Biomarkers are defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention.Biomarkers can help the decision-making process for new drug research and development, provide guidance for the early clinical development of candidate drugs and reduce the risk of failure. Therefore, as a key factor in the development of new drugs, the discovery and research on biomarkers has increased the interest of the pharmaceutical industry and regulatory agencies. Guidelines on the development and use of biomarkers have been issued by drug regulatory agencies including the EMA, FDA and ICH. Biomarkers are encouraged to be used to facilitate drug development by these relevant regulatory agencies, and also to be used to monitor the safety and efficacy of drugs in post-marketing drug surveillance. The application of biomarkers is encouraged at different stages of a drug's life cycle, including at the stage of basic science research and target identification, prototype design or discovery, preclinical development, clinical development, FDA filling/approval and launch, as well as post-marketing was reviewed. The identification, development, and application of biomarkers in pharmaceutical research is discussed.

With the development of the research on innovative drugs in our country, first-in-class drugs are becoming a main goal for both pharmaceutical companies and scientific institutions. Discovery of first-in-class drugs require amounts of basic research, a massive investment and novel methods, acting as a beacon for the new drug development. In 2020, FDA totally approved 53 novel drugs with 38 small molecules, which still accounting for a major component. Among them, many first-in-class drugs are important including a first EZH2 inhibitor(tazemetostat) for the treatment of epithelioid sarcoma, a first attachment inhibitor(fostemsavir) with novel mechanism for the treatment of HIV, a first farnesyltransferase inhibitor(lonafarnib) for the treatment of HutchinsonGilford progeria syndrome(HGPS) and a first MC4 receptor agonist for the treatment of rare genetic diseases of obesity, etc. The research procedures of the above drugs are representative with new ideas. In this review, we outline3 of the first-in-class drugs to discuss the research background, discovery and development process as well as the therapeutic potentials to provide methods and ideas for the further drug development.

Ten triterpenoid saponins were isolated and purified from the water extract of Glycyrrhiza glabra by polyamide resin combined with macroporous resin column chromatography, ODS medium pressure column chromatography and semi-preparative RP-HPLC. Their structures were elucidated by physicochemical properties, NMR and MS spectra, and determined as 3β-O-[β-D-glucuronpyranosyl-(1→2)-β-D-glucuronpyranosyl]-30β-O-β-D-glucuronpyranosyl-oleanane-11-oxo-12(13)-ene(1), 3β-O-[β-D-glucuronpyranosyl-(1→2)-β-D-glucuronpyranosyl]-30 β-O-α-L-rhamnopyranosyl-oleanane-11-oxo-12(13)-en-22 β, 30-diol(2), uralsaponin C(3), licorice-saponin A3(4), licorice-saponin P2(5), 22β-acetoxyl-glycyrrhizin(6), macedonoside A(7), 29-hydroxyl-glycyrrhizin(8), licorice-saponin G2(9), glycyrrhizin(10). Compounds 1 and 2 are two new compounds and named as licorice-saponin R3 and licorice-saponin S3.

Rhamnose synthase (RHM) is a key enzyme in the biosynthesis of uridine diphosphate rhamnose (UDP-Rha), reversibly converting uridine diphosphate-glucose (UDP-Glc) into UDP-Rha in the presence of NADH or NADPH. In this research, yeast extract (YE) was used to stimulate Sorbus aucuparia suspension cells. Based on a previous study of the transcriptome database of S. aucuparia suspension cells, two RHMs were cloned from S. aucuparia and named SaRHM1 (GenBank No.: MK213340) and SaRHM2 (GenBank No.: MK213341). The SaRHM1 gene contained a 2 007 bpopen reading frame (ORF) encoding a polypeptide of 668 amino acids with a molecular weight of 75.25 kD, and a theoretical isoelectric point (pI) of 7.24. The SaRHM2 gene contained a 2 040 bpORF encoding a polypeptide of 679 amino acids with a molecular weight of 76.26 kD and pI of 6.41. Bioinformatic analysis indicated that SaRHM1 and SaRHM2 contained two special sequences of GxxGxxG/A and YxxxK. Multiple sequence alignments and phylogenetic trees show that SaRHM1 and SaRHM2 have high sequence similarity with other plant species of RHMs. The results of enzyme activity assays in vitro revealed that both recombinant SaRHM1 and SaRHM2 are able to convert UDP-Glc into UDP-Rha. SaRHMs displayed maximum activity at 40 ℃ and a pH of 8 and 9, respectively. The K_m values of SaRHM1 and SaRHM2 for UDP-Glc were 212.4 ± 56.70 and 361.0 ± 63.74 μmol·L^-1, respectively, with V_max values of 235.5 ± 18.98 and 516.5 ± 22.30 nmol·min^-1·μg^-1, respectively. This study reports the cloning and sequencing of RHMs from S. aucuparia and verifies their function, which likely provide rhamnose donors for the subsequent biosynthesis of rhamnosides.

In this study, we investigated the inhibitory effect of SYT-1, a new compound of tetrahydroisoquinoline, on tumor cell proliferation and underlying mechanisms. Cell counting kit-8(CCK-8) method was used to detect cell proliferation; clone formation experiment was used to detect cell clone formation ability; JC-1 probe was used to detect cell mitochondrial membrane potential; 2', 7'-dichlorodihydrofluorescein diacetate(DCFH-DA)probe was used to detect intracellular reactive oxygen species; Annexin V-FITC/PI(fluorescein isothiocyanate/propidium) counterstaining method was used to detect apoptosis; Western blot assay was used to detect the expression level of related proteins. The experimental results show that SYT-1 has a significant inhibitory effect on the proliferation of six human-derived cancer cells. Among them, the inhibitory effect on breast cancer MCF-7 cells is the strongest, the half maximal inhibitory concentration(IC₅₀) of SYT-1 of 48 h administration on MCF-7 cells is 5.87 μmol·L^-1, which is better than that of cisplatin(8.92 μmol·L^-1). Further studies have shown that SYT-1 can dose-dependently inhibit the monoclonal formation ability of MCF-7 cells, and can cause the mitochondrial membrane potential of the cells to decrease and the level of reactive oxygen species to increase. In addition, SYT-1 can significantly inhibit the activation of PI3 K-Akt(phosphatidylinositol 3-kinase/protein kinase B) signaling pathway and induce apoptosis of MCF-7 cells. The above research results show that, as a new type of tetrahydroisoquinoline compound, SYT-1 has the potential to inhibit tumor cell proliferation.

Fatigue is a common complication of type 2 diabetes mellitus (T2DM).We examined the relationship between T2DM fatigue and the skeletal muscle 5-hydroxytryptamine (5-HT) system.In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin.The mice were treated with the 5-HT_2A receptor antagonist sarpogrelate hydrochloride (SH) and the 5-HT synthesis inhibitor carbidopa (CDP)(separately and in combination).In cell culture experiments, C2C12 cells were stimulated with D-glucose, palmitic acid or 5-HT.5-HT_2AR, 5-HT synthesis and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor.The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University.The results showed that 5-HT_2AR, 5-HT synthase and MAO-A were expressed in mouse skeletal muscle and C2C12 cells.The expression of these proteins was significantly up-regulated in T2DM mice or when C2C12 cells were exposed to palmitic acid and D-glucose; palmitic acid was a stronger stimulant of their expression than D-glucose.Rotating rod experiments and biochemical index tests have shown that T2DM fatigue is associated with an increase in skeletal muscle 5-HT_2AR, 5-HT synthesis and 5-HT degradation.5HT_2AR mediates the expression of MAO-A and the synthesis of 5-HT, which indirectly regulates the degradation of 5-HT.MAO-A regulates cell inflammation, mitochondrial ROS production and membrane potential depolarization by mediating 5-HT degradation.MAO-A also inhibits the expression of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1), carnitine palmitoyltransferase-1 (CPT1) and ATP synthase-6 (ATP6), thus inhibiting mitochondrial functions such as fatty acid β oxidation and ATP synthesis.SH and CDP can effectively treat T2DM fatigue, and can also reduce blood glucose and blood lipid, and the combination of SH and CDP has a clear synergistic effect.

The quality markers(Q-markers) of traditional Chinese medicine(TCM) have become a topic of interest in TCM research in recent years. Nonetheless, there is still no consensus on how to scientifically characterize TCM Q-markers. Our study establishes an identification method for TCM Q-markers based on the analytical hierarchy process(AHP) and the entropy weight comprehensive method. By constructing an evaluation system encompassing the target layer, the factor layer and the control layer, AHP can be used to analyze the weight of three core TCM quality attributes, including effectiveness, testability and specificity. Following that, the entropy weight method is employed to analyze the specific indicators for each attribute based on the literature and experimental data. Finally, the comprehensive weight of each index is obtained by combining the two weights, and the comprehensive weight and the specific value of each component is multiplied and summed to obtain the integrated score ranking, and thereby identify the TCM Q-markers. Taking Shaoyao Gancao decoction as an example, the analysis revealed that the top 8 components are as follows: paeoniflorin > quercetin > albiflorin > glycyrrhizic acid > naringenin > liquiritin > oxypaeoniflorin > benzoylpaeoniflorin, and can be identified as Q-markers of Shaoyao Gancao decoction. This study not only provides support for the establishment of quality standards and process quality control of TCM formulae, but also provides innovative ideas and methods for quantitative evaluation and accurate identification of TCM Q-markers.

The emerging nano-black phosphorus materials have created a new platform for biomedical research. Nano-black phosphorus has the following advantages: black phosphorus can produce singlet oxygen under near-infrared light irradiation, so it can be used as a photosensitizer for photodynamic therapy; black phosphorus has extensive light absorption in the long wavelength region, and this near-infrared photothermal property can be used in photothermal therapy. The high specific surface area and unique fold structure of the black phosphorus nanosheet make it have very high drug loading.This paper mainly reviews the applications of black phosphorus in biological imaging, photothermal therapy, photodynamic therapy, and as a drug carrier in recent years. Based on the photoelectric properties of black phosphorus nanomaterials combined with intelligent drug delivery platform, the synergistic effects of light/heat/chemistry, light/chemistry/gene, and light/chemistry/immunity can be produced, which has a broad application prospect.

Eight polyacetylenes were isolated from the extract of the stems and leaves of Chrysanthemum morifolium by various chromatographic methods. Their structures were determined as 2E, 4E, 12Z-tetradecatriene-1-pyrrolidine-1-oxo-8,10-diynoic(1), tetradeca-2E, 4E, 12E-trien-8,10-diynoic acid pyrrolidide(2), tetradeca-2E, 4E-dien-8,10-diynoic acid pyrrolidide(3), tetradeca-2E, 4E, 10Z-trien-8-ynoic acid pyrrolidide(4), 2E, 4E, 12E-tetradecatriene-8,10-diynoic acid isobutylamide(5), 2E, 4E-undecyldiene-8,10-diynoic acid isobutylamide(6), 2E, 4E, 10E-N-isobutyl-2,4,10-tetradecatrien-8-ynoic acid amide(7), and undeca-2E, 4E-diene-8,10-diynoic acid phenylethylamide(8) by spectroscopic methods, including UV, IR, ESI-MS, HR-ESI-MS, 1D and 2D NMR spectra.Among them, compound 1 is a new polyacetylene, and compounds 2-8 were isolated from this plant for the first time. Compounds 5-8 inhibited the proliferation of A549 cell significantly at certain concentration, showing potent antitumor activity.

In the treatment of hypertensive crisis, the novel Rho kinase inhibitor DL0805-2 can rapidly lower systematic blood pressure, reduce pulmonary artery pressure, and has a significant protective effect on lung injury.This experiment intends to evaluate the efficacy of DL0805-2 against pulmonary arterial hypertension (PAH) and preliminarily reveals its underlying mechanism. Animal welfare and experimental procedures are in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. Sprague Dawley (SD) rats were randomly divided into DL0805-2 low, medium, and high dose groups(1, 3, and 10 mg·kg^-1), bosentan positive control group, model group, and blank control group. The drug was administered daily on the 7th day after model establishment by monocrotaline injection. On the 25th day of the experiment, relevant indicators were examined to observe the therapeutic effect of DL0805-2 on pulmonary hypertension. DL0805-2 significantly relieved the abnormal changes in the physiological parameters related to PAH induced by monocrotaline, including reducing right ventricular systolic pressure, alleviating cardiac damage caused by pressure overload, and reducing the levels of endothelin-1 and inflammatory factors in lung tissues.DL0805-2 also attenuated pulmonary arteries remodeling. It was preliminarily discovered that DL0805-2 exerts preventive and therapeutic effect on PAH through Rho-kinase pathway. Our results suggested that DL0805-2 had good therapeutic effects on monocrotaline-induced PAH rat model. It intervened early in the disease process, effectively prevented the development of the disease, and reduced the mortality of the diseased animals. The mechanism is related to Rho-kinase pathway.