Sangzhi alkaloids (SZ-A) are derived from traditional Chinese medicine Ramulus Mori, serving well as an innovative antidiabetic drug, due to α-glucosidase inhibition. To evaluate the potency of glucosidase inhibitory effect of SZ-A, the enzyme-based screening platforms, including sucrase, maltase and amylase were established, and IC₅₀ was calculated. The effects of SZ-A on postprandial blood glucose at a single dose, oral sucrose, starch and glucose loading were determined in normal ICR mice and alloxan-induced hyperglycemic mice. To confirm the anti-diabetic effects of SZ-A on glucose and lipid metabolism after long-term administration, the postprandial and fasting blood glucose, serum insulin, urinary glucose levels, glycosylated serum proteins and blood lipid levels were determined in high-fat fed C57 obese mice (pre-diabetic HFC57 mice) and diabetic rats induced by streptozotocin (STZ). The Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College approved all of the protocols for this research. We found that SZ-A exhibited a significant inhibitory effect on the sucrase and maltase. SZ-A showed no effect on amylase. In normal ICR mice and alloxan-induced hyperglycemic mice, SZ-A at a single dose significantly delayed and reduced the peak of blood glucose after sucrose or starch loading, but showed no effect on the increase of blood glucose after glucose loading. In STZ diabetic rats, SZ-A significantly reduced the postprandial or fasting blood glucose levels, glycosylated serum proteins and urinary glucose. SZ-A also reduced serum triglyceride (TG) and cholesterol (TC) levels after 3 weeks of treatment. SZ-A ameliorated the postprandial blood glucose or the fasting blood glucose elevation, and reduced the incidence of hyperglycemia in HFC57 mice. SZ-A decreased the basal insulin level, improved insulin sensitivity, and ameliorated glucose intolerance in pre-diabetic HFC57 mice. Our results indicated that SZ-A had a novel inhibitory activity on α-glucosidase, especially on disaccharidases. SZ-A at a single dose significantly reduced the peak of blood glucose elevation and delayed the increase of blood glucose in normal and diabetic mice after disaccharide and polysaccharide loading. Long-term SZ-A treatment improved glucose and lipid metabolic profiles by delaying carbohydrate absorption from the intestine and reduced the postprandial blood glucose levels in both pre-diabetic and diabetic animal models. Therefore, SZ-A application may display a beneficial role in preventing the development and complications of diabetes.

Codeine-O-demethylase (CODM) is a key enzyme in the biosynthesis of codeine and morphine. In this study, CODM gene sequences were cloned from Papaver somniferum and Papaver rhoeas, and were compared with each other by sequence alignment and bioinformatics analysis. The results showed that there were three genotypes of CODM in Papaver somniferum and five genotypes of CODM in Papaver rhoeas. Bioinformatics analysis showed that all CODM proteins had no signal peptide sequence, and these proteins were predicted to be non-secretory proteins, belonging to the Pcbc supergene family. Although the amino acid sequences of CODM in poppies are the same, the expression levels of CODM in different poppy resources are significantly different. It is speculated that the variation of transcription level of CODM may be related to its non-coding region sequence, which lays a foundation for further research on the synthesis and regulation mechanism of alkaloids in poppies.

In 2018, FDA approved 59 kinds of new drugs in all, breaking the record of 53 set in 1993. There were 34 types of small molecule drugs, which accounted for 64% of the whole new drugs. Of these 34 new small molecule drugs, 9 first-in-class ones marked a milestone for the subsequent drug discovery and development. These include Glasdegib, the world's first small molecule inhibitor targeting Smo through Hedgehog signaling pathway; Ivosidenib, the first small molecule inhibitor targeting mutant IDH1; Tecovirimat, the first small molecule drug for anti-variola virus therapy through targeting p37; Baloxavir marboxil, the first anti-flu drug targeting cap-dependent endonuclease; Elagolix sodium, the first small molecule inhibitor in treating endometriosis by targeting GnRH-R, etc. The research and development of first-in-class drugs is always full of obstacles and challenges. However, once they were successfully recognized as the "heavy bomb" drugs, they would become huge benefits. This article chose the representative first-in-class small molecule drugs that were approved in 2018 as examples to analyze their development processes in an attempt to provide guidance for the research and development of more first-in-class drugs.

To explore the effect of total extract of Chrysanthemum morifolium on lipopolysaccharide (LPS)-induced acute lung injury in mice, we studied the effects of three caffeoyl quinic acids isolated from Chrysanthemum morifolium on vascular endothelial cell injury and their mechanisms of action. All animal experiments were carried out strictly in accordance with the National Animal Welfare Ethics and Protection Regulations. A mouse model of acute lung injury was established by intranasal instillation of LPS. After 6 days of oral administration of chrysanthemum extract, the lung wet weight/dry weight ratio, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured in mouse bronchoalveolar lavage fluid. Human umbilical vein endothelial cells (HUVEC) were serum starved for 12 h and treated with 2.5 μg·mL^-1 LPS for 24 h to establish the in vitro model of vascular endothelial cell injury. After 24 h of treatment of caffeoyl quinic acids from Chrysanthemum morifolium, the levels of TNF-α, IL-6, IL-1β, vascular cell adhesion molecule-1 (VCAM-1) and endothelin-1 (ET-1) were measured by ELISA in the cell culture supernatant, the malondialdehyde (MDA) level was detected by TBA method, the superoxide dismutase (SOD) level was determined by hydroxylamine method, and the nitric oxide (NO) level was assayed by a one-step method. The levels of p-MEK1/2, MEK1/2, p-ERK1/2, ERK1/2, p-JNK, JNK, p-P38 and P38 of mitogen-activated protein kinase (MAPK) signaling pathway were detected by Western blot. The total extract of Chrysanthemum morifolium can significantly reduce the wet weight/dry weight ratio of lung in mice and the levels of TNF-α, IL-6 and IL-1β in alveolar lavage fluid. The caffeoyl quinic acids from Chrysanthemum morifolium significantly increased the levels of SOD and NO, decreased the levels of TNF-α, IL-6, IL-1β, VCAM-1, ET-1 and MDA, and significantly reduced the levels of p-MEK1/2, p-ERK1/2. In conclusion, total extracts of Chrysanthemum morifolium exhibit certain protective effect on mice with acute lung injury, and three caffeoyl quinic acids from Chrysanthemum morifolium may improve LPS-induced vascular endothelial cell injury by inhibiting inflammatory cytokines and oxidative stress, and regulating inter-cellular adhesion molecule and vasomotor factors through ERK/MAPK signaling pathway.

Elabelas/Toddlers belong to a group of endogenous active peptides recently discovered from zebrafish. The sequences of these peptides have 25% homology to Apelin. These peptides regulate physiological functions of organisms through putative protein receptors related to the angiotensin receptor AT1 (APJ). Functional roles of Elabela include early embryonic development, angiogenesis, fluid homeostasis, and feeding or dietary behavior control. Elabela also participates in the development of many diseases, such as heart failure, preeclampsia, acute kidney injury, hypertension, and diabetes. Increasingly, studies have shown that Elabela/APJ signaling can promote normal development of early embryos, including differentiation of mesoderm and endoderm, and formation of cardiac morphology and function. At the same time, the signaling can also promote angiogenesis or migration and proliferation of tumor cells. Here we describe the molecular structure, biological characteristics, functions and application prospects of Elabela/APJ signaling.

This study aims to investigate the effect of down-regulation of miR-205-5p by transfection of miR-205-5p inhibitor on the sensitivity of HNE1/DDP cells to cisplatin (DDP) induced apoptosis and explore the underlying mechanism. qRT-PCR was used to detect the expression of miR-205-5p in HNE1 or HNE1/DDP cells. The expression level of miR-205-5p was analyzed after transfecting HNE1/DDP cells with miR-205-5p inhibitor. MTT assay was used to evaluate the inhibitory effect of DDP alone or in combination with miR-205-5p inhibitor on the proliferation of HNE1/DDP or HNE1 cells. Apoptosis of cells treated with miR-205-5p inhibitor alone or in combination with DDP (8 μmol·L^-1) was assessed using flow cytometry with PI staining, with the nucleus was counterstained with DAPI staining. The expression of Bax, Bak, Mcl-1, or Bcl-2 was analyzed by Western blot. HNE1/DDP cells showed a high level of expression of miR-205-5p, and the expression of miR-205-5p was significantly decreased by transfection of miR-205-5p inhibitor. Down-regulation of miR-205-5p significantly increased the sensitivity of HNE1/DDP cells to DDP (P < 0.05). Transfection of miR-205-5p inhibitor enhanced the sensitivity of HNE1/DDP cells to DDP induced apoptosis. Treatment of HNE1/DDP cells with miR-205-5p inhibitor combined with DDP (8 μmol·L^-1) for 24 h resulted in an apoptotic rate of 28.93% ±2.50%, significantly higher than that treated with miR-205-5p inhibitor (9.83% ±1.31%) or DDP alone (10.83% ±1.70%) (P < 0.05). DAPI staining showed that HNE1/DDP cell nucleus became significantly condensed and fragmented in miR-205-5p inhibitor combined with DDP group. The combined group up-regulated the expression of Bax and down-regulated the expression of Bcl-2 in HNE1/DDP cells. Therefore, down-regulation of miR-205-5p can enhance the sensitivity of HNE1/DDP cells to cisplatin induced apoptosis, and the mechanism may involve up-regulation of Bax and down-regulation of Bcl-2 expression.

Flavonoids are important active ingredients in traditional Chinese medicine. However, their applications for the pharmaceutical use are greatly limited by low oral bioavailability due to poor aqueous solubility. The study of pharmaceutical crystallography is a potential approach to solve many problems of poor solubility. Research progress of flavonoid compounds in pharmaceutical crystallography field was reviewed from following aspects:polymorphism, cocrystal, amorphous/co-amorphous and nanocrystals. The information provided here is expected to serve as a reference for the applications of pharmaceutical crystallography in the poorly soluble components of traditional Chinese medicine.

In this manuscript, a rapid and simple analysis method for aconitine alkaloids was established. The method was based on the use of direct ionization and wooden tip spray ionization technology to detect the aconite. The aconite tuber slices were wrapped with wet filter paper overnight, cut into triangles, and extracted with a few solvents for direct ionization and wooden tip spray mass spectrometry. The results showed that alkaloids in aconite tuber can be rapid detected by two mass spectrometric methods without tedious sample pretreatment. Both methods are superior to that of traditional capillary electrospray ionization mass spectrometry (ESI-MS). The direct ionization MS is better than the wooden tip spray MS for analysis of aconite except under the condition of methylene chloride as extract or spray solvent. Different types of alkaloids in aconite tuber can be selectively detected when different solvents are used. The experiments provide a rapid and no pretreatment MS spectrometric method for analysis of alkaloids in aconite. These sample methods are important for research on aspects of plant varieties, storage, prescription compatibility, and quality control of aconite.

Network pharmacology and rat ischemia-reperfusion injury (MIRI) model was used to analyze the mechanism of cardiac protection by Trichosanthes. The animal experiments were approved by the Medical Ethics Committee of Wannan Medical College. Compounds were screened by TCMSP database and TCM Database@Taiwan according to oral bioavailability (OB > 30%) and drug like activity (DL > 0.18). The PDBID value of the compound (Z'-score < 0.5) was obtained in DRAR-CPI database and converted into a target protein by UniProt database. Human genes of target proteins were identified using the term "myocardial ischemia reperfusion injury" as the keyword through the CoolGeN database. GOTERM_BP _DIRECT enrichment analysis of target proteins related to MIRI and KEGG PATHWAY annotation analysis were performed using the DAVID database. The component-target protein-signal pathway network was constructed using Giphi0.9.2 software. The expression of mitogen-activated protein kinase (MAPK) signaling pathway-related proteins in MIRI rats pretreated with Trichosanthes (0.2, 1.0 and 2.0 g·kg^-1) was analyzed by Western blot with compound Danshen (85.05 mg·kg^-1) as a positive control. Network pharmacology found that 12 compounds, including schottenol in Trichosanthes, synergistically inhibit MIRI through multiple targets or biological pathways, involving target proteins such as extracellular regulated protein kinase 2 (ERK2), c-jun-N-terminal kinase-1 (JNK1) and p38MAPK in MAPK signaling pathways. Western blot results showed that phosphorylation of ERK1/2 was dose-dependently up-regulated in MIRI rats pretreated with Trichosanthes, while the level of p38MAPK or JNK1 phosphorylation was down-regulated in a dose-dependent manner. Compared with the control group, phosphorylation of ERK1/2, JNK1 and p38MAPK protein showed significant difference in medium and high dose groups (1.0 and 2.0 g·kg^-1) (P < 0.01). Therefore, Trichosanthes could play an anti-MIRI role by regulating phosphorylation of ERK1/2, JNK1 and p38MAPK proteins in rats. In conclusion, the targets and pathways of Trichosanthes on anti-MIRI were revealed by network pharmacology and verified in rat MIRI model, providing the scientific basis for further study on the mechanism of Trichosanthes for cardiac protection.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously threatens the life of the elderly and there is no effective therapy to treat or delay the onset of this disease. Due to the multifactorial etiology of this disease, the multi-target-directed ligand (MTDL) approach is an innovative and promising method in search for new drugs against AD. In order to find potential multi-target anti-AD drugs through reposition of current drugs, the database of global drugs on market were mined by an anti-AD multi-target prediction platform established in our laboratory. As a result, inositol nicotinate, cyproheptadine, curcumin, rosiglitazone, demecarium, oxybenzone, agomelatine, codeine, imipramine, dyclonine, melatonin, perospirone, and bufexamac were predicted to act on at least one anti-AD drug target yet act against AD through various mechanisms. The compound-target network was built using the Cytoscape. The prediction was validated by molecular docking between agomelatine and its multiple targets, including ADORA2A, ACHE, BACE1, PTGS2, MAOB, SIGMAR1 and ESR1. Agomelatine was shown to be able to act on all the targets above. In conclusion, the potential drugs for anti-AD therapy in the database for global drugs on market was partially uncovered using machine learning, network pharmacology, and molecular docking methods. This study provides important information for drug reposition in anti-AD therapy.