In the Member States of the European Union (EU), a harmonized legislation on medicinal products has been enforced, which specifically defines herbal medicinal products and traditional herbal medicinal products. The scope was to create a regulatory environment that takes into account the particular characteristics of herbal medicinal products. The harmonization of standards is intended to harmonize assessment and facilitate access to the market in different Member States. The standards defined by the EU herbal monographs of the Committee on Herbal Medicinal Products (HMPC) and the quality requirements laid down in the European Pharmacopoeia represent an excellent model of multinational harmonization of the regulatory environment for herbal and traditional medicines. It has also been demonstrated that this framework is at least partially applicable for herbal and traditional medicines from traditional Chinese medicine (TCM) to gain access to the EU market. Moreover, the HMPC provides specific guidance documents and pilot projects on monographs on the safety and efficacy of Chinese herbal drugs. In the European Pharmacopoeia, the number of quality monographs of herbal drugs with an origin in TCM is continuously growing. These developments indicate that globalization of traditional medicines is an ongoing process. Communication and cooperation between regulators, the scientific community, and interested stakeholders will set the stage for the convergence of diverse regulatory environments. This will contribute to worldwide availability of traditional medicines based on appropriate standards.
Artemisinin and its derivatives represent the most important and influential class of drugs in the fight against malaria. Since the discovery of artemisinin in the early 1970s, the global community has made great strides in characterizing and understanding this remarkable phytochemical and its unique chemical and pharmacological properties. Today, even as artemisinin continues to serve as the foundation for antimalarial therapy, numerous challenges have surfaced in the continued application and development of this family of drugs. These challenges include the emergence of delayed treatment responses to artemisinins in malaria and efforts to apply artemisinins for non-malarial indications. Here, we provide an overview of the story of artemisinin in terms of its past, present, and future. In particular, we comment on the current understanding of the mechanism of action (MOA) of artemisinins, and emphasize the importance of relating mechanistic studies to therapeutic outcomes, both in malarial and non-malarial contexts.
Traditional Chinese medicines (TCMs) have a long history of playing a vital role in disease prevention, symptom alleviation, and health improvement. However, their complex ingredients and as-yet-unknown mechanisms restrict their application. With increasing evidence indicating that the gut microbiota is important in host health and may be associated with the therapeutic activity of TCM components, it may now be possible to assess the effects of TCMs from the perspective of the gut microbiota. The gut microbiota functions within four major physiological pathways as follows: It participates in host metabolism, forms global immunity, maintains homeostasis of the gastrointestinal tract, and affects brain function and host behavior. This article reviews the reported correlations between TCMs and certain diseases, such as chronic liver disease, ulcerative colitis, obesity, and type 2 diabetes, and elucidates the underlying mechanisms, with a focus on changes in the gut microbiota. In future, further studies are required with more advanced experimental design in order to reveal the interactions between TCMs and the gut microbiota, and provide new insight into and guidance for TCM-based drug discovery.
In ethnopharmacology, and especially in traditional Chinese medicine, medicinal plants have been used for thousands of years. Similarly, agricultural plants have been used throughout the history of mankind. The recent development of the genetic engineering of plants to produce plants with desirable features adds a new and growing dimension to humanity’s usage of plants. The biotechnology of plants has come of age and a plethora of bioengineering applications in this context have been delineated during the past few decades. Callus cultures and suspension cell cultures offer a wide range of usages in pharmacology and pharmacy (including Chinese medicine), as well as in agriculture and horticulture. This review provides a timely overview of the advancements that have been made with callus cultures in these scientific fields. Genetically modified callus cultures by gene technological techniques can be used for the synthesis of bioactive secondary metabolites and for the generation of plants with improved resistance against salt, draft, diseases, and pests. Although the full potential of callus plant culture technology has not yet been exploited, the time has come to develop and market more callus culture-based products.
Evaluation of the efficacy of traditional Chinese medicines (TCMs) is an important prerequisite for discovering effective substances, lead compounds, and quality markers (Q markers). At present, there is an urgent need to develop a biological language that can act as abridge for the scientific elaboration of the efficacy of TCMs, and to further highlight the significant value of TCM. Chinese medicinal syndromes and formulae are two essential parts of TCM that directly relate to its efficacy. Syndromes and formulae have been taken as the research objects. The serum pharmacochemistry of the TCM approach with metabolomics were integrated to establish an innovative chinmedomics strategy, which is able to explore syndrome biomarkers and evaluate TCM efficacy in order to discover effective substances from TCMs. A great deal of concrete work in chinmedomics has already performed to bridge the gap between Chinese and Western medicine, and to provide a powerful approach to enhance the scientific value of TCM theory and clinical practice. This article summarizes the application of chinmedomics in identifying the candidate biomarkers of a syndrome and revealing the efficacy of the related formula. We also highlight the discovery of lead compounds and Q markers from TCMs.
Andrographolide (AG) is the characteristic constituent of Andrographis paniculata, of the Acanthaceae family. This plant is a well-known Asian medicinal plant that is widely used in India, China, and Thailand. A monograph of Herba Andrographidis (Chuan Xin Lian) is included in the Pharmacopoeia of the People’s Republic of China, which reports that this decoction can “remove heat, counteract toxicity, and reduce swellings.” The numerous potential activities of AG range from anti-inflammatory to anti-diabetic action, from neuroprotection to antitumor activity, and from hepatoprotective to anti-obesity properties. However, AG has low bioavailability and poor water solubility, which can limit its distribution and accumulation in the body after administration. In addition, AG is not stable in gastrointestinal alkaline and acidic environments, and has been reported to have a very short half-life. Among the diverse strategies that have been adopted to increase AG water solubility and permeability, the technological approach is the most useful way to develop appropriate delivery systems. This review reports on published studies related to microparticles (MPs) and nanoparticles (NPs) loaded with AG. MPs based on polylactic-glycolic acid (PLGA), alginic acid, and glucan derivatives have been developed for parenteral oral and pulmonary administration, respectively. NPs include vesicles (both liposomes and niosomes); polymeric NPs (based on polyvinyl alcohol, polymerized phenylboronic acid, PLGA, human serum albumin, poly ethylcyanoacrylate, and polymeric micelles); solid lipid NPs; microemulsions and nanoemulsions; gold NPs; nanocrystals; and nanosuspensions. Improved bioavailability, target-tissue distribution, and efficacy of AG loaded in the described drug delivery systems has been reported.
Traditional Chinese medicine (TCM) is a medical system that has collected and summarized abundant clinical experience over its long history of more than 2000 years. However, the frequent occurrence of TCM-induced adverse reactions has hindered the modernization and internationalization of TCM, while attracting increasing attention from around the world. Unlike chemical drugs and biological agents, the difficulties involved in research on the toxicity and safety of TCM mainly include the complexity of its components and the unpredictability of drug–body interactions. Much of TCM, which has overall therapeutic effects, has the typical mechanisms of multiple components, multiple pathways, and multiple targets. While considering the gradualness and unpredictability of TCM toxicity, the ambiguity of toxicants and safe dosage, and individual differences during long-term TCM administration, we have systematically established key techniques for the toxicity assessment of TCM. These techniques mainly include TCM toxicity discovery in an early phase, based on a combination of drug toxicology genomics and metabolomics; methods to identify dose–toxicity relationships in TCM; and integrated techniques for the exploration of TCM interactions, such as fast-screening tests based on drug-metabolizing enzymes and receptor pathways. In particular, we have developed a new technical system for TCM safety evaluation using molecular toxicology, which has been validated well in research on TCM compatibility contraindication, quality control, and allergen discovery. The application of this key technical platform is introduced here in detail. This application includes model organisms, toxicant biomarkers, a magnetic suspension technique, and the application of network toxicology and computational toxicology in research on the toxicity of Fructus toosendan, Semen cassiae, Polygonum multiflorum, and Fructus psoraleae.
Traditional Chinese medicines (TCMs), a complex system of natural resources with many diverse components, are widely used as approved medicinal agents in China. Quality control of TCMs is a huge challenge for the government and for testing institutes and is associated with numerous scientific issues. Among these considerations include the following questions: How many components are in TCMs? How can the multiple components in TCMs be comprehensively delineated and subsequently characterized? What is the level and range of these (active) metabolites within these multiple-component TCMs, in order to recommend standards? and What are the qualities required for a marker constituent to be selected, and from a practical perspective, how can these components be assessed with low cost and in a short time? All of these factors require significant and deep thinking in order to understand the individualistic chemistry of TCM in order to develop enhanced TCM quality standards for improved and consistent patient care. In this review, the latest exploratory research in TCM chemistry analytical techniques and methods is summarized in order to begin to develop responses to these scientific issues. Advances in these methods have included multidimensional separation for liquid chromatography–high-resolution mass spectrometry (LC–HRMS), smart triggering data-dependent acquisition of LC–HRMS, target analysis with liquid chromatography–mass spectrometry (LC–MS), supercritical fluid chromatography, and data mining of large mass spectrometry (MS) datasets. In addition, two quality strategies have been introduced in order to save reference standards and the analysis time for a TCM quality standard, including the application of the single standard to determine multi-components (SSDMC) and monomethodheterotrait matrix methods. Finally, a series of future improvements for analytical methods for TCMs are proposed.
The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses; however, this renders the recipients functionally T cell deficient and hence highly susceptible to infections and tumor recurrence. Depletion is often accomplished through the use of broadly reactive antibodies, while functional impairment is typically achieved by pharmacological agents that require long-term administration (usually six months or more), have significant side effects, and may not result in tolerance (i.e., nonresponsiveness) of donor T cells to conditioning regimen-resistant host alloantigen-bearing cells. As our knowledge of immune system homeostasis has increased, cell populations with immune regulatory function have been identified and characterized. Although such cell populations are typically present in low frequencies, methods to isolate and expand these cells have permitted their supplementation to the donor graft or infusion late post-transplant in order to stifle GVHD. This review discusses the biology and preclinical proof of concept of GVHD models, along with GVHD outcomes that focus exclusively on immune regulatory cell therapies that have progressed to clinical testing.
Natural killer (NK) cells are key innate immune cells that provide the first line of defense against viral infection and cancer. Although NK cells can discriminate between "self" and "non-self," recognize abnormal cells, and eliminate transformed cells and malignancies in real time, tumors develop several strategies to escape from NK cell attack. These strategies include upregulating ligands for the inhibitory receptors of NK cells and producing soluble molecules or immunosuppressive factors. Various types of NK cells are currently being applied in clinical trials, including autologous or allogeneic NK cells, umbilical cord blood (UCB) or induced pluripotent stem cell (iPSC)-derived NK cells, memory-like NK cells, and NK cell line NK-92 cells, for the treatment of different types of tumors. Chimeric antigen receptors (CARs)-NK cells have recently shown great potential due to their redirect specificity and effective antitumor activity. In this review, we summarize the mechanisms of tumor escape from NK cell recognition, the current status and advanced progress of NK cell-based immunotherapy, ways of enhancing the antitumor capacity of NK cells in vivo, and major challenges for clinical practice in this field.
Forkhead box P3 (FOXP3) is a "master regulator" of regulatory T cells (Tregs), which are a subset of T cells that can suppress the antigen-specific immune reaction and that play important roles in host tolerance and immune homeostasis. It is well known that FOXP3 forms complexes with several proteins and can be regulated by various post-translational modifications (PTMs) such as acetylation, phosphorylation, ubiquitination, and methylation. As a consequence, the PTMs change the stability of FOXP3 and its capability to regulate gene expression, and eventually affect Treg activity. Although FOXP3 per se is not an ideal drug target, deacetylases, acetyltransferases, kinases, and other enzymes that regulate the PTMs of FOXP3 are potential targets to modulate FOXP3 and Treg activity. However, FOXP3 is not the only substrate for most of these enzymes; thus, unwanted "on target/off FOXP3" side effects must be considered when inhibitors to these enzymes are used. In this review, we summarize recent progress in the study of FOXP3 cofactors and PTM proteins, and potential clinical applications in autoimmunity and cancer immunity.
Adoptive cell therapy using chimeric antigen receptor T (CAR-T) cells, which is a promising cancer immunotherapy strategy, has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells that can specifically recognize tumor specific antigens on the surface of tumor cells, and then effectively kill tumor cells. At present, exciting results are being achieved in clinical applications of CAR-T cells for patients with hematological malignancies. The research and development of CAR-T cells for various targets and for the treatment of solid tumors have become a hot topic worldwide, so an increasing number of investigational new drug applications (INDAs) and new drug applications (NDAs) of CAR-T cell products are expected to be submitted in future. The quality control and nonclinical research of these products are of great significance in ensuring the safety and effectiveness of these products; however, they also present great challenges and difficulties. This article discusses the general principles of and key issues regarding the quality control and nonclinical research of CAR-T cell products based on their product characteristics and on relevant guidelines for gene and cell therapy products.
Cancer is a potentially life-threatening disease characterized by the immortalization of tumor cells in the host. Immunotherapy has recently gained increasing interest among researchers due to its tremendous potential for preventing tumor progression and metastasis. Regulatory T cells (Tregs) are a subgroup of suppressive CD4+ T cells that play a vital role in the maintenance of host immune homeostasis. Treg deficiency can induce severe autoimmune, hypersensitivity, and auto-inflammatory disorders, among other diseases. Tregs are commonly enriched in a tumor microenvironment, and a greater number of immune-suppressive Tregs often indicates a poorer prognosis; therefore, there is renewed interest in the function of Tregs and in their clinical application in antitumor immunotherapy. Accumulating strategies that focus on the depletion of Tregs have appeared to be effective in antitumor immunity. It is expected that Treg-targeting strategies will provide great opportunities for improving antitumor efficiency in combination with other therapeutics (e.g., Car-T-based cell therapy or immune checkpoint blockading.)
Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy; adverse effects (AEs); and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.
Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with BALL after allo-HSCT have a very short median survival. Minimal residual disease (MRD) is predictive of forthcoming hematological relapse after hematopoietic stem cell transplantation (HSCT); furthermore, eliminating MRD effectively prevents relapse. Donor lymphoblastic infusion (DLI) is the main established approach to treat B-ALL with MRD after allo-HSCT. However, about one-third of patients with MRD are non-responsive to DLI and their prognosis worsens. Although donor-derived cluster of differentiation (CD)19-directed chimeric antigen receptor-modified (CAR) T cells (CART19s) can potentially cure leukemia, the efficiency and safety of infusions with these cells have not yet been investigated in patients with MRD after HSCT. Between September 2014 and February 2018, six patients each received one or more infusions of CART19s from HSCT donors. Five (83.33%) achieved MRD-negative remission, and one case was not responsive to the administration of CAR T cells. Three of the six patients are currently alive without leukemia. No patient developed acute graft-versus-host disease (aGVHD), and no patient died of cytokine release syndrome. Donor-derived CAR T cell infusions seem to be an effective and safe intervention for patients with MRD in B-ALL after allo-HSCT and for those who were not responsive to DLI.
It is essential to utilize deep-learning algorithms based on big data for the implementation of the new generation of artificial intelligence. Effective utilization of deep learning relies considerably on the number of labeled samples, which restricts the application of deep learning in an environment with a small sample size. In this paper, we propose an approach based on a generative adversarial network (GAN) combined with a deep neural network (DNN). First, the original samples were divided into a training set and a test set. The GAN was trained with the training set to generate synthetic sample data, which enlarged the training set. Next, the DNN classifier was trained with the synthetic samples. Finally, the classifier was tested with the test set, and the effectiveness of the approach for multi-classification with a small sample size was validated by the indicators. As an empirical case, the approach was then applied to identify the stages of cancers with a small labeled sample size. The experimental results verified that the proposed approach achieved a greater accuracy than traditional methods. This research was an attempt to transform the classical statistical machine-learning classification method based on original samples into a deep-learning classification method based on data augmentation. The use of this approach will contribute to an expansion of application scenarios for the new generation of artificial intelligence based on deep learning, and to an increase in application effectiveness. This research is also expected to contribute to the comprehensive promotion of new-generation artificial intelligence.
The autonomous exploration and mapping of an unknown environment is useful in a wide range of applications and thus holds great significance. Existing methods mostly use range sensors to generate two-dimensional (2D) grid maps. Red/green/blue-depth (RGB-D) sensors provide both color and depth information on the environment, thereby enabling the generation of a three-dimensional (3D) point cloud map that is intuitive for human perception. In this paper, we present a systematic approach with dual RGB-D sensors to achieve the autonomous exploration and mapping of an unknown indoor environment. With the synchronized and processed RGB-D data, location points were generated and a 3D point cloud map and 2D grid map were incrementally built. Next, the exploration was modeled as a partially observable Markov decision process. Partial map simulation and global frontier search methods were combined for autonomous exploration, and dynamic action constraints were utilized in motion control. In this way, the local optimum can be avoided and the exploration efficacy can be ensured. Experiments with single connected and multi-branched regions demonstrated the high robustness, efficiency, and superiority of the developed system and methods.
The tools of synthetic biology can be used to engineer living biosensors that report the presence of analytes. Although these engineered cellular biosensors have many potential applications for deployment outside of the lab, they are genetically modified organisms (GMOs) and are often considered dangerous. Mitigating the risk of releasing GMOs into the environment while enabling their use outside a laboratory is critical. Here, we describe the development of a biosensing system consisting of a synthetic biological circuit, which is engineered in Escherichia coli that are contained within a unique 3D-printed device housing. These GMOs detect the chemical quorum signal of Pseudomonas aeruginosa, an opportunistic pathogen. Using this device, the living biosensor makes contact with a specimen of interest without ever being exposed to the environment. Cells can be visually analyzed in the field within culture tubes, or returned to the lab for further analysis. Many biosensors lack the versatility required for deployment in the field, where many diseases can go undiagnosed due to a lack of resources and equipment. Our bioassay device utilizes 3D printing to create a portable, modular, and inexpensive device for the field deployment of living biosensors.