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| 1 | The SLC transporter in nutrient and metabolic sensing, regulation, and drug development显示文摘The prevalence of metabolic diseases is growing worldwide. Accumulating evidence suggests that solute carrier (SLC) transporters contribute to the etiology of various metabolic diseases. Consistent with metabolic characteristics, the top five organs in which SLC transporters are highly expressed are the kidney, brain, liver, gut, and heart. We aim to understand the molecular mechanisms of important SLC transporter-mediated physiological processes and their potentials as drug targets. SLC transporters serve as Metabolic gate’ of cells and mediate the transport of a wide range of essential nutrients and metabolites such as glucose, amino acids, vitamins, neurotransmitters, and inorganic/metal ions. Gene-modified animal models have demonstrated that SLC transporters participate in many important physiological functions including nutrient supply, metabolic transformation, energy homeostasis, tissue development, oxidative stress, host defense, and neurological regulation. Furthermore, the human genomic studies have identified that SLC transporters are susceptible or causative genes in various diseases like cancer, metabolic disease, cardiovascular disease, immunological disorders, and neurological dysfunction? Importantly, a number of SLC transporters have been successfully targeted for drug developments。 This review will focus on the current understanding of SLCs in regulating physiology, nutrient sensing and uptake, and risk of diseases. | Yong Zhang Yuping Zhang Kun Sun Ziyi Meng Ligong Chen | 2019 | Journal of Molecular Cell Biology2019，11，1： | 11 |
| 2 | Drug metabolism in drug discovery and development显示文摘Drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics(PK), pharmacodynamics(PD), and safety should be carefully considered. This communication provides an overview of common strategies in the area of drug metabolism for improving PK/PD and safety profiles of drug candidates; these include, but are not limited to, collaboration with medicinal chemists on structure–activity relationships(SAR) to overcome high clearance, using deuterium replacement to further optimize a lead, prodrug approaches to circumvent formulation and delivery difficulties, and addressing issues such as species differences in metabolism,drug–drug interactions(DDI) and formation of reactive metabolites. | Zhoupeng Zhang Wei Tang | 2018 | Acta Pharmaceutica Sinica B2018，8，5： | 9 |
| 3 | Mouse models of colorectal cancer: Past, present and future perspectives显示文摘Colorectal cancer(CRC)is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union.While the incidence and mortality rates in western,high developed countries are declining,reflecting the success of screening programs and improved treatment regimen,a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index.Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades,preclinical in vivo models are still indispensable for the development of new treatment approaches.Since the development of carcinogen-induced rodent models for CRC more than 80 years ago,a plethora of animal models has been established to study colon cancer biology.Despite tenuous invasiveness and metastatic behavior,these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis.Genetically engineered mouse models(GEMM)mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited.Although the vast majority of CRC GEMM lack invasiveness,metastasis and tumor heterogeneity,they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses;thus,supporting development of new therapeutic avenues.Induction of metastatic disease by orthotopic injection of CRC cell lines is possible,but the so generated models lack genetic diversity and the number of suited cell lines is very limited.Patient-derived xenografts,in contrast,maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development–even in comparison to GEMM or cell line-based analyses.However,subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses.The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models. | Florian Bürtin Christina S Mullins Michael Linnebacher | 2020 | World Journal of Gastroenterology2020，26，13： | 9 |
| 4 | Current status and future prospects of stem cell therapy in Alzheimer’s disease显示文摘Alzheimer’s disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer’s disease, and the current state of stem cell transplantation in the treatment of Alzheimer’s disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer’s disease. | Fu-Qiang Zhang Jin-Lan Jiang Jing-Tian Zhang Han Niu Xue-Qi Fu Lin-Lin Zeng | 2020 | Neural Regeneration Research2020，15，2： | 7 |
| 5 | N^6-Methyladenosine modification: a novel pharmacological target for anti-cancer drug development显示文摘N6-Methyladenosine(m6 A) modification is the most pervasive modification of human mRNA molecules. It is reversible via regulation of m6 A modification methyltransferase, demethylase and proteins that preferentially recognize m6 A modification as 'writers', 'erasers' and 'readers', respectively. Altered expression levels of the m6 A modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the m6 A modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of m6 A modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key m6 A modification regulators for cancer drug development.& 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://gffzzeb6f7f563f66445dhcvpup906bqx06p6n.ffgz.tsg.suse.edu.cn/licenses/by-nc-nd/4.0/). | Yi Niu Arabella Wan Ziyou Lin Xiongbin Lu Guohui Wan | 2018 | Acta Pharmaceutica Sinica B2018，8，6： | 5 |
| 6 | Cancer chemoprevention through dietary avonoids: what's limiting?显示文摘Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their e ective use, including(1) the isolation and purification of flavonoids from their natural resources;(2) demonstration of the e ects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and(3) numerous pharmacokinetic challenges(e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and e orts that are being made to surmount these challenges. | Haneen Amawi Charles R. Ashby Jr Amit K. Tiwari | 2017 | Chinese Journal of Cancer2017，36，10： | 4 |
| 7 | Recent advances in dopaminergic strategies for the treatment of Parkinson’s disease显示文摘Parkinson’s disease(PD)is the second most common progressive neurodegenerative disease worldwide.However,there is no available therapy reversing the neurodegenerative process of PD.Based on the loss of dopamine or dopaminergic dysfunction in PD patients,most of the current therapies focus on symptomatic relief to improve patient quality of life.As dopamine replacement treatment remains the most effective symptomatic pharmacotherapy for PD,herein we provide an overview of the current pharmacotherapies,summarize the clinical development status of novel dopaminergic agents,and highlight the challenge and opportunity of emerging preclinical dopaminergic approaches aimed at managing the features and progression of PD. | Qi Mao Wang-zhi Qin Ao Zhang Na Ye | 2020 | Acta Pharmacologica Sinica2020，41，4： | 2 |
| 8 | Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target显示文摘Malaria is a major cause of morbidity and mortality in humans. Artemisinins remain as the first-line treatment for Plasmodium falciparum(P. falciparum) malaria although drug resistance has already emerged and spread in Southeast Asia. Thus, to fight this disease, there is an urgent need to develop new antimalarial drugs for malaria chemotherapy. Unlike human host cells, P. falciparum cannot salvage preformed pyrimidine bases or nucleosides from the extracellular environment and relies solely on nucleotides synthesized through the de novo biosynthetic pathway. This review presents significant progress on understanding the de novo pyrimidine pathway and the functional enzymes in the human parasite P. falciparum. Current knowledge in genomics and metabolomics are described, particularly focusing on the parasite purine and pyrimidine nucleotide metabolism. These include gene annotation, characterization and molecular mechanism of the enzymes that are different from the human host pathway. Recent elucidation of the three-dimensional crystal structures and the catalytic reactions of three enzymes: dihydroorotate dehydrogenase, orotate phosphoribosyltransferase, and orotidine 5'-monophosphate decarboxylase, as well as their inhibitors are reviewed in the context of their therapeutic potential against malaria. | Sudaratana R.Krungkrai Jerapan Krungkrai | 2016 | Asian Pacific Journal of Tropical Medicine2016，9，6： | 0 |
| 9 | Thoughts on Development and Internationalization of Traditional Drug Enterprises显示文摘Hi, I will introduce a Chinese patent medicine enterprise with a history of 112 years. I will report to you the characteristics of an enterprise of Chinese patent medicine in 3 parts as follows: In the first part, I will give an overview of the development of Chinese medicine and phytomedicine. | 杨朝林 | 2019 | World Journal of Integrated Traditional and Western Medicine2019，5，3： | 0 |
| 10 | Successful generic drug product development:From research to marketing approval显示文摘Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for healthcare professionals.Generic drug products are proven therapeutically equivalent to the corresponding innovator’s product,and hence can be substituted in clinical practice.The objective of generic drug development is to develop a stable and bioequivalent generic drug product with desirable properties in a timely manner.This presentation is intended to summarize three important sequential stages essential for successful generic drug development based on a regulatory experience in reviewing and evaluating the Pharmaceutical Development Section(P2)of the ASEAN Common Technical Dossier(ACTD)of generic drug product applications submitted to the Food and Drug Administration,Thailand[1,2]. | Suchart Chongprasert | 2016 | Asian Journal of Pharmaceutical Sciences2016，11，1： | 0 |
| 11 | Scope of translational medicine in developing boroncontaining compounds for therapeutics显示文摘The ubiquitousness of naturally occurring boron-containing compounds(BCCs) has led to their constant contact with humankind.Recently,many synthetic BCCs have been elaborated for a broad spectrum of purposes,especially boric,boronic and borinic acids.Although BCCs were once employed primarily as antiseptics and later as antibiotics,they have become an increasingly relevant therapeutic tool.Nevertheless,this potential of BCCs has been drastically limited due to some unfortunate intra-hospital accidents in the 1940 s and 1950 s.The increasing use of BCCs as insecticides,antimicrobials,and other agents is providing new insights into their role in the physiology of several living species and in the pathophysiology of humans.It is becoming clear that BCCs act through a wide range of mechanisms,as do their corresponding boron-free counterparts.When comparing BCCs and similar boron-free compounds,in many cases the former show advantages in the medical field.The current minireview focuses on how BCCs have been developed by means of translational medicine,a process connecting biomedical research with clinical applications.This process of discovery is currently in an exponential stage. | Ana Karen García-ávila Eunice Dalet Farfán-García Juan Alberto Guevara-Salazar José Guadalupe Trujillo-Ferrara Marvin Antonio Soriano-Ursúa | 2017 | World Journal of Translational Medicine2017，6，1： | 0 |
| 12 | Regulation of Drug Clinical Trials in China: Course and Development Trend显示文摘Objective To provide a basis for future regulation reform of drug clinical trials in China in the context of the continuous deepening of drug regulation reform. Methods Literature review and regulation study were conducted to analyze the course and development trend of drug clinical trial regulation in China. Results and Conclusion It is found that the regulation system and the standardization for clinical trials in China are gradually improving, but there is still a gap compared with developed countries. In the future, the regulation authorities still need to further improve relevant regulations, clarify regulation responsibilities, and to improve the drug clinical trial review system to ensure the quality of clinical trials and the safety and effectiveness of listed drugs. | Zhang Xu Tian Lijuan | 2019 | Asian Journal of Social Pharmacy2019，14，3： | 0 |
| 13 | Risk Control Strategy in the Research and Development of Pediatric Drugs显示文摘Objective To analyze the risk control strategy in the research and development of pediatric drugs and to provide references for pharmaceutical enterprises to avoid the risks so that they can produce more and much better drugs for children in China. Methods An expert questionnaire and expert interviews were conducted to identify the specific risks and the key factors, and valuable advices were put forward. Results and Conclusion There are four risk factors in the research and development of pediatric drugs. The first is that parents are concerned and they are unwilling to allow their children to participate in drug trial. Secondly, adult drug safety data cannot support pediatric drug study. Thirdly, pediatric drugs often have adverse events. Last, regulations for pediatric drugs clinical trials are not perfect. Some valuable recommendations are provided to control these risks. | Tang Ying Chen Yuwen | 2019 | Asian Journal of Social Pharmacy2019，14，3： | 0 |
| 14 | Regulation of “Checkpoint Molecule” Sheds New Light on Anti-Cancer Drug Development显示文摘The rivalry between T cells and tumor cells somewhat mimics the scene of 'Tom and Jerry,' an animated series in which Tom (a house cat) rarely succeeds in catching Jerry (a mouse), mainly because of Jerry’s cleverness and cunning abilities. In a way, tumor cells are like Jerry, in terms of their crafty and sneaky features. | YAN Fusheng | 2018 | Bulletin of the Chinese Academy of Sciences2018，32，4： | 0 |
| 15 | Investigative safety strategies to improve success in drug development显示文摘Understanding and reducing attrition rate remains a key challenge in drug development.Preclinical and clinical safety issues still represent about 40%of drug discontinuation,of which cardiac and liver toxicities are the leading reasons.Reducing attrition rate can be achieved by various means,starting with a comprehensive evaluation of the potential safety issues associated to the primary target followed by an evaluation of undesirable secondary targets.To address these risks,a risk mitigation plan should be built at very early development stages,using a panel of in silico,in vitro,and in vivo models.While most pharmaceutical companies have developed robust safety strategies to de-risk genotoxicity and cardiotoxicity issues,partly driven by regulatory requirements;safety issues affecting other organs or systems,such as the central nervous system,liver,kidney,or gastro-intestinal system are less commonly addressed during early drug development.This paper proposes some de-risking strategies that can be applied to these target organ systems,including the use of novel biomarkers that can be easily integrated in both preclinical and clinical studies.Experiments to understand the mechanisms’underlying toxicity are also important.Two examples are provided to demonstrate how such mechanistic studies can impact drug development.Novel trends in investigative safety are reviewed,such as computational modeling,mitochondrial toxicity assessment,and imaging technologies.Ultimately,understanding the predictive value of non-clinical safety testing and its translatability to humans will enable to optimize assays in order to address the key objectives of the drug discovery process,i.e.,hazard identification,risk assessment,and mitigation. | Franck Atienzar Annie Delaunois Frédéric Brouta Miranda Cornet Renaud Fleurance Helga Gerets Stéphanie Glineur Catrin Hasselgren Andrea Kiessling Andre Nogueira da Costa Marie-Luce Rosseels Karen Tilmant Jean-Pierre Valentin | 2016 | Journal of Medicines Development Sciences2016，2，1： | 0 |
| 16 | ε/ζ systems: their role in resistance, virulence, and their potential for antibiotic development显示文摘Cell death in bacteria can be triggered by activation of self-inflicted molecular mechanisms. Pathogenic bacteria often make use of suicide mechanisms in which the death of individual cells benefits survival of the population. Important elements for programmed cell death in bacteria are proteinaceous toxin –antitoxin systems. While the toxin generally resides dormant in the bacterial cytosol in complex with its antitoxin, conditions such as impaired de novo synthesis of the antitoxin or nutritional stress lead to antitoxin degradation and toxin activation. A widespread toxin –antitoxin family consists of the ε/ζ systems, which are distributed over plasmids and chromosomes of various pathogenic bacteria. In its inactive state, the bacteriotoxic ζ toxin protein is inhibited by its cognate antitoxin ε. Upon degradation of ε, the ζ toxin is released allowing this enzyme to poison bacterial cell wall synthesis, which eventually triggers autolysis. ε/ζ systems ensure stable plasmid inheritance by inducing death in plasmiddeprived offspring cells. In contrast, chromosomally encoded ε/ζ systems were reported to contribute to virulence of pathogenic bacteria, possibly by inducing autolysis in individual cells under stressful conditions. The capability of toxin – antitoxin systems to kill bacteria has made them potential targets for new therapeutic compounds. Toxin activation could be hijacked to induce suicide of bacteria. Likewise, the unique mechanism of ζ toxins could serve as template for new drugs. Contrarily, inhibition of virulence-associated ζ toxins might attenuate infections. Here we provide an overview of ε/ζ toxin–antitoxin family and its potential role in the development of new therapeutic approaches in microbial defense. | Hannes Mutschler Anton Meinhart | 2015 | 世界最新医学信息文摘2015，15，5： | 0 |
| 17 | More than boric acid:Increasing relevance of boron in medicine显示文摘Although boron has been a chemical element of interest since the ancient times,only a few boron-containing compounds(BCCs)had been used for medicinal purposes before the 21^(st) century.Among these,only boric acid has been explored in multiple therapeutic applications.Hence,it is common to extrapolate from boric acid to all BCCs,supposing a similar biological effect.However,boric acid is just one of dozens of BCCs in nature and thousands available from chemical synthesis.Nowadays,there is a boom in research on new BCCs as potential tools in the prevention,diagnosis and therapy of human disease.We herein discuss the new role of BCCs in drug development,with emphasis on the compounds for which a mechanism of action has been proposed or demonstrated.Because of data gathered in recent years,BCCs have expanded beyond the well-known fields of antimicrobial and antineoplastic agents,now being explored for their possible use as enzyme inhibitors,regulators of protein expression and modulators of the immune response,as well as in biomaterials.We suggest that translational medicine can accelerate the medicinal applications of BCCs,which is especially important for the human diseases that are generating a high global burden. | Eunice D Farfán-García Emily L Castillo-García Marvin A Soriano-Ursúa | 2018 | World Journal of Translational Medicine2018，7，1： | 0 |
| 18 | 3-80 Heavy-ion Irradiation Drug Development in Retrospect and Prospect显示文摘The world is facing severe challenges of sustainable development, which requires the joint effort of the globalscience community to solve. As China continues to grow at a very impressive pace, the state appears acutely awareof the need to expand the Chinese science and technology portfolio to help fuel its growth and keep it sustainable.China also needs to continue on the path to innovations and modernization, focusing on endogenous growth torealize full, coordinated, and sustainable development. | Zhou Xiang Liang Jianping Lu Xihong Li Xuehu Xin Zhijun Wang Liang Du Wenyue Wu Zhengqian | 2014 | IMP & HIRFL Annual Report2014，，1： | 0 |
| 19 | Choroid plexus tumor necrosis factor receptor 1:a new neuroinflammatory piece of the complex Alzheimer's disease puzzle显示文摘Due to the aging of the population and despite the enormous scientific effort,Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine.Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer's disease.Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2,but that also regulates several brain functions in health and disease.However,clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer's disease led to inconclusive results,partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1,but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials.We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer's disease patients,signaling via tumor necrosis factor receptor 1.In agreement with this,choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer's disease mouse models.Interestingly,both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer's disease-associated inflammation,choroidal morphology and cognitive functioning.Here,we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in(early) Alzheimer's disease,and the consequences this might have on the disease progression.As the main hypothesis in Alzheimer's disease clinical trials is still based on the amyloid beta-cascade,the importance of Alzheimer's disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer's disease and prevent the irreversible neurodegeneration and resulting memory decline. | Sophie Steeland Roosmarijn E.Vandenbroucke | 2019 | Neural Regeneration Research2019，14，7： | 0 |
| 20 | Serendipity in anticancer drug discovery显示文摘It was found that the discovery of 5.8%(84/1437) of all drugs on the market involved serendipity. Of these drugs, 31(2.2%) were discovered following an incident in the laboratory and 53(3.7%) were discovered in a clinical setting. In addition, 263(18.3%) of the pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in total, 24.1%(347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this elusive phenomenon. In the case of anticancer drugs, 35.2%(31/88) can be attributed to a serendipitous event, which is somewhat larger than for all drugs. The therapeutic field that has benefited the most from serendipity are central nervous system active drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack of laboratory-based assays for many of the diseases of the mind. | Emily Hargrave-Thomas Bo Yu Jóhannes Reynisson | 2012 | World Journal of Clinical Oncology2012，3，1： | 0 |
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