Effect of multi-target protein tyrosine kinase inhibitor Ponatinib on proliferation,adhesion and migration ability of human liver cancer cell line SK-Hep-1 / 中国生物制品学杂志

@#Objective To investigate the effect of a multi-target protein tyrosine kinase inhibitor,Ponatinib,on proliferation,homogeneity adhesion and migration ability of human liver cancer cell line SK-Hep-1.Methods SK-Hep-1 cells were cultured routinely and added with 24 tyrosine kinase inhibitors such as Ponatinib respectively,and the effect of Ponatinib on the survival and proliferation of SK-Hep-1 cells was detected by MTT assay.SK-Hep-1 cells were cultured routinely until the fusion degree reached 90%,then added with 0.1,0.5 and 1.0 μmol/L Ponatinib respectively,and the control group(without Ponatinib) was set up.The effect of Ponatinib on adhesion ability of SK-Hep-1 cells was detected by cell slow aggregation assay and dissociation assay,while the effect on migration ability by scratch test,and the effect on E-cadherin protein expression in SK-Hep-1 cells by Western blot.Results All 24 tyrosine kinase inhibitors inhibited SK-Hep-1 cells,among which Ponatinib showed the strongest inhibitory effect with a IC_(50) of(0.288±0.044) μmol/L.Compared with the control group,the number of cell mass(t=16.143,44.002 and 44.853 respectively,each P <0.001) and N_(TC)/N_(TE) [ratio of single cell number(N) after digestion by trypsin containing EDTA(TE) and CaCl_2(TC)](t=4.276,10.625 and 27.571 respectively,each P <0.05) decreased significantly and E-cadherin protein expression increased significantly(t=-3.757,-4.561and-6.922 respectively,each P <0.05) in 0.1,0.5 and 1.0 μmol/L Ponatinib groups;Scratch migration rate significantly decreased in 0.5 and 1.0 μmol/L Ponatinib groups(t=6.272～16.733 respectively,each P <0.01),while there was no significant difference in 0.1 μmol/L Ponatinib group(t=0.473 and 0.872 respectively,each P> 0.05) after 24 h and 48 h of scratch.Conclusion Ponatinib inhibited proliferation and migration of SK-Hep-1 cells and promoted cell adhesion.

Identification of multi-target anti-cancer agents from TCM formula by in silico prediction and in vitro validation / 中国天然药物

Cancer is a complex disease associated with multiple gene mutations and malignant phenotypes, and multi-target drugs provide a promising therapy idea for the treatment of cancer. Natural products with abundant chemical structure types and rich pharmacological characteristics could be ideal sources for screening multi-target antineoplastic drugs. In this paper, 50 tumor-related targets were collected by searching the Therapeutic Target Database and Thomson Reuters Integrity database, and a multi-target anti-cancer prediction system based on mt-QSAR models was constructed by using naïve Bayesian and recursive partitioning algorithm for the first time. Through the multi-target anti-cancer prediction system, some dominant fragments that act on multiple tumor-related targets were analyzed, which could be helpful in designing multi-target anti-cancer drugs. Anti-cancer traditional Chinese medicine (TCM) and its natural products were collected to form a TCM formula-based natural products library, and the potential targets of the natural products in the library were predicted by multi-target anti-cancer prediction system. As a result, alkaloids, flavonoids and terpenoids were predicted to act on multiple tumor-related targets. The predicted targets of some representative compounds were verified according to literature review and most of the selected natural compounds were found to exert certain anti-cancer activity in vitro biological experiments. In conclusion, the multi-target anti-cancer prediction system is very effective and reliable, and it could be further used for elucidating the functional mechanism of anti-cancer TCM formula and screening for multi-target anti-cancer drugs. The anti-cancer natural compounds found in this paper will lay important information for further study.

Multi-target combinatory strategy to overcome tumor immune escape / 医学前沿

Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multiimmune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.

Progress of multi-target directed drugs based on tacrine and donepezil in alzheimer′s disease / 中国药学杂志

Alzheimer′s disease (AD) is a progressive multifactorial neurodegenerative disorder in elder people. Currently, the pathogenesis of AD is unclear, and it is presently incurable. In view of the complex network pathological features of AD, a single small molecule compound that can act simultaneously with multiple targets, called multi-target directed ligands (MTDLs), is considered to be an effective therapeutic strategy at present. Here, we review highlights recent MTDLs approach based cholinesterase inhibitors, antioxidant, metal chelator and neuroprotectant in the novel drug candidate prototypes for the treatment of AD.

Research advances in neurovascular unit mechanism in acupuncture treatment of ischemic stroke / 针刺研究

Ischemic stroke is a type of clinical syndrome caused by brain blood supply disorders due to various cerebrovascular diseases, which lead to local cerebral ischemia, hypoxic necrosis, and corresponding neurological defects. In recent years, the neurovascular unit mechanism of ischemic stroke has been proposed in modern medicine. With the principles of syndrome differentiation-based treatment and holistic view in traditional Chinese medicine, acupuncture has the advantage of multi-target and multi-link effect and good clinical efficacy on this disease, and current studies have shown that acupuncture has a marked effect on each component and the whole of neurovascular unit. This article reviews the effect of acupuncture on the regulation of blood-brain barrier, astrocytes, microglial cells, neurons, and neurovascular units.

Application and prospect of fecal DNA test in colorectal cancer screening / 中华胃肠外科杂志

Effective early screening and primary prevention is one of the major initiatives to decrease the morbidity and mortality of colorectal cancer in China. As a new non-invasive screening method for colorectal cancer in recent years, fecal DNA test detects colorectal cancer by analyzing gene mutations from intestinal tumor cells in the feces. The most widely used method among fecal DNA test is multi-target stoolDNA test (MT-sDNA). Many studies abroad on this emerging technique have been carried out to verify its high sensitivity, and it is gradually used in the clinic with continuous improvement and development of technology. Meanwhile, domestic MT-sDNA is still in the prototype stage, and more researches from Chinese population are needed. Compared with traditional screening methods, MT-sDNA technology has the advantages of non-invasiveness, painlessness and convenience. But its defects exist, such as high cost and low specificity. MT-sDNAis in accordance with precision medicine, and can largely make up for the shortcomings of traditional screening methods for colorectal cancer. It also holds a great promise for promoting the screening for colorectal cancer. This paper is aimed to discuss the application value of fecal DNA test by introducing its related researches at home and abroad,and summarizing its merits and demerits.

Repositioning drug discovery for Alzheimer's disease based on global marketed drug data / 药学学报

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.

Application of network biology on study of traditional Chinese medicine / 中国中药杂志

With the completion of the human genome project, people have gradually recognized that the functions of the biological system are fulfilled through network-type interaction between genes, proteins and small molecules, while complex diseases are caused by the imbalance of biological processes due to a number of gene expression disorders. These have contributed to the rise of the concept of the "multi-target" drug discovery. Treatment and diagnosis of traditional Chinese medicine are based on holism and syndrome differentiation. At the molecular level, traditional Chinese medicine is characterized by multi-component and multi-target prescriptions, which is expected to provide a reference for the development of multi-target drugs. This paper reviews the application of network biology in traditional Chinese medicine in six aspects, in expectation to provide a reference to the modernized study of traditional Chinese medicine.

Effect of Toll-like receptor nano-inhibitor P12 on pulmonary inflammation in acute lung injury mice / 上海交通大学学报（医学版）

Objective: To investigate the effect of the Toll-like receptor (TLR) nano-inhibitor P12 on THP-1 derived macrophages and acute lung injury (ALI) mouse model induced by lipopolysaccharides (LPS). Methods: In in vitro experiments, THP-1 cells were differentiated into macrophage-like cells and then treated with LPS in the absence and presence of P12. After 24 h incubation, medium was collected to quantify the secretion of pro-inflammatory cytokines using enzyme-linked immunosorbent assay (ELISA). Six- to eight-week-old C57BL/6 mice were randomly divided into three groups, i.e. PBS control, LPS challenge and P12 pretreatment plus LPS. The bronchial alveolar lavage fluid (BALF) and lung tissue of each mouse were collected, and the acute inflammatory response within lung was evaluated by total cell counts, differential cell counts and ELISA. Pathological injury scores in ALI mice were assessed with hematoxylin and eosin (H-E) staining of lung tissue sections under microscope. Results: In THP-1 derived macrophages, P12 significantly inhibited LPS-induced inflammatory cytokine production. In the LPS-induced ALI mouse model, P12 significantly attenuated the acute inflammatory response and alveolar damage in lung, including reducing the number of total cells and neutrophils in BALF, decreasing the expression of chemokine production (KC and CCL-2), and lowering lung injury scores. Conclusion: P12 exhibits potent anti-inflammatory activity in THP-1 derived macrophages and in the LPS-induced ALI mouse model, providing new concepts for the early treatment of ALI.

Multi-target drug design strategy and its research progress / 药学学报

Currently, single-target drugs are often difficult to achieve the desired results in the treatment of multifactorial diseases such as tumors, cardiovascular and endocrine diseases, and may also cause toxicity. Multi-target drugs can improve the efficacy, reduce side effect and drug resistance by regulating multiple links of the disease, showing good prospects for the application. The main aim of this article is to review the strategies of designing multi-target directed ligands (MTDLs) (including conjugated-pharmacophore, fused-pharmacophore and merged-pharmacophore) and the research progress in recent years. The existing problems and challenges of multi-target drugs are also discussed, to provide new ideas for the study of multi-target drugs.

Research advances of multi-targeted flavonoids in the intervention of Alzhei-mer's disease / 中国药科大学学报

Alzheimer′s disease(AD)is a chronic progressive neurodegenerative disease in the elderly,which causes heavy burden for the society and family.The current drugs could only improve the cognitive symptoms in the short term,but could not reverse or stop the disease progression.In view of the complexity of AD,multi-targe-ted drugs could be a potential strategy for the treatment of AD.Flavonoids,widely exising in the natural world, have multiple pharmacological activities.This paper summarizes flavonoids as promising multi-targeted anti-AD candidates according to the reported references previonsly published,which could provide important evidences in the development of anti-AD durgs.

The present status and problems of multi-target therapy of myasthenia gravis / 中华神经科杂志

The clinical manifestation of myasthenia gravis is due to the acetylcholine transmission defect of neuromuscular junction caused by autoimmune disturbance. With the intensive understanding of the pathogenesis and the emerging of specific immunological targeting therapy, therapeutic investigations are widely expanding. A multi-target therapy pattern is now available based on treatments primed to distinct immunopathological processes and improving neuromuscular junction transmission. We will comment the status and problems in this article.

Network mechanism of effective constituents from the compound Yizhihao against influenza / 中国药理学与毒理学杂志

Influenza caused by influenza virus,seriously threaten human life and health.Drug treatment is one of the effective measurement. However, there are only two classes of drugs, one class is M2 blockers and another is neuraminidase (NA)inhibitors. The recent antiviral surveillance studies reported a global significant increase in M2 blocker resistance among influenza viruses, and the resistant virus strains against NA inhibitor are also reported in clinical treatment.Therefore thediscovery of new medicines with low resistance has become very urgent.As all known,traditional medicines with multi-target features and network mechanism often possess low resistance. Compound Yizhihao, which consists of radix isatidis,folium isatidis,Artemisia rupestris,is one of the famous traditional medicine for influenza treatment in China, however its mechanism of action against influenza is unclear. In this study, the multiple targets related with influenza disease and the known chemical constituents from Compound Yizhihao were collected, and multi-target QSAR (mt-QSAR) classification models were developed by Na?ve Bayesian algorithm and verified by various datasets. Then the classification models were applied to predict the effective constituents and their drug targets.Finally,the constituent-target-pathway network was constructed,which revealed the effective constituents and their network mechanism in Compound Yizhihao. This study will lay important basis for the clinical uses for influenza treatment and for the further research and development of the effective constituents.

Progress in research for pharmacological effects of Pu-erh tea / 中国中药杂志

Pu-erh tea has gradually aroused general concern with social development and people's enhanced awareness of health. Pu-erh tea is rich in multiple active constitute such as flavonoids, catechins, phenolic acids, flavanols polymer, purine alkaloids, and hydrolysable tannin as a microbial-fermented tea.It is reported that Pu-erh tea have a variety of pharmacologically activities, such as anti-hyperlipidemic, anti-diabetic, anti-oxidative, anti-tumor, anti-bacterial, anti-inflammatory, and anti-viral effects. In this paper, the main pharmacological effects of Pu-erh tea are reviewed. We wish this work will provide some references and clues for further research of Pu-erh tea.

Multiple-target agents in the therapy of Alzheimer’s disease: Research advances / 国际药学研究杂志

Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is mainly Acetyl cholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) antagonist, which are single-target AD drugs. They are limited symptomatic treatment and their efficacy remains unsatisfactory. Due to the complexity and multifactorial etiology of AD, the multi-target-directed ligand approach is a hopeful way of searching new anti-AD drugs. Here we review the advancement of multitarget AD drugs in recent years: single compound with more than one target, multicomponent drug and drug combination.

Evaluation of the protective effect of salvianolic acid A on ischemic heart failure by a multi-target pharmacokinetic-pharmacodynamic model / 中国药科大学学报

@#The aim of this study was to develop a multi-target pharmacokinetic-pharmacodynamic(PK-PD)model for the evaluation of the protective effect of salvianolic acid A(Sal A)on ischemic heart failure based on a metabolic balance model. The rats were assigned to 3 groups: sham-operated group(saline), ischemic heart failure group(saline)and Sal A-treated group(Sal A, 1 mg/(kg ·d), ip). The concentrations of brain natriuretic peptide(BNP), angiotensin II(Ang II), malondialdehyde(MDA), asymmetric dimethylarginine(ADMA)and the activity of glutathione peroxidase(GSH-Px)in rat plasma were determined before and at 1, 2, 3, and 4 weeks after ligation in all the groups. A multi-target PK-PD model was developed based on the change rate of metabolic disruption parameter k and was eventually used to integrally evaluate the protective effect of Sal A on ischemic heart failure. Sal A showed improvement effects on multiple biomarkers and the correlation study demonstrated a good relationship between dynamic parameter k and left ventricular ejection fraction(LVEF). More importantly, the multi-target model well fitted the relationship between AUC and the change rate. The multi-target PK-PD model provides a novel method to integrally evaluate the protective effect of Sal A, which might offer a new strategy for the establishment of a PK-PD model that embodies the characteristics of traditional Chinese medicine.

Progress of clinical trials in Alzheimer's disease drugs / 药学学报

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease. The pathogenesis of AD is unclear, and it is presently incurable. Medicines currently available for AD treatment are only for improving the cognitive symptoms, but not able to stop or delay disease progression. Here, we summarized the interventions in early phases of AD in clinical trial. As a complex disease, AD is difficult to be restored through a treatment on a single target. Multi-target and cocktail drugs might be a strategy for development of AD therapies. In addition, AD is characterized by progressive neuronal loss in the cortex and hippocampus. The induction of neurogenesis by small molecule compounds has drawn attention in the AD field. The study of natural products in China is leading the way in the AD world. Numerous natural products have been identified for pharmacological effects on multi-targets in the regulation of neurogenic activity, which may open up a new avenue for AD treatments.

Advances in studies on HIV-1 multi-target drugs from natural products / 中草药

During the curing of complex disease, prospective therapeutic effect has been more and more difficult to achieve by using single-target inhibitors. Along with the development of systems biology and network pharmacology, the nosogenesis and the pathological process have been studied in depth, and people find that multi-target inhibitors can overcome many defects by using single-target inhibitors. Multi-target inhibitors include multicomponent and single component, but single component takes more advantages. The treatment of AIDS is a world problem, single-target inhibitors and multicomponent multi-target inhibitors (i.e. HAART) are used; However, viral height variability and severe drug resistance restrict the wide application of the two therapeutics. Therefore, the single component multi-target inhibitors with low toxicity and highperformance have been the most important choice to treat AIDS caused by HIV-1. The single component multi-target HIV-1 inhibitors mostly come from rational drug design and screening. Some HIV-1 inhibitors have been discovered from the natural products which have extensive sources and wide variety of kinds. That is an important way to develop lead compounds of HIV-1 inhibitors. This paper summarizes the advances in studies on HIV-1 multi-target drugs from natural products.

Th1/Th2 imbalance in ischemia-reperfusion injury and the application prospects of traditional Chinese medicine with multi-target effect / 中国药理学通报

The damage of tissue increases dramatically after reperfusion of blood supply to ischemic tissues.Immune response is one of the key reasons of ischemia-reperfusion injury.Th1 /Th2 generally stays balanced in normal states.Under the envi-ronment of ischemia reperfusion,Th1 /Th2 shifting let Th1 domi-nant to mediate cellular immunity.Excessive immune reaction may cause cell apoptosis and tissue damage.Recent studies showed that induction of transferring Th1 dominant to Th2 domi-nant was feasible for the treatment of ischemia-reperfusion inju-ry.With the progress of modern drug development paradigm“multi-composition,multi-target”,Chinese medicine has advan-tages in treating complex diseases.This paper summarizes the research of the relationship between Th1 /Th2 imbalance and is-chemia-reperfusion injury,together with the prospects of tradi-tional Chinese medicine with multi-target effect in ischemia-reperfusion injury.

Preliminary clinical observation of multi-target therapy for the treatment of ANCA-associated vasculitis with renal involvement / 医学研究生学报

Objective The treatment of anti-neutrophil cytoplasmic antibodies ( ANCA) associated vasculitis ( AVV) such as mycophenolate mofetil ( MMF ) can improve the remission rate, however, it also results in high recurrence rate and high incidence of adverse reaction related to the treatment.The article was to observe the clinical efficacy and safety of multi-target therapy ( MT ) in the treatment of AAV with renal involvement. Methods Retrospective observation was made on 7 AVV patients treated with multi-target therapy in our department from June 2009 to October 2013.The pa-tients (1 male, 6 females) aged from 21 to 54 years were accompa-nied with renal damage and serum creatinine (SCr≤3 mg/dL).All patients had positive myelopeeroxidase-ANCA (MPO-ANCA), high-grade proteinuria and hematuria.4 patients had elevated SCr (1.47-2.94 mg/dL) with EGFR90 mL/min in 2 patients and EGFR60 mL/min) .At the end of follow-up, the EGFR expres-sion was normal in 4 patients, 60-90 mL/min in 1 patient and less than 60 mL/min in 2 patients, without end stage renal disease. ANCA level turned to normal in 3 patients and significantly decreased in 4 patients.No patients had adverse reaction, died, or re-lapsed during the follow-up. Conclusion MT is effective in the control of renal activities of AVV patients with mild or moderate re-nal function damage.It attributes to great improvement of renal function and urine protein, as well as good tolerance.However, pro-spective study is required to confirm the efficacy of this new therapy.