Effects of Natural Products on Enzymes Involved in Ferroptosis: Regulation and Implications.

Ferroptosis is a form of regulated cell death that is characterized by the accumulation of iron-dependent lipid peroxides. The regulation of ferroptosis involves both non-enzymatic reactions and enzymatic mechanisms. Natural products have demonstrated potential effects on various enzymes, including GPX4, HO-1, NQO1, NOX4, GCLC, and GCLM, which are mainly involved in glutathione metabolic pathway or oxidative stress regulation, and ACSL3 and ACSL4, which mainly participate in lipid metabolism, thereby influencing the regulation of ferroptosis. In this review, we have provided a comprehensive overview of the existing literature pertaining to the effects of natural products on enzymes involved in ferroptosis and discussed their potential implications for the prevention and treatment of ferroptosis-related diseases. We also highlight the potential challenge that the majority of research has concentrated on investigating the impact of natural products on the expression of enzymes involving ferroptosis while limited attention is given to the regulation of enzyme activity. This observation underscores the considerable potential and scope for exploring the influence of natural products on enzyme activity.

The Changing Global Landscape in the Development of Artemisinin-Based Treatments: A Clinical Trial Perspective.

Artemisinin and its derivatives (ARTs), due to their potent antimalarial activities, are widely used as frontline antimalarials across the world. Although the large-scale deployment of ARTs has significantly contributed to a substantial decline in malaria deaths, the global malaria burden is still high. New antimalarial treatments need to be developed to manage the growing artemisinin resistance. Understanding the status of ART development is crucial for developing strategies for new alternatives and identifying opportunities to develop ART-based treatments. This study sampled ART clinical trials from the past two decades to gain an overview of the global ART-development landscape. A total of 768 trials were collected to analyze the disease focuses, activity trends, development status, geographic distribution, and combination treatment profiles of ART trials. The findings highlighted the constant focus of ARTs on malaria, the evolving combination research focus, the distinctions between ART development preferences across global regions, the urgent demands for treatments for artemisinin-resistant malaria, and the unavoidable need to consider ART combinations in the development of new antimalarials.

ChemGenerator: a web server for generating potential ligands for specific targets.

In drug discovery, one of the most important tasks is to find novel and biologically active molecules. Given that only a tip of iceberg of drugs was founded in nearly one-century's experimental exploration, it shows great significance to use in silico methods to expand chemical database and profile drug-target linkages. In this study, a web server named ChemGenerator was proposed to generate novel activates for specific targets based on users' input. The ChemGenerator relies on an autoencoder-based algorithm of Recurrent Neural Networks with Long Short-Term Memory by training of 7 million of molecular Simplified Molecular-Input Line-Entry System as the basic model, and further develops target guided generation by transfer learning. As results, ChemGenerator gains lower loss (<0.01) than existing reference model (0.2~0.4) and shows good performance in the case of Epidermal Growth Factor Receptor. Meanwhile, ChemGenerator is now freely accessible to the public by http://smiles.tcmobile.org. In proportion to endless molecular enumeration and time-consuming expensive experiments, this work demonstrates an efficient alternative way for the first virtual screening in drug discovery.

Interactions of antithrombotic herbal medicines with Western cardiovascular drugs.

Thrombotic events act as a critical factor that interferes with Cardiovascular Diseases (CVDs), and antithrombotic herbal medicine is a long-standing controversial issue. Although a dispute is involved in their clinical application, all parties unanimously agree that herbal products have been widely used in folk medicine, and their interactions with conventional drugs are of high concern. This study aims to investigate how antithrombotic herbal medicines interact with Western cardiovascular drugs on the molecular level by taking an example of the most frequently used herbal pair, Danshen-Chuanxiong (DS-CX), and to discover more scientific evidence on their potential herb-drug interactions. Network pharmacology (NP), as an analytical approach of a complex system, is used to visualize and compare target profiles of DS-CX and Western cardiovascular drugs, which can be applied to predict common herb-drug targets and to construct a solid context for discussing herb-drug interactions. These interactions are further validated by in vitro assays, while in vivo zebrafish model employed for evaluating an overall pharmacological efficacy of herbal pairs in specific combination ratios. The study finds that DS could react directly to the Western cardiovascular drug targets relevant to antithrombotic pathways (i.e., thrombin, coagulation factor Xa and cyclooxygenase-1), whereas CX could not react directly and can synergistically affect antithrombotic effects with DS in specific combination ratios. Moreover, it is indicated that DS-CX may generate wide biological functions by a complicated mechanism of "neuro-immune-metabolism/endocrine" (NIM), which can further cause multiple direct and indirect interactions with Western cardiovascular drugs. From the clinical perspective, herb-drug interactions should be given high attention, especially when multiple herbs are used simultaneously.

Expression change of NBL1 in rats with pulmonary arterial hypertension / 中国药理学通报

Aim To study the expression pattern of neuroblastoma, suppression of tumorigenicity 1 (NBL1) in pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Methods Forty rats were randomly allocated into control group (n = 10) and MCT group (n= 30). Intraperitoneal injection of 60mg 'kg"1 MCT for MCT group or equal volume normal saline for control group was performed. The changes of NBL1 in lungs and plasma of the 3 rd, 4 th and 5 th week after MCT injection were detected respectively. NBL1 levels in rat plasma were detected by enzyme linked immunosorbent assay. Results At the 3 rd, 4 th, and 5 th week after MCT injection, the mRNA level of NBL1 decreased by 70%, 81% and 89% , the protein level decreased by 36% , 78% and 99% , and the plasma concentration of NBL1 decreased from (2. 82 ± 0. 58) xg L"1 (control rats) to (1. 90±0.55) fig L-1, (1.51 ±0.43) jxg L'1, (0.64 ±0. 34)ug L-l and presented a negative correlation with pulmonary hemodynamic indices and right ventricular hypertrophy. Immunohistochernical staining demonstrated that NBL1 was mainly expressed in small pulmonary arteries in normal lungs from control group but seldom detected in severely remodeled pulmonary arteries from MCT group. Furthermore, NBL1 significantly inhibited the activation of BMP signal in pulmonary artery endothelial cells induced by BMP2/4. Conclusions NBL1 level demonstrates a stepwise decrease in MCT induced PAH, implying its vital roles in the pulmonary vascular remodeling process and the possibility of NBL1 to be a potential biomarker for PAH.