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Based on the strategy of metabolomics combined with bioinformatics, this study analyzed the potential allergens and mechanism of pseudo-allergic reactions (PARs) induced by the combined use of Reduning injection and penicillin G injection. All animal experiments and welfare are in accordance with the requirements of the First Affiliated Experimental Animal Ethics and Animal Welfare Committee of Henan University of Chinese Medicine (approval number: YFYDW2020002). Based on UPLC-Q-TOF/MS technology combined with UNIFI software, a total of 21 compounds were identified in Reduning and penicillin G mixed injection. Based on molecular docking technology, 10 potential allergens with strong binding activity to MrgprX2 agonist sites were further screened. Metabolomics analysis using UPLC-Q-TOF/MS technology revealed that 34 differential metabolites such as arachidonic acid, phosphatidylcholine, phosphatidylserine, prostaglandins, and leukotrienes were endogenous differential metabolites of PARs caused by combined use of Reduning injection and penicillin G injection. Through the analysis of the "potential allergen-target-endogenous differential metabolite" interaction network, the chlorogenic acids (such as chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, and isochlorogenic acid A) and β-lactam allergens in the combination of the two may be mainly regulated by PLD1, PLA2G12A and CYP1A1. The three upstream signal target proteins mainly activate the arachidonic acid metabolic pathway, promote the degranulation of mast cells, release downstream endogenous inflammatory mediators, and induce PARs.
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Although small molecule drugs (SMD) are still mainstream for the treatment of diseases, large molecule biologicss of many advantages, pose a challenge to the further discovery and use of SMD. The advantages of SMD are the convenience of oral administration and good patient compliance. However, the challenge with SMD is to integrate the PD, PK, selectivity and safety into a chemical structure. Because of their small size and surface area they often bind to various proteins, and off-target actions can cause adverse reactions. In this sense, selectivity is critical. Based upon target as the core to construct a chemical structure, it is necessary to consider the requirements of all the attributes, but achievement of the full-dimensional optimization is difficult. Modern drug discovery has been greatly enhanced by molecular biology and structural biology, and new strategies and technologies have emerged, which have created many successful medicines. For example, under the guidance of structural biology, covalent binding drugs connect moderate "electrophilic warheads" to the appropriate positions of molecules, and upon binding to their targets the electrophiles are irreversibly linked to the target by covalent bonds. Molecular biology can be directly applied to the development of antibody-coupled drugs (ADC). The antibody (A) acts as a carrier and a guide (for PK), and carries toxic molecules (D) into cancer cells, thus playing a killing role (for PD). The separate pharmacodynamic and pharmacokinetic entities are coupled (C) by linkers. PROTACs are also bifunctional molecules, which recruit a target protein and ubiquitin ligase E3 to form a ternary complex, which then acts as a catalyst to ubiquitinate the target protein and lead to degradation by the proteasome. In addition, in recent years, the combination of two fixed-dose drugs has improved selectivity, safety, and long-term benefit with many severe diseases, and can be regarded as an innovative strategy of physical combination. This review discusses some successful examples to briefly present the principles from the perspective of medicinal chemistry and therapeutic application.
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Due to the complexity of tumor pathology, the demand for the combined use of multiple drugs in clinical treatment has become increasingly clear-cut. Multi-drug combination can act on multiple pathways and multiple targets simultaneously to exert synergistic effects. However, the current delivery strategy for multi-drug combination still needs to be optimized. Nano-drug delivery systems can carry drugs to overcome physiological and pathological barrier to target tumor tissues and cells, achieve the goal of continuous, controllable, and targeted delivery, and enhance the efficacy of anti-tumor synergism and detoxification. To meet the new requirements for smarter and more accurate antitumor multi-drug combinational therapy, the nano-drug delivery system has been well-designed to realize more functions. For instance, delivery of multiple drugs in accurate proportions and doses can make the multi-drug synergistic effect more precise; stimulus-responsive drug release can improve selectivity and reduce side effects; controlling the time-course relationship of multiple drugs can realize sequential drug combination effect. It has shown broad prospects in the field of tumor multidrug therapy and has become one of the new directions of research and development. This article reviews the recent developments in the application of tumor drug combination therapy strategies and their delivery systems, and analyzes the new requirements and challenges of multidrug combination for the development of nano-drug delivery systems.
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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, which is characterized by complex pathogenesis, inconspicuous early symptoms, rapid progress and poor prognosis. Immunotherapy and targeted therapy are important methods to treat advanced and metastatic liver cancer in recent years. With the FDA's approval of sorafenib and other tyrosine kinase inhibitors and programmed cell death protein 1 and cytotoxic T lymphocyte-associated antigen-4 immune checkpoint inhibitors for the treatment of liver cancer, great progress has been made in single-agent therapy and combination therapy, bringing a new turning point for the improvement of survival rate of patients with advanced liver cancer. However, the mechanism of immunotherapy and drug resistance is still unclear, and its clinical application combined with targeted and other therapies is still under research, which needs to be further explored by researchers. In this paper, the clinical research progress of immunotherapy combined with other therapies in advanced hepatocellular carcinoma was reviewed, in order to grasp the current development trend of the treatment of hepatocellular carcinoma and provide reference for the further development direction of immunotherapy.
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This study aimed to explore the anti-tumor activity and mechanisms of action of isorhamnetin, a compound isolated from Astragalus membranaceus, in combination with sorafenib for treatment of renal cell carcinoma (RCC). The anti-tumor activity of isorhamnetin in combination with sorafenib was detected by MTT assay with cells in culture or Renca xenograft model in mice. Western blot was used to study the mechanisms of isorhamnetin in combination with sorafenib. Lymphocyte proliferation assay was also used to investigate the effects of the two drugs in combination. The results indicated that isorhamnetin inhibited the proliferation of RCC cells, with IC50 for A498, 786-O and Renca cell lines with being 31.7, 28.8 and 106.0 μmol·L-1, respectively. Isorhamnetin in combination with sorafenib improved the anti-lymphocyte proliferation activity of sorafenib with the IC50 down to 12.0 μmol·L-1. Isorhamnetin inhibited the growth of RCC in mice slightly with the inhibition efficiency at 26.9%. With 50.0 mg·kg-1 isorhamnetin in combination with 20.0 mg·kg-1 sorafenib, the anti-tumor activity of sorafenib was enhanced, with inhibition of growth rate increased to 60.7%. Meanwhile, isorhamnetin in combination with sorafenib could promote the lymphocytes proliferation in Renca xenograft model. Western blot results showed that combination of isorhamnetin and sorafenib could inhibit c-Raf/MEK/ERK and AKT/mTOR signaling pathways. In conclusion, the combination of isorhamnetin with sorafenib could increase the anti-tumor activity of sorafenib in RCC in vitro and in vivo. The mechanisms may be related to the inhibition of c-Raf/MEK/ERK and AKT/mTOR signaling pathways. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College.
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Based on special scientific facts demonstrated in traditional Chinese medicine (TCM) complex system, this paper proposes a hypothesis of "one output multi-source", discussing the concept, features, structures and the scope. The law of interaction between the integrity and multiple components of TCM complex system was examined. Feasibility, technical methods and evidence supporting the hypothesis have been presented here. We present a basic model of the hypothesis, i.e. artificial neural network (ANN) model. This hypothesis promotes a deeper modern scientific understanding towards the TCM complex system and advancement in research of the material basis. TCM compatibility and quality control will serve as the theoretical foundation for guiding the research on drug combination including chemical, biological and herbal medicines.