide new vision and illustration of scientific evidences for the hepatotoxicity assessment and rational use of those drugs containing anthraquinones.

This study was designed to determine the metabolites of Renduining injection in rats. The ultra-high performance liquid chromatography-LTQ Orbitrap mass spectrometric (UHPLC-LTQ-Orbitrap-MS) and mass defect filter techniques were applied to analyze the metabolites of Reduning injection in rat plasma, bile, urine and feces. As a result, we determined 14 metabolites of geniposide, including oxidation, dehydration, hydroxymethylene loss, hydrolysis, ring-opened, cysteine conjugation and glucuronidation conjugation of aglycone; 9 metabolites of geniposidic acid, consisting of dehydration, ring-opened, double-bond reduction and cysteine conjugation; 6 metabolites of secoxylogain including hydrolysis, hydroxymethylene loss, hydroxylation and ethylation; 12 metabolites of chlorogenic acid, containing decarboxylation, hydrolysis, methylation, acetylation, cysteinylglycine conjugation and glutathione conjugation. It provided information for the therapeutic effect of Reduning in vivo.

This study was designed to study the chemical constituents from bulbil of Dioscorea opposite Thunb.. Four compounds were isolated by silica gel column chromatography. On the basis of physic-chemical characters and spectroscopic data analysis, these compounds were identified as lyzalkaloid (3, 4-dihydro-6-hydroxy-4-methyl-6H-pyrido[6, 5-b]indol-5(1H)-one) (1), anoectochine (2), ginsenine (3), and 2-hydroxy-3-(1H-indol-3-yl) propanoic acid methyl ester (4). Compound 1 is a new indole alkaloid, named as lyzalkaloid. Compounds 2-4 were isolated from this plant for the first time. The cytotoxic activities were assessed by MTT assay. All compounds exhibited the cytotoxic activity against HepG2 and MDA-231 with IC₅₀ values of over 100 μmol·L^-1, respectively. All compounds show no significant cytotoxic activities against HepG2, MDA-231 cancer cell.