Network pharmacology investigates the interaction between the drug and body by mapping drug-target (polypharmacology) networks onto biological networks. Network pharmacology challenges the traditional concept "one disease, one target, one drug", and represents the modern philosophy and pattern of biomedical research as a new branch of pharmacology. Based on systems biology and network biology, network pharmacology with holistic and systemic features is focused on network equilibrium (or robustness) and network disturbance. Understanding the status, fundamental dynamics and kinetics of individual biological molecules in the biological network is more important than the specific biological function. Understanding the biological and kinetic profile of the drug is more important than individual validation of targets or combinations of targets. Network-based drug discovery is to create new drugs-regulating networks. Network pharmacology has profound influence on the philosophy of clinical drug therapeutics and drug discovery.

The anti-tumor effect of Ganoderma(Lingzhi)is closely related to immunoregulation. Based on our research and other references,this article discussed the antitumor effect of Ganoderma mediated by immunological mechanism,including promoting the function of mononuclear-macro-phages,and natural killers,promoting maturation and differentiation of dendritic cells,increasing its antigen presentation,activating lymphocytes and increasing cytotoxicity of cytotoxin T lymphocyte, promoting production of cytokines,inhibiting tumor escape from immune surveillance. Also, clinical studies with immunological indexes were reviewed.

Traditional Chinese medicine(TCM),a comprehensive medicinal system,is characterized by holistic theory that emphasizes the regulation of the integrity of the human body and the interactions between human individuals and their environments. The diagnostic and therapeutic methods of TCM are based on the differentiation of syndrome(Zheng in Chinese)and the use of herbal formula(Fang-Ji in Chinese). There is an urgent need to develop scientific research methods in accordance with the above characteristics for TCM modernization. In the era of big data and with the rapid progress in systems biology,polypharmacology and bioinformatics,network pharmacology has emerged as a promising drug discovery approach that takes the same view as the theory of TCM. This methodology has explored correlations between drugs and complex diseases from the perspective of the holistic theory and has highlighted the paradigm shift from "one drug,one target" to "network target". Thus,it is an original idea to combine network pharmacology with the modern research of TCM. This paper briefly analyzed and discussed the progress and major scientific challenges in network pharmacology applied to TCM diagnosis and treatment. To promote the development of TCM network pharmacology, several suggestions were also raised.

One of the most promising antimalarial drugs which are widely used throughout the world is the artemisinin (ARS) and its derivatives, e.g., artemether, arteether, and artesunate. Their true potential lies in broader anti-disease applications. The mechanism of action of these compounds appears to involve the endoperoxide bridge to produce carbon-centred free radicals. Large clinical studies did not show serious side effects, however, there is a paucity of large-scale clinical trials suitable to detect rare but significant toxicity. Therefore, a final and definitive statement on the safety of artemisinins still cannot be made. In contrast, animal experiments at high doses shown considerable toxicity upon application of artemisinins. In the present review, the authors give a comprehensive overview on toxicity studies in cell culture and in animals (mice, rats, rabbits, dogs, and monkeys) as well as on toxicity reported in human clinical trials. The authors emphasize the current knowledge on neurotoxicity, embryotoxicity, genotoxicity, hemato-and immunotoxicity and cardiotoxicity. Rapid elimination of artemisinins after oral intake represents a relatively safe route of administration compared to delayed drug release after intramuscular (im) injection. There are drug-related differences, i.e., intramuscular application of artemether or arteether, but not to artesunate, which is safe and gives good profiles after im administration in severe malaria. It might also be important in determining dose limitations for treatment of other diseases such as cancer. Questions about dosing regimens, safety of long-term use and possible interactions with existing therapies and toxicities that might be related to the treatment of tumors should be answered by appropriate clinical and preclinical studies.

Ferroptosis is a novel form of cell death in an iron-dependent manner, which is characterized by iron overload, lipid peroxides accumulation and condensed mitochondrial membrane densities. Ferroptosis is closely related to the physiological and pathological processes such as cancer, myocardial infarction, ischemic stroke and neurodegenerative diseases. A variety of ferroptosis inducers or inhibitors have been identified so far, which can induce or inhibit ferroptosis through different targets and mechanisms, and are of potential clinical value in treating above-mentioned various diseases. This review summarizes the existing ferroptosis inducers and inhibitors in terms of structures, targets, features and application models in order to provide data for subsequent research and clinical application.

Polypeptide drugs have a short half- life, small volume of distribution, low toxicity, and have been widely used for the prevention and treatment of cancer and metabolic diseases. A good knowledge of the pharmacokinetic characteristics and metabolic mechanisms of polypeptide drugs can facilitate the synthesis and structural optimization. Polypeptide drugs are often delivered intravenously, intraperitoneally, or subcutaneously. The drugs can be directly injected into the circulatory system through intravenous injection, and the bioavailability is close to 100%, which is an ideal mode of administration. In general, polypeptides have low membrane permeability, and their transmembrane transport is limited by such factors as size, polarity, and conformation. Both the plasma protein binding and the potential immunogenicity of such drugs can affect their pharmacokinetic characteristics and interfere with the quantitative analysis of drugs. The main elimination mechanism of polypeptide drugs is metabolic enzyme degradation and glomerular filtration elimination, and there are also endosomal-lysosomal based endocytosis elimination mechanisms. In this review, we discussed the research progress and current difficulties with peptide pharmacokinetics.

Folium Perillae (FP) is a traditional Chinese materia medica, which has been used for treating inflammatory diseases. In order to clarify the material basis of FP′s pharmacological activity and anti-inflammatory mechanism, we presented a review about some of the primary chemical components in FP, such as volatile oils, flavonoids, anthocyanins, phenolic acids, glycosides, triterpenes and steroids, and about the anti-inflammatory activity of FP extract and its major mechanism, such as regulating the viability and function of innate immune cells, controlling the balance of helper T cells, based on related research in recent years. This study aims to provide reference for further research and development of new drugs based on FP.

It is generally known that P. lactiflora is a traditional Chinese materia medica(TCMM), which has been used in the treatment of an array of diseases. In recent years, many papers have been published describing the new chemical constituents and pharmacological effects of P. lactiflora. Besides many proverbial chemical constituents, such as paeonifiorin and benzoylpaeoniflorin, there are many new chemical constituents found from the root, flower, leaf and fruit of P. lactiflora, such as isopaeoniflorin and 4-O-methyl-paeoniflorin. Meanwhile, P. lactiflora has a number of pharmacological activities, including anti-inflammatory, analgesic, antibacterial, antioxidant, anticancer, antidepressant and anti-liver fibrosis effects. P. lactiflora can also treat autoimmune diseases, cardiovascular and cerebrovascular diseases as well as neurodegenerative diseases. All these findings related to pharmacological effects and mechanisms of P. lactiflora not only provide an experimental support and theoretical basis for clinical application, but also help make TCMM better-known to the world.

The seminar on novel ideas and methods in pharmacological researches，and new drug research and development of traditional Chinese medicine（TCM），organized by the Professional Committee of Pharmacology on Traditional Chinese Medicine and Natural Medicine， Chinese Pharmacology Society，was held in Tengzhou，Shandong Province，on August 5，2016. Professor ZHANG Yong-xiang，chair of the committee，presided over the seminar. Professor LIU Jian-xun and LI Lin delivered keynote speeches. More than 30 members of the committee from all over the country attended the seminar. The participants had a broad and in-depth discussion on issues concerning phar⁃ macological researches and new drug research and development of TCM. The ideas and proposals by some committee members were summarized，hoping to provide reference in the pharmacological researches and new drug research and development of TCM.

Currently,a physiologically based pharmacokinetic(PBPK)model plays a key role in pharmaceutical research,which has been widely used at each stage of drug discovery and develop-ment. In the process of drug discovery, the selection of drug candidates is finished using the PBPK model to predict the pharmacokinetic properties of the drugs. In the process of preclinical development, through a combination of in vitro and physiological data amplification coefficient,the PBPK model can be used to predict not only the overall pharmacokinetic behavior of drug candidates in humans and animals and in vitro metabolism experiments,but also drug-drug interactions(DDI). In the course of clinical development,the PBPK model can help predict the difference between reference populations (age,different disease state,and polymorphism),especially the dosage and sampling time of the children. At present,the input parameters of PBPK model are mostly the mean values of the population,making it difficult to serve individuals. It is hoped that the input parameters of the model can reflect more of the individual characters according to the individual requirement,and that the time parameters of the input accord more with the actual physiological condition. In this article,we briefly introduced the characteristics of common PBPK software,and reviewd the principle and feature of the PBPK model,as well as its application to drug discovery,preclinical development and clinical development,DDI,and individualized medication.

Ricin is a plant toxin isolated from the seed of the castor plant（Ricinus communis）. As a typical II ribosome inactivating protein，ricin consists of two polypeptide chains named ricin toxin A chain（RTA）and ricin toxin B chain（RTB），linked via a disulfide bridge. RTB binds to both glycoprotein and glycolipid at the surface of the target cell and mediates ricin to be endocytosed and transported retrogradely to the endoplasmic reticulum. After being reduced and retrotranslocated to the cytosol，RTA mediates its toxicity due to its activity of a RNA N- glycosidases. Aside from its main toxic effect of protein synthesis inhibition，ricin also displays other properties that contribute to its toxicity such as inducing apoptosis，cytokine secreting and peroxidation. Ricin is stable and can be easily isolated. It has many routes of intoxication with no specific antidotes. Due to its natural abundance，remarkable toxicity，and the potential to be used in biological warfare as well as terrorist attacks，ricin has been classified as a Category B biothreat agent. Here we reviewed its history as a biothreat agent，constitution，intoxication mechanism，detection methods and the development of specific antitodes.

An organoid is a novel in vitro model, formed by self-organization of stem cells or tumor cells under three-dimension culture. It recapitulates many aspects of structural organization and functionality of its in vivo organ counterparts and maintains the stability of genetic materials under long-term culture, thus holding great promise for modeling disease, drug screening and personalized medicine. So far, normal and tumor organoids from structures such as esophagus, stomach, intestine, liver, pancreas and prostate and mammary gland have been established, providing a new culture platform in vitro. This article reviews the classification and biomedical applications of organoids.

The identification of drug-target interactions (DTIs) is a critical step in drug discovery, which can effectively narrow down the candidate drug compounds to be searched for. Meanwhile, DTI prediction also underlies polypharmacology and drug repurposing. However, the study of DTIs through biological experiments is time-consuming, costly and not clearly-targeted. With the rapid development of information science, artificial intelligence (AI) has become a widely-used and effective strategy to study DTIs. Depending on the design principles of algorithms, AI methods for DTI prediction can be classified into four categories: similarity-based, feature-based, network-based and deep-learning methods. This paper introduces the construction of these methods and discusses the problems with model evaluation and negative samples. Overall, AI has a great potential in DTI prediction, which can bring new opportunities for drug research and development.

Berberine is an isoquinoline alkaloid isolated from Rhizoma Coptidis and Cortex Phellodendri, which has a long medical history in China. Recent studies have indicated that berberine has multiple pharmacological activities including anti-inflammatory, anti-microorganisms, anti-cancer, cardiac protection, glucose lowering, regulating lipid metabolism and immune suppression. Berberine has been used for the treatment of intestinal infectious diseases for many years. With the continuous progress of the research, it is reported that berberine has many new clinical applications, including treatment of the cardiovascular disease, metabolic syndrome and its complications, cancers, abdominal adhesions and chlamydia trachomatis infection. This review is intended to introduce the role of berberine in various aspects of pharmacological effects, molecular mechanisms and clinical applications.

Titanium dioxide (TiO2) and its nanoparticles (TiO2 nanoparticles, TiO2 NP) have excellent properties and are widely used in foods, pharmaceuticals, cosmetics and other industries. Since the European Union classified TiO2 as "Carcinogen Category 2 (inhalation)" and gradually prohibited its use as a food additive, its safety has attracted much attention in this industry. TiO2 and TiO2 NP can pose risks to human safety through four exposure pathways (oral, percutaneous/inhalation and injection). Oral administration of TiO2 has potential genotoxicity, and its nanoparticles may affect intestinal function and flora. Inhalation of TiO2 NP is likely to lead to pulmonary inflammation, and whether it has skin permeability is controversial. This article introduces the progress in safety assessment and management at home and abroad, and recommends new areas of research and regulatory suggestions for the supervision of foods, drugs and cosmetics in China.

With the increasing trade of traditional Chinese medicine（TCM），the issue of excessive levels of toxic heavy metals metals in TCM has raised worldwide concerns. Some countries and regions have set strict limits on the heavy in TCM. There are currently no uniform limits on heavy metals，partly for lack of a good understanding of heavy metals in TCM. The toxicity of heavy metals varies with their chemical forms so that it is not rational to evaluate safety in terms of total contents. Cinnabar and realgar are widely used TCM containing heavy metals in clinical practice. Because of the potential toxicity of heavy metals such as mercury or arsenic，and the related adverse reactions reported occasionally，the safety of cinnabar，realgar and their preparations has also attracted public attention. In the present paper，the progress in toxicological studies on cinnabar，realgar as well as commonly used preparations was reviewed while priorities of future research were proposed.

Spermidine，presented widely in animal and plant cells，plays a variety of biological roles.  Autophagy is a pivotal intracellular degradative pathway. Autophagy-lysosome pathway contributes to maintenance of intracellular homeostasis via clearance of long-lived proteins and damaged cellular organelles. There is much evidence that spermidine-modulated autophagy is involved in the regulation of several pathophysiological processes. However，the abnormal level of spermidine may accelerate aging and lead to the development of neurodegenerative diseases. Here，we reviewed the pathophysiological significance of spermidine in mediating autophagy induction. In addition， the association between spermidine-induced autophagy and pathophysiological processes（e.g. aging and neurodegenerative diseases）was discussed.

Cell senescence is a state of irreversible growth arrest, which can be triggered by a variety of different cellular stress. Currently, the detection indexes involved in the study of cell senescence include senescence-associated β-galactosidase, telomeres and telomerase, senescence-associated heterochromatin foci, senescence-associated secretory phenotype, reactive oxygen species, and tumor suppressor genes p53 and p16. These indexes are widely used in the study of cell senescence, each with its own characteristics or advantages. This review summarizes several common cell senescence indexes and compares their accuracy, credibility, specificity, and potential applications.

Inflammatory dermatoses are a group of diseases in which dysregulation of the immune system leads to disruption of the skin barrier, including psoriasis, atopic dermatitis, and Netherton syndrome. In patients with inflammatory dermatoses, the level of lipids is closely related to the level of inflammatory factors, both of which are jointly involved in the development of the disease. Abnormal skin lipid secretion leads to impaired skin barrier function, while high levels of inflammatory factors lead to abnormal blood lipid levels and affect the expression of enzymes related to lipid metabolism and further aggravate skin inflammation. Peroxisome proliferators-activated receptors and liver X receptors improve skin barrier function by regulating lipid metabolism and inflammatory signaling pathways. In this paper, the role of lipid metabolism disorders in inflammatory dermatoses was analyzed, and the current therapeutic agents for inflammatory dermatoses were summarized.

Unlike apoptosis, ferroptosis is a mode of iron-dependent cell death. The ferroptosis-inducing drugs discovered so far can induce ferroptosis in cancer cells through various pathways or targets and have a great potential to inhibit the malignant multidrug-resistant tumors. These ferroptosis-inducing drugs are of three categories: cystine/glutamate antiporter inhibitors, glutathione peroxidase 4 (GPX4) inhibitors, and Fenton reaction-like inducers. For example, ferroptosis is induced by directly or indirectly affecting GPX4, inhibiting GPX4 protein levels and activities, inducing Fenton reaction to oxidize Fe2+ and promoting lipid peroxide accumulation. This article reviews the ferroptosis-inducing drugs and their anticancer mechanisms in hopes of providing helpful information about ferroptosis-based cancer therapy and drug development.

A drug target refers to specific molecules that exist within tissue cells and interact with a drug to produce the drug effect. More than 98% of drug targets belong to protein. The interactions between a drug and the target in cells play a key role in the drug effect. How to use various methods to find and confirm the new target of a drug is one of the important challenges facing researchers. Drug affinity responsive target stability （DARTS）is a new technique based on the principle that when a small molecule compound binds to a protein，the interaction stabilizes the target protein′s structure so that it becomes protease resistant. This technique is universally applicable to drug screening and target identification because it requires no modification of the drug and is independent of the mechanism of drug action. This paper reviews the discovery of DARTS method，technical principles，methodology and its applications in researches.

Influenza is a contagious respiratory illness caused by influenza viruses. Although vaccination is the most powerful means of mitigating the impacts of influenza epidemics, anti-influenza drugs play an important role in containing the spread of new pandemic viruses and treating hospitalized patients with complicated influenza. Current anti-influenza drugs in non-clinical and clinical phases include hemagglutinin inhibitors, matrix 2 ion channel protein inhibitors, RNA-dependent RNA polymerase (RdRp) inhibitors and neuraminidase inhibitors. Based on the activity and mechanism against influenza viruses, RdRp inhibitors may rapidly reduce viral load, have a broad spectrum of antiviral effects and rarely develop drug resistance compared with the other three inhibitors. For prevention and treatment of influenza, neuraminidase inhibitors are commonly used clinical drugs, whereas the clinical efficacy of RdRp inhibitors needs to be further evaluated. This review focuses on the mechanism of action, antiviral activity, and clinical applications of anti-influenza drugs in order to provide reference for the development of novel anti-influenza drugs with broad-spectrum activities.

With the development of life sciences, biomarkers are used more widely in medicine. Biomarkers generally refer to a measurable indicator of disease occurrence, development and prognosis. According to their characteristics, biomarkers can be classified into small molecules, macromolecules, complexes and microbes. Biomarkers can be used for disease diagnosis and classification, monitoring development and severity of disease, and for indicating the clinical therapeutic effect. Biomarkers also can be used to predict the risk of a disease for individuals and to screen high-risk populations. The development of biomarkers requires appropriate and rigorous clinical validation studies, and feasibility and accessibility in particular clinical situations. In recent years, biomarkers have already been used from single application to combined one. Combined with other detection means, biomarkers will be of great benefit to earlier, quick and accurate diagnosis of disease and facilitate clinical treatment.

Given the complexity of diseases and etiology of multiple targets and links，therapies with multi- drug combination towards multiple targets are better options for treating serious diseases，such as cancer，than a single- target medicine. Multi- drug combination may cause interactions at different levels，but the efficacy of these drugs manifests itself as synergism，addition or antagonism. Because there is no reliable quantitative method for synergism，addition and antagonism that can simultaneously withstand double test of mathematics and pharmacology，the development of novel drug combinations has come to a standstill. By exchanging the equivalent doses and introducing two basic principles that have been long neglected in the pharmacological field（the sequential principle for multi- drug use and the collective property of efficacy）into the geometrical analysis of the dose- effect relationships，the author has found the mathematical laws for the expected additive effect in multi-target drug combination，and worked out a universal formula. The dose- effect relationship of the expected addition is a number set function of multi-drug combination doses with a closed interval，which performs as a belt in a two- dimensional coordinate，while the actual observed one presents as a curve. The number of curves that constitute the belt increases exponentially whith the incnease of combined drugs. By solving the equation groups composed of the belt and the curve，related parameters in multi-drug combination can be precisely calculated，such as dose ranges of synergism，addition and antagonism，as well as combination indexes based on dose and one based on efficacy，which will also provide a quantitative analysis method for interactions between various factors in biological systems.

Metals，due to their unique and excellent antibacterial properties，have been widely used in biomedical fields. However，their antibacterial mechanisms are not yet completely clear，so that studies on metal toxicity to bacteria have been a frontier in recent years. There are two main antibacterial mechanisms that have been reported so far. One is based on oxidative damage to bacteria induced by the reactive oxygen species，and the other is based on structural changes induced by
the Coulomb attraction. The results of bacterial damage could be due to the combination of the two mechanisms. In this paper，current research progress in antibacterial mechanisms of metal has been discussed，which will technically facilitate further development and applications of antimicrobial metallic materials.

New drug development is a hot point in life sciences. For a developing country like China, it is always economically and socially important to deliver a series of new drugs or repurposed drugs in order to provide people with safe, effective and affordable therapies. Because of low throughput pharmacology/toxicology assays and clinical trials, traditional drug development pipelines are subject to long cycles, high cost and failure risk. As an interdisciplinary subject, bioinformatics shows specific advantage in management and processing of large-scale biological and medical data, at relatively low cost and high throughput. In drug development, bioinformatics is more often used to discover drug efficacy, mechanisms of action and side effects and to guide research and development. Based on the experience of drug development and drug repositioning in international pharmaceutical enterprises, the authors proposed the application of bioinformatics to new drug development and illustrated the importance and necessity of bioinformatics platforms in China.

AIM To investigate if cactus polysaccharides（CP）protect rat cerebral cortical and hippocampal slices against oxidative stress injuries induced by H₂O₂. METHODS Rat cerebral cortex and hippocampus slices were prepared and incubated in artificial cerebrospinal fluid (ACSF)， then the slices were co-incubated with 2 mmol·L^-1 H₂O₂ for 30 min to cause oxidative stress injury. These slices were incubated with CP 0.333 and 1.67 mg·L^-1 during different duration, pre-incubated with H₂O₂ for 30 min, co-incubated with H₂O₂ for 30 min and postincubated with H₂O₂ for 2 h, respectively. Injury of brain slices was determined by TTC method. Lactate dehydrogenase (LDH), superoxide dismutase (SOD) activities, glutathion (GSH) content and total antioxidation capability (T-AOC) in incubation medium were detected. RESULTS Incubated with H₂O₂ 2 mmol·L^-1 for 30 min, rat cerebral cortical and hippocampal slices were significantly damaged, indicated by decreased A_{490 nm} value of TTC staining. Meanwhile, the release of LDH in supernatant increased, but GSH and T-AOC decreased. CP 0.333 and 1.67 mg·L^-1 pre-incubation for 30 min significantly inhibited the decrease in TTC value and the elevation of LDH release, and increased the contents of GSH, SOD and T-AOC in supernatant. CONCLUSION CP can protect rat cerebral cortical and hippocampal slices against injury induced by H₂O₂, which may relate to strengthening the ability of anti-oxidative stress.

About 30% of human cancers can be associated with RAS gene mutations. The three RAS genes—KRAS, HRAS and NRAS—are the most common oncogenes in human cancers. KRAS is one of the most commonly mutated genes in human cancers, including pancreatic, lung, and colon cancers. The clinical activity of drugs targeting KRAS-mutated cancers has not been promising over the years. Amgen has successfully developed the covalent inhibitor AMG510 using the cysteine residues generated by KRAS mutation. Based on the mechanism of action, this paper classified KRAS inhibitors into two categories: inhibitors that directly target KRAS and inhibitors that indirectly act on KRAS. In order to contribute to the development of new anti-tumor drugs of KRAS small molecule inhibitors, this paper reviews the research progress in the representative structure, mechanism of action, and biological activity in small molecule inhibitors of KRAS.

Peptide and protein drugs (PPD) play an important role in clinical applications because of specific targets, limited adverse reactions and strong biological activity. Some barrier systems including acids, enzymes and biomembranes prevent PPD from absorption by oral administration. Oral delivery of peptides and proteins is desirable to patients and will improve their compliance. PPD has been one of the most intensively studied research subjects in the field of biological pharmacy over the past twenty years. This paper reviewed mechanisms of oral absorption of peptides and proteins, factors that hamper absorption of PPD and strategies to improve absorption of PPD in the gastrointestinal tract.

Disfunction of ATP-binding cassette (ABC) transporters will result in multidrug resistance (MDR). P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP) play an important role in MDR. This review focused on signal pathways associated with P-gp, BCRP and MRP in recent years, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signal transduction pathway, mitogen-activated protein kinase (MAPK) transduction pathway, phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) signal transduction pathway, and sonic hedgehog (Shh) signal transduction pathway. Important regulatory nodes NF-κB, activator protein 1 (AP-1), c-Jun and Gli were analyzed, which have the potential to become a target for multidrug resistance reversal agents. This paper is intended to provide a systematic and forward-looking overview for study of multidrug resistance mechanisms and development of reversal agents.

Poisoning caused by different types of heavy metals can cause serious harm to the human body despite the varied poisoning mechanisms. Therefore, rational use of high-efficiency antidotes has become critical to the treatment of heavy metal poisoning. Mercaptopropanol, dimercaptosuccinic acid, sodium dimercaptopropanesulfonate, penicillamine and lipoic acid are the most widely used therapeutic drugs for heavy metal poisoning and detoxification. Different sulfhydryl chelating agents have different chemical characteristics, and their complex mechanisms with heavy metal ions are also significantly different. Different forms heavy metal poisoning require different clinical drugs. Combined medications can improve the detoxification effect in case of heavy metal poisoning.

Proteolysis-targeting chimeras (PROTACs) recruit the target protein to E3 ubiquitin ligase for ubiquitination labeling to degrade it through the ubiquitin-proteasome pathway so as to eliminate the overexpressed or mutated pathogenic protein. A brief overview of research and development of PROTAC pharmaceuticals was given in this paper. Strategies were recommended to address the larger molecular mass, poor stability, low bioavailability and poor penetration of PROTACs. Problems related to non-clinical evaluation that need to be considered in terms of pharmacodynamics, metabolism and safety evaluation were also analyzed in this paper in order to provide reference for the non-clinical evaluation of PROTAC drugs.

Microglia are a type of immune cells and widely distributed in the central nervous system (CNS), accounting for about 5% to 20% of the total number of glial cells. Microglia were first identified by Hortega using the silver carbonate method. It is believed that microglia originate from the mesoderm and invade the brain during the formation of blood vessels in the late embryonic development. Recent research shows that microglia are derived from yolk sac-derived macrophages. As a resident immune cell of the CNS, microglia belong to the monocyte-macrophage cell line and are an important immunological defense against the invasion of pathogens. The resting microglia play a role in monitoring the nervous system to maintain the homeostasis. The activated microglia play a role in phagocytosis of cell debris and have neuroprotective and neurotoxic dual roles under different pathological conditions by secreting different cytokines.

Alzheimer disease (AD) is a neurodegenerative disease mainly seen in elder populations aged 65 or above. The pathological hallmarks in the AD brain include senile plaques due to amyloid-β (Aβ) deposition, neurofibrils composed of hyperphosphorylated tau within neurons, chronic inflammation and neuron death, which, besides aging, are regarded as the main pathogenesis of AD. Here we review the current development of therapeutic approaches to AD. All the five AD therapeutics approved so far are designed to improve AD patient cognition by decreasing the effects of excitatory neurotransmitters, the efficiency of which, however, is quite limited. Moreover, the targets of most potential drugs acting on the nervous system are the excitatory system, but there is little progress. As for drug development based on the tau hypothesis, the main strategies are to inhibit tau phosphorylation, fibrillization and transmission. However, due to the difficulties in specifically inhibiting tau phosphorylation, two of the four tau drugs in clinical trials are tau active vaccines, which show no promise. In the Aβ hypothesis, the main strategies are to inhibit Aβ production/aggregation and promote Aβ clearance. Due to the severe adverse effects of γ-secretase inhibitors, the main approaches are to develop β-secretase (BACE1) inhibitors and Aβ vaccines. In addition, another potential therapeutic approach is to inhibit chronic inflammation in the AD brain. None of the nonsteroidal antiinflammatory drugs (NSAIDs) have succeeded. Potential antiinflammatory drugs acting on other inflammation factors, such as TNF and TGF, are still in clinical trials and making good progress.Generally speaking, the major obstacle to AD drug development is that the potential molecules lack druggability, and that most of the clinical trials have failed due to adverse effects and insufficiency. However, there are 82 potential drugs in clinical trails including 18 currently in phase Ⅲ/Ⅳ. Meanwhile, application of new techniques, such as computer designed precise-targeting, and CRISPR/caspase9, is expected to significantly accelerate AD drug discovery.

Drug repositioning, as an important application of network pharmacology, is concerned with identification of new indications for existing drugs. Drug repositioning can offer a better risk vs reward trade-off than other drug development strategies. There are more than 100 successfully repositioned drugs. Beyond serendipitous observations, there are several in silico methods that have been established to address the issues of drug-target interaction prediction and drug repositioning. These methods base on the feature of ligand (including quantitative structure-activity relationships and similarity search) or receptor (including reverse docking) or phenotype-based (including drug-based similarity inference, target-based similarity inference and network-based inference). Drug repositioning is playing a vital role in drug research and development with the increasing demand on market and rapid advanvement in systems biology, computational biology and network pharmacology.

Exosomes, the vesicle-like nanostructures with a diameter between 40-100 nm,  are derived from the cell inner membrane system and can be secreted and released by various types of cells. The molecules in exosomes, such as proteins, mRNA, miRNA and lipids, derive from parent cells and participate in the body′s physiological and pathological processes. Given the low toxicity, non-immunogenicity and good permeability, exosomes are considered to be an ideal carrier for the drug delivery system. Based on the unique nanostructures and physiological functions of exosomes, this article summarizes the current research on exosomes as a drug carrier, advantages of exosomes and possible problems with engineering preparation.