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.

The enteric-hepatic axis plays an important role in the occurrence, progression and regression of nonalcoholic fatty liver disease (NAFLD). Obeticholic acid (OCA) is a farnesoid X receptor agonist. In this study, C57BL/6 mice were fed with methionine and choline deficient (MCD) diet for 8 weeks with OCA (6.5 mg·kg^-1·d^-1) administration by gavage at the same time. The effects of OCA on serum lipid and bile acid metabolomics and ileal gut microbiota (GM) of MCD mice were studied by UPLC-MS and 16S rDNA sequencing. The results were as follows: (1) OCA decreased the activities of alanine aminotransferase and aspartate aminotransferase in serum and the contents of triglyceride (TG) and malondialdehyde in liver, alleviated the accumulation of liver fat and inflammation of MCD mice. OCA down-regulated the contents of 2 eicosanoids (12, 13-EPOME, 9, 10-EPOME) and 4 free fatty acids (FFA16∶1, FFA18∶1, FFA16∶2, FFA18∶3) and TG (16∶1_16∶1_18∶2) in serum, and up-regulated the content of 1 eicosanoid thromboxanes B3. KEGG differential metabolite pathway analysis showed that fatty acid biosynthesis might be the main way that OCA ameliorated lipid metabolism disorder of MCD mice. OCA reduced the relative abundance of Christensenellaceae and Lachnospiraceae_UCG-006 in the GM of MCD mice; OCA decreased the serum levels of 23-deoxycholic acid, porcine deoxycholic acid, 3-deoxycholic acid, glycine deoxycholic acid, glycine cholic acid, taurine deoxycholic acid, taurocholic acid and taurine. These results suggest that the alleviating effect of OCA on NAFLD of MCD mice may be related to its above-mentioned regulation of the metabolism of the free fatty acids, oxidized lipids, 12α-hydroxylated bile acids and the abundance of GM. The animal experiments were approved by the Experimental Animal Ethics Committee of Hubei University (No. 20220036).

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.

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.

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.

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.

The epidemic of Zika virus (ZIKV) raises critical public health and safety problems. However, there are currently no vaccines or drugs that are clinically approved for ZIKV infections. Since RNA-dependent RNA polymerase (RdRp) plays an important role in replication and transcription of ZIKV and is absent in human beings, it is a potential drug screening target of anti-ZIKV agents. According to the fluorescence-based alkaline phosphatase-coupled polymerase assay method, we established the NS5 RdRp inhibitor screening model. Through screening from an anti-infection compound library, we found a compound octenidine dihydrochloride (OCT) that could inhibit ZIKV RdRp activity with a half maximal inhibitory concentration (IC₅₀) of 5.43 μmol·L^-1. Biolayer interferometry (BLI) assay showed that OCT could bind to ZIKV RdRp and had a strong affinity. Moreover, OCT exhibited an inhibitory effect on ZIKV replication with a half maximal effective concentration (EC₅₀) of 29.94 μmol·L^-1. All these results indicated that OCT had the anti-ZIKV activity by targeting ZIKV RdRp, and it is likely to be a promising lead compound against ZIKV.

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).