Albert Einstein once eloquently stated “We still do not know one thousandth of one percent of what nature has revealed to us.” Mother Nature has proven time and again to be the best engineer, architect, scientist, and doctor. This fact has not been lost on mankind, and since time immemorial, we have looked to nature for answers to human conditions and diseases. Indeed, our first evidence dates back to preliterary history as long as 50,000 years ago, in archaeological discoveries from a Middle Eastern grave site at Shanidar, Iraq, of a Neanderthal man which contained plant specimens, 7 of which are still used in local traditional medicine.1 Since then, the use and application of herbal medicine has been recorded in every society from Traditional Chinese, Ayurvedic, Yunani, and other cultures in the developing world. The diversity and range of Archaeplastida and Fungi continues to grow with new species, approximately 2000 species per annum, being continually recorded by the Royal Botanical Gardens Kew, annual publication (https://www.kew.org/science/state-of-the-worlds-plants-and-fungi), a significant and necessary milestone. To date, there are approximately 391,000 species of vascular plants currently known to science. This diversity, both qualitative and quantitative, is a biological fingerprint of evolutionary biology. It reflects the adaptive nature of variation in plant life, shaped spatially and temporally by genetic architecture and developmental processes.2 These hugely diverse plant and fungi kingdoms continually evolve to a multiplicity of environmental stressors and conditions through adaptive synergy. This evolutionary phenomenon has created a wealth of biomolecules and molecular entities. It potentially stands as a rich resource for biomolecules, drug development, novel chemotypes and pharmacophores, and templates for efficacious biomimetics for a multitude of disease indications. Such a wealth must be carefully curated and protected. Ethnopharmacology was originally based on an empiric framework of understanding and application. Classical examples include the Sumerian Nagpur clay slabs (circa 3000 BC), “Pen T'Sao” (Emperor Shen Nung, circa 2500 BC), the Ebers Papyrus (circa 1550 BC), “De re medica” (Celsus, 25 BC–50 AD), and the seminal works of both Pedanius Dioscorides (40–90 AD), and Pliny the Elder (23 AD-79), “De Materia Medica,” and “Historia Naturalis,” respectively. The Roman physician and pharmacist, Galen (131–200 AD), added to this knowledge, introducing novel plant drugs such as uva-ursi folium, a uroantiseptic and diuretic. These classical works detailed all contemporary medicinal plants at the time and remained the basic materia medica for therapeutics and prophylaxis until the Renaissance era.3 With the development of iatrochemistry in the 16th century, scientific knowledge and understanding grew, and the basis of specific medicinal plants for treatment of diseases was being discovered, and thus, their use became founded on explicatory fact.4 Although the use of bioactive natural products as herbal drug preparations dates back thousands of years, their application as isolated and characterized compounds to modern pharmaceutical R&D started only in the 19th century with the advancement of synthetic chemistry. It is well-acknowledged that natural products played critical roles in modern drug development, especially for antibacterial, analgesic, and antitumor agents. Although the popularity and attractiveness of synthetic products increased because of production costs, time effectiveness, quality control, and regulation, their safety and efficacy have remained a challenge. These limiting factors associated with synthetic drugs, together with the increasing contraindications of their usage has refocused our attention on the discovery, development, and application of natural drugs. Pharmaceutical programs to develop new drugs through de novo synthesis can take years and are extremely costly, from establishing a new R&D program, defining targets, synthesizing and screening the activity of potential leads, and finally selecting the optimal few to further define pharmacokinetic, pharmacodynamic, and safety profiles. Furthermore, it is not uncommon for some therapeutics to be withdrawn within a few years of licensing because of unexpected side effects unobserved during phase III clinical trials. Although technological advances such as combinatorial chemistry, high-throughput screening, data analytics and molecular modeling, molecular and cell biology, as well as the “omics” platforms have streamlined this process, the evidence to date of these increasing the chances of success is limited but that is not to say these significant initiatives and advancements will not come to fruition in the near future. It therefore seems an attractive proposition that the accumulated evidence derived from centuries of use of traditional medicine or from knowledge of how species of plants have evolved and adapted to their environment can optimize therapeutic development and substantially reduce time, cost, and effort in identifying novel bioactive candidates. Whether by chance, serendipity, or design, many characterized endogenous human biochemical and signal transduction pathways, receptors, and molecular and cellular regulatory systems, important in physiological function, are targeted by plant-derived biochemicals and molecules, eg, the opioid and cannabinoid receptors. It is a logical hypothesis that many more structure–function–signaling relationships, of (patho-)physiological and pharmacological significance, involving plant biomolecules and derivatives have yet to be discovered and characterized. Furthermore, older phytochemicals are finding new applications through better understanding of pharmacology, cell and molecular biology, translational sciences and clinical observations. For instance, forskolin, an alkaloid extract from Coleus forskohlii and phytochemicals from Stephania glabra, are now being repurposed as adenylate cyclase and nitric oxide (NO) activators, potential therapeutics in the prevention of obesity and atherosclerosis. Traditional Chinese Medicine (TCM) has thousands of years of history and provenance and proven to be very effective in the prevention and treatment of diseases. TCM continues to be popular and has a profound influence on Asian countries, with many people choosing TCM as a primary treatment for many conditions. It has numerous advantages, such as low side effects, naturalness, and its excellent efficacy, especially for chronic inflammatory diseases, such as cardiovascular disease (CVD). However, its widespread adoption in western cultures and medicine has been hindered because of the complex nature of TCM. One capsule often contains dozens of herbal ingredients, and there is a lack of standards for quality testing, production technology, and efficacy/safety evaluation. Nevertheless, significant advances have been made using knowledge from TCM. Professor Tu Youyou was awarded the 2015 Nobel Prize in Physiology or Medicine for her outstanding work on the development of antimalarial drugs using the phytochemical extract, artemisinin. Professor Xiu-Min Li, the Icahn School of Medicine, was awarded the “2016 Future of Health Technology Award” for “Innovative Research on Botanical Drugs for Allergies and Immune System Diseases” during the 20th Future Health Technology Summit. During the recent pandemic, TCM proved to be an excellent alternative for the treatment of the COVID-19. Lianhua Qingwen (LHQW) is a TCM composed of 11 herbs and 2 medicinal minerals which exhibits anti-inflammatory activity and is effective in treating pneumonia. Using a network pharmacology approach, Yang et al5 demonstrated that LHQW alleviates lipopolysaccharide (LPS)-induced acute lung injury by inhibiting p53-mediated intrinsic apoptosis pathways. LHQW is now approved for phase II clinical trials by the FDA for acute uncomplicated influenza (ClinicalTrials.gov Identifier: NCT02867358). Other TCMs with indications for CVD include KYUSHIN, which has cardiotonic and arrhythmogenic effects; XueZhiKang extracted from red yeast with cholesterol lower properties has passed phase II clinical trials (ClinicalTrials.gov Identifier: NCT016864); and Fufang Danshen Diwan, which has an antianginal effect, is approved for phase III clinical trials by FDA (ClinicalTrials.gov Identifier: NCT03789552). Diao Xin Xue Kang is approved by the Netherlands (Reg No: RVG102142) for treatment of dilating coronary vessels and improving myocardial ischemia and is the first TCM approved by the EU. In this current issue of JCVP, Hong-yu Wu and colleagues eloquently demonstrate that Icariside II (ICS-II) has significant antiproliferative qualities in vascular smooth muscle cells (VSMCs) that counteracts aberrant vascular neointimal hyperplasia postangioplasty. Herba Epimedii, a Berberidaceae medicinal plant, is a traditional Chinese herb used for the treatment of CVDs, inflammation, and osteoporosis, as well as sexual and neurological disorders. Icariin is the major pharmacologically active flavonol diglycoside extracted from Herba Epimedii, that is metabolized to 3 derivatives—Icariside I, ICS-II, and Icaritin. These all have similar structures and are bioactive components of Epimedium brevicornum, with extensive and widespread applications and proven efficacy in treating several age-related diseases by its antioxidative effect on DNA damage, β-amyloid–mediated neurotoxicity, and oxidative injury within the cardiovascular compartment. ICA has been demonstrated to improve cognitive impairment through various mechanisms in a number of animal models of dementia and Alzheimer's disease.6 It has been demonstrated to be a cGMP-specific phosphodiesterase type-5 inhibitor for the treatment of erectile dysfunction through the NO/cGMP signaling pathway. ICA also improves learning and memory ability in APP/PS1 transgenic mice by again stimulating NO/cGMP signaling.7 ICS-II, the principle primary active metabolite of ICA in vivo which lacks a glucose moiety at C-7, has been demonstrated to be more bioavailable than ICA.8 ICS-II has been demonstrated to have an extensive range of pharmacological effects and may have the potential to improve an individual's “health span.” Hence, it is pertinent to further investigate the potential beneficial effects and the underlying mechanisms of ICS-II, which may reveal novel clues and applications of ICS-II. The extensive range of pharmacological effects and indications of ICS-II include anti-inflammatory,9 anticancer,10 antioxidative,11 antiaging activities,12 and neuroprotective capabilities in the hippocampus. In addition, ICS-II exerts beneficial effects on LPS-induced neuroinflammation by regulating the TLR4/MyD88/NF-κB signaling pathway in rats, thus inhibiting LPS-induced astrocyte overactivation.13 To add to our body of knowledge and understanding, this study, using both in vivo and in vitro techniques, demonstrated the cytoprotective effects of ICS-II on vascular remodeling by inhibiting VSMC proliferation (Fig. 1). The authors interrogated the molecular and cellular effects of ICS-II on balloon-induced neointimal hyperplasia in rats. To support these in vivo findings, the inhibitory effects of ICS-II on platelet-derived growth factor–induced vascular proliferation in primary rat VSMCs were assessed in vitro. In these investigations, ICS-II was as effective as rapamycin (positive control) in inhibiting neointimal formation in injured rat carotid arteries and notably reduced the expression of both Wnt7b and cyclin D1 as assessed by immunohistochemical staining. ICS-II significantly counteracted platelet-derived growth factor–induced VSMCs proliferation as determined by the CCK8 assay. Flow cytometric cell cycle analysis determined that ICS-II arrested the cell cycle during the G1/S transition. This finding was supported by western blot analysis which indicated that this cell cycle arrest was likely through Wnt7b suppression resulting in cyclin D1 inhibition.FIGURE 1.: A, Arterial intervention and reconstruction procedures, including balloon angioplasty, are used to restore blood flow in atherosclerotic arteries. Angioplasty is also known as percutaneous coronary intervention or percutaneous transluminal coronary (B) angioplasty, involves insertion of a tiny balloon up to the area which is narrowed and temporarily inflating the balloon to widen the artery. C, Restenosis occurs after 30%–50% of transcatheter coronary procedures, within 6 months. Postangioplasty restenosis results from 2 major processes: neointimal formation and constrictive remodeling. Neointimal formation is initiated by arterial injury with a resultant loss of contractile phenotype in tunica media, leading to VSMC migration from the tunica media to the intima. Migrating VSMCs contribute to the intimal thickening by the excessive synthesis of extracellular matrix and proliferation. D, The important role of both canonical (β-catenin–dependent) and noncanonical (β-catenin–independent) Wnt signaling in VSMC proliferation has been reported. These signaling events have been demonstrated to upregulate proproliferative cyclin D1 and downregulate p21 in arterial and venous SMCs. E, Icariin is the index compound of Epimedii Herba. Its pharmacokinetics, pharmacodynamics, and metabolism are well-studied. F, Icariin is metabolized by the human intestinal microbiome to Icariside I, Icariside II, Icaritin, and desmethylicaritin. Icariin is quickly transformed to ICS-II before absorption in the human intestine. G, Hong-yu Wu et al have demonstrated, both in vitro and in vivo, that ICS-II inhibits VSMC proliferation by downregulation of Wnt7b expression and inhibition of cyclin D1. ICS-II thereby significantly reduced SMC proliferation through cell cycle arrest during the G1/S transition phase. Created & illustrated by RPM with BioRender.com.Plants continue to provide an infinite wealth of naturally occurring, biologically active phytochemicals, many of which have proven therapeutic effects, and many more are yet to be discovered. In the quest for medicines and novel therapeutic pipelines, Mother Nature continues to know best.