Abstract
Hematopoiesis is a dynamic process of the continuous production of diverse blood cell types to meet the body's physiological demands and involves complex regulation of multiple cellular mechanisms in hematopoietic stem cells, including proliferation, self-renewal, differentiation, and apoptosis. Disruption of the hematopoietic system is known to cause various hematological disorders such as myelosuppression. There is growing evidence on the beneficial effects of herbal medicines on hematopoiesis; however, their mechanism of action remains unclear. In this study, we conducted a network pharmacological-based investigation of the system-level mechanisms underlying the hematopoietic activity of Samul-tang, which is an herbal formula consisting of four herbal medicines, including Angelicae Gigantis Radix, Rehmanniae Radix Preparata, Paeoniae Radix Alba, and Cnidii Rhizoma. In silico analysis of the absorption-distribution-metabolism-excretion model identified 16 active phytochemical compounds contained in Samul-tang that may target 158 genes/proteins associated with myelosuppression to exert pharmacological effects. Functional enrichment analysis suggested that the targets of Samul-tang were significantly enriched in multiple pathways closely related to the hematopoiesis and myelosuppression development, including the PI3K-Akt, MAPK, IL-17, TNF, FoxO, HIF-1, NF-kappa B, and p53 signaling pathways. Our study provides novel evidence regarding the system-level mechanisms underlying the hematopoiesis-promoting effect of herbal medicines for hematological disorder treatment.
Highlights
Hematopoiesis refers to the process of development of immature precursor cells into various mature and functional blood cells, which initiates from the self-renewing multipotent hematopoietic stem cells (HSCs) [1, 2]. is biological process involves accurate coordination of cellular proliferation, differentiation, and survival of progenitor cells to maintain hematopoietic homeostasis modulated by the activity of various cytokines, growth factors, and key regulatory factors, as well as the complex interactions between hematopoietic cells, tissues, and organs [1, 2]
We investigated the chemical compounds contained in the four herbal medicines (i.e., AGR, RRP, PRA, and CR) that comprise SMT from a number of traditional Chinese medicine (TCM)-related databases (e.g., Traditional Chinese Medicine Systems Pharmacology (TCMSP), Traditional Chinese Medicine Integrated Database (TCMID), and Herb Ingredients’ Targets (HIT))
We explored the system-level pharmacological mechanisms underlying the hematopoietic effects of SMT by employing a network pharmacology approach [47, 184]. e following are our key findings: (i) 16 potentially active phytochemical compounds present in SMTmay interact with 158 myelosuppression-related targets to exhibit therapeutic activities; (ii) GO enrichment analysis demonstrated that the targets of the active compounds in SMT were involved in diverse hematopoiesis-associated biological processes such as cell proliferation, cell differentiation, cell cycle process, cell migration, cell apoptosis, immune response, response to iron binding, inflammation, and hemopoiesis; (iii) the myelosuppression-associated targets of SMT were significantly enriched in various pathways, including the PI3K-Akt, MAPK, IL-17, TNF, FoxO, HIF-1, NF-kappa B, and p53 signaling pathways, which are associated with the hematopoiesis and hematological disorders (HDs) development
Summary
Hematopoiesis refers to the process of development of immature precursor cells into various mature and functional blood cells, which initiates from the self-renewing multipotent hematopoietic stem cells (HSCs) [1, 2]. is biological process involves accurate coordination of cellular proliferation, differentiation, and survival of progenitor cells to maintain hematopoietic homeostasis modulated by the activity of various cytokines, growth factors, and key regulatory factors, as well as the complex interactions between hematopoietic cells, tissues, and organs [1, 2]. Hematopoietic homeostasis disruption caused by various reasons, including anticancer therapies (e.g., chemotherapy and radiotherapy), myeloid malignancies, nutritional deficiencies, or viral infection, may lead to the development of hematological disorders (HDs) such as myelosuppression [3,4,5]. Evidence-Based Complementary and Alternative Medicine colony-stimulating factor (GM-CSF) [10,11,12]; they have been reported to cause unfavorable side effects such as bone and muscle pains, fever, flushing, and nausea [13, 14]. Previous studies have reported that the hematopoietic effects of SMT partly involve the modulation of cellular processes in bone marrow cells, HSCs, and blood cells (e.g., erythrocytes, leukocytes, and thrombocytes), as well as the activities of key hematopoietic factors (e.g., EPO, G-CSF, interleukins (ILs), and interferon(IFN-) c) [42, 44,45,46]. The system-level molecular therapeutic mechanisms of SMT are yet to be fully elucidated
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