Oxidative stress is a redox imbalance in the body, which is one of the important factors leading to tissue damage and diseases. The nuclear factor E2-related factor 2 (Nrf2)-Kelch like ECH-associated protein 1 (Keap1) signaling pathway is not only an important defense system against oxidative damage, but also one of the key signaling pathways of the antioxidant capacity. Numerous studies have shown that targeting the Keap1-Nrf2 signaling pathway to activate Nrf2 has become an effective strategy for the treatment of oxidative stress and related diseases. Using small molecules to directly block the Keap1-Nrf2 protein-protein interaction (PPI) is one of the important directions for activating Nrf2 and exerting the cytoprotective effect, which can avoid the potential side effects of covalent modification of Nrf2. On the other hand, the Keap1 is an efficient E3 ubiquitin ligase that has been used in the design of proteolysis targeting chimeras (PROTACs). This review summarizes the research progresses of Keap1-Nrf2 protein interaction inhibitors and degraders based on the Keap1 E3 ubiquitination system in recent years.

We identified molecular mechanisms by which Isatidis Radix might prevent or mitigate influenza and corona virus disease 2019 (COVID-19) based on chemical composition and network pharmacology. High performance liquid chromatography coupled to tandem quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS) was used to analyze the components of Isatidis Radix. Seventy compounds were identified, of which 33 prototype compounds entered the blood. Network pharmacological analysis of 41 potential active components demonstrated that Isatidis Radix can regulate protein kinase B1 (AKT1), serum albumin (ALB), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), vascular endothelial growth factor A (VEGFA), tyrosine-protein kinase SRC (SRC), epidermal growth factor receptor (EGFR), intercellular adhesion molecule-1 (ICAM1) and other key genes, which have preventive effects on influenza and COVID-19 through hypoxia inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF), influenza A, Toll-like receptor (TLR), phosphatidylinositol-3-kinase-protein kinase B (PI3K-AKT), COVID-19 and other signaling pathways. This study identifies mechanisms by which Isatidis Radix might act against influenza and COVID-19 that are related to the inflammatory response, immunomodulation and viral defense, and provides a basis for subsequent clinical research. All animal experiments were approved by the Ethics Committee of Shenyang Pharmaceutical University (SYPU-IACUC-S2020-12.23-201).

Lysine-specific demethylase 1 (LSD1) plays vital roles in cell stemness, differentiation, cell motility, metabolic control and epithelial-mesenchymal transition, which is closely associated with tumorigenesis processes including cell proliferation, invasive, metastasis and poor prognosis. Besides, LSD1 also contributes to the occurrence of other diseases such as neurodegenerative diseases and viral infections. Since 2013, the irreversible inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, LH-1802 and reversible inhibitors including CC-90011 and SP-2577 have been approved for clinical assessment. This review comprehensively summarizes the clinical research of LSD1 drug candidates and briefly discusses the prospects, opportunities and challenges of LSD1-targeted drug discovery, aiming to provide a landscape for the related drug development.

At present, majority of the small molecular drugs used in clinics target proteins, they exert the efficacy through the binding to specific sites on the target protein. However, the "druggable" protein targets account for a small portion of the total number of proteins, and "non-druggable" proteins account for 80%, because of not having suitable drug binding sites. In the central rule, RNA is located in the upstream of proteins and controls the transcription of proteins. The research of small molecule drugs targeting RNA can solve the problem of protein "undruggable proteins" in some extent. This review summarizes the representative research achievements of small molecular drugs targeting RNA in recent years, and the screening methods applied to this field, with the focuses on the latest progress of small molecular drugs targeting novel coronavirus RNA.

Model-informed drug development (MIDD) in the development of pediatric drugs is drawing more and more attention due to the insufficiency of subjects, lack of research on ontogeny, and the limitation of ethic. The core of MIDD used for dose selection includes the population pharmacokinetic (PopPK) model and physiologically based pharmacokinetic (PBPK) model, as well as model-based simulation and prediction. PBPK model has the advantage of predicting the optimal pediatric dose before the clinical trials and has the ability of extrapolation from adult model to pediatric model. PopPK model characterizes the pediatric PK feature based on the analysis of clinical data and can be used to explore the significant covariates, which is a power tool for individualized medicine in children. With their own advantages and disadvantages, PBPK and PopPK model should be jointly used in the pediatric drug development to refine the dose regimen for children at different ages. In this study, the pediatric drug development of rivaroxaban was taken as an example to introduce the combined application of PBPK model and PopPK model in the design and validation of pediatric dose regimen in Phase Ⅰ, Ⅱ and Ⅲ trials, which may provide reference to MIDD in other pediatric drug development.

Gentiana rhodantha is a characteristic medicinal material of Miao Ethnomedicine. It has significant curative effect in the treatment of acute jaundice hepatitis, dysentery, pediatric pneumonia and bronchitis, etc. However, the evolutionary relationship and taxonomic identification of G. rhodantha are controversial. In this study, we sequenced the chloroplast genome of G. rhodantha using the second and third generation sequencing technology. Then, the structural characteristics and suitability evolution characteristics were analyzed. The results showed that the G. rhodantha chloroplast genome was 148 844 bp in length with 37.75% GC content, consisting of a large single copy region (LSC) of 80 076 bp, a small single copy region (SSC) of 17 596 bp and an inverted repeat region (IR) of 25 586 bp. A total of 124 genes were annotated, including 80 protein-coding genes, 36 tRNA genes, and 8 rRNA genes; the chloroplast genome of G. rhodantha has a weak codon preference, and the influencing factors are mainly natural selection. The optimal codons are CUU, UCU, UCA, CCA, and ACU. A total of 169 SSRs were found in MISA, of which the single nucleotide repeats were the most (114, 67.50%), followed by dinucleotide repeats (43, 25.44%). The phylogenetic analysis support that G. rhodantha belong to Sect. Stenogyne which can be clearly distinguished from other groups. Compared with other species, the Ka/Ks value of chloroplast genes of G. rhodantha is basically less than 1 except for psaI, rpl22 and rps11, indicating that they have been subjected to strong purification selection in the long-term evolutionary process. The photosynthesis gene psaI and the expression-related genes rpl22 and rps11 showed differences between groups, which supported the view that Sect. Stenogyne was an independent genus. This study will provide a reference for future researches on chloroplast genetic engineering and molecular breeding of G. rhodantha.

Nine compounds were isolated from the leaves of Chimonanthus nitens Oliv. by silica gel, ODS, Sephadex LH-20 column chromatography and semi-preparative HPLC. They were identified as chimnitensene B (1), 1α-hydroxyisodauc-4-en-15-al (2), trans-4, 5-dihydroxycorocalane (3), trefoliol B (4), oplopanone (5), oplodiol (6), 3-(3'-hydroxybutyl)-2, 4, 4-trimethylcyclohexa-2, 5-dienone (7), 9(S)-4-oxo-7, 8-dihydro-β-ionol (8), and saniculamoid D (9) respectively, by MS, NMR and single crystal diffraction. Among them, compound 1 is a new guaiane-sesquiterpenoid, and compounds 2-9 were isolated from this plant for the first time.

In this study, a research strategy integrating network pharmacology analysis and animal experimental validation was applied to explore the molecular mechanism of Chuanxiong Qingnao Granules (CXQN) in improving migraine headache (MH). All animal experiments were followed the regulation of the Laboratory Animal Ethics Committee of the China Academy of Chinese Medical Sciences. Based on the network pharmacology analysis, the 27 active ingredients and their corresponding 940 targets were obtained, and 99 common targets of CXQN in the treatment of MH were obtained by intersection, and tumor necrosis factor-α (TNF-α), interleukin (IL)-6, vascular endothelial growth factor A (VEGFA), IL-1β, brain-derived neurotrophic factor (BDNF) were screened out as hub targets. Enrichment analysis showed that the targets of CXQN in the treatment of MH were mainly involved in cyclic adenosine monophosphate (cAMP), hypoxia inducible factor-1 (HIF-1), phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling pathways. In addition, the experimental verification in the MH rat induced by nitroglycerin showed that the CXQN administrated groups could significantly improve the behavioral symptoms and regulate the level of vasoactive substances, and reduce the expression of TNF-α, IL-6, VEGFA, IL-1β, and BDNF at gene and protein levels. This study revealed the multi-component, multi-target, and multi-pathway characteristics of CXQN in the treatment of MH, and elucidated the potential mechanism of CXQN in the treatment of MH, laying a theoretical foundation and scientific basis for its clinical application in the treatment of MH diseases.

Compared with the traditional two-dimensional (2D) monolayer culture, three-dimensional (3D) organoid can better simulate the physiological and pathological microenvironment of organs and tissues. In this study, 3D cardiac organoids were constructed using cardiac fibroblasts (CFs), cardiac myocytes (CMs) and endothelial cells (ECs) isolated from hearts of 1-3-day Sprague-Dawley (SD) neonatal rats. The experimental scheme was approved by the Experimental Animal Welfare and Ethics Committee of Tianjin University of Traditional Chinese Medicine and met the standards of experimental animal welfare and ethics. Optimal seeding cell density and culture time were determined by observing the sphere diameter and pulsation. The hierarchical structure and cardiac-like function were evaluated by fluorescence staining. The results showed that the cardiac-like microspheres constructed with cell number of 1×10⁴ still beated spontaneously even after 34 days in culture, and maintained characteristic cellular hierarchical structure. Then, based on these cardiac microspheres, a phenylephrine (PE)-induced cardiac hypertrophy model was established and evaluated by mitochondrial mass, intracellular Ca²⁺ concentration and mitochondrial membrane potential. Guanxinning Injection (GXNI) was tested to verify that the established model can be used for myocardial hypertrophy drug screen. The results showed that GXNI significantly reversed the enlargement of cardiac microsphere area and diameter, the increase of mitochondrial mass, intracellular Ca²⁺ concentration and the decrease of mitochondrial membrane potential caused by PE, and reduced upregulation of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC). In conclusion, this study successfully established a 3D in vitro model of cardiac remodeling induced by cardiac hypertrophy. In this new system, cardiac microspheres not only have cardiac-like morphology and extracellular matrix components, but also exhibit spontaneous and rhythmic systolic and diastolic function. Therefore, the cardiac microsphere is an effective model to investigate the pathological mechanism of cardiac hypertrophy and screen related drugs.

Dementia is a series of diseases with severe cognitive decline caused by brain diseases, that closely related to kidney deficiency in traditional Chinese medicine, including Alzheimer's disease (AD), dementia caused by cerebral stroke, vascular dementia (VAD) and so on. Dipsaci Radix is the dried root of Dipsacus asper Wall. ex Henry and its curative effects mainly focus on nourishing the liver and kidney, strengthening muscles and bones, as well as dredging blood vessels. The main chemical components of Dipsaci Radix are triterpenoid saponins and iridoid glycosides. In recent years, studies have found that Dipsaci Radix and its active compounds could ameliorate dementia symptoms via multiple targets and molecular mechanisms. In this review, we summarize the recent research progress of Dipsaci Radix in dementia prevention, which will provide reference for further exploration of its mechanism and application in the prevention and treatment of dementia.