Artesunate: A Comprehensive Review of Its Organ and Tissue Protective Effects

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In recent years, lower respiratory tract infections, depression, ischemic heart disease, stroke, and cancer have emerged as significant disease burdens across various age groups. Among these, certain diseases precipitate structural and functional impairments or organ and tissue failures. Thus, addressing dysfunctions in various organs and tissues promptly may hold the key to treating a wide array of ailments. Upon invasion by novel coronaviruses, patients have exhibited pathological alterations such as diffuse alveolar injury, myocardial edema, acute tubular injury, and fibrosis in multiple organs. Notably, individuals with cardiovascular diseases like hypertension have shown heightened susceptibility to renal end-organ damage.

Furthermore, external factors such as medications and trauma, including commonly used antibiotics like amoxicillin–clavulanic acid, non-steroidal anti-inflammatory drugs, and statins, can inflict harm on organs and tissues. Research indicates that organ and tissue damage involves a complex interplay of mechanisms encompassing inflammation, oxidative stress, cellular senescence, apoptosis, autophagy, fibrosis, and metabolic disorders. In addressing the multifaceted nature of diseases marked by diverse pathological changes, natural products with multi-targeted actions have shown promise. Compounds like luteolin, silymarin, and carvacrol have demonstrated remarkable protective effects on damaged tissues and organs.

As artemisinin has successfully tackled malaria—one of the most infectious, destructive, and debilitating diseases—the exploration of new mechanisms and indications for artemisinin and its derivatives has garnered significant attention to meet clinical demands. Artemisinin semi-synthetic derivatives, including artesunate (AS), artemether, dihydroartemisinin, artether, and arteether, have substantially enhanced the physicochemical properties and drug-forming characteristics of artemisinin while exhibiting ~10 times greater biological potency than artemisinin itself. Among these derivatives, AS has received the most scrutiny due to its more favorable pharmacokinetic–pharmacodynamic profile.

Compared to compounds like luteolin, silymarin, and carvacrol, AS boasts superior aqueous solubility and oral bioavailability, largely attributable to the hemisuccinate moiety in its structure, thereby conferring higher clinical value. Previous reviews addressed either the anti-malarial effects of AS or its therapeutic impacts on respiratory diseases, cancer, central nervous system disorders, viruses, skin ailments, and diabetes. To our knowledge, a comprehensive, up-to-date review exclusively focusing on the available reports regarding the organ- and tissue-protective effects of AS has not yet been conducted.

Considering AS’s promising prospects in organ and tissue protection and the scarcity of relevant reviews, this paper aims to compile the most recent advancements of AS in mitigating organ damage caused by various factors and safeguarding organs. With the keywords “Artesunate,” “biological activity of AS,” “organ damage,” “fibrosis,” “anti-oxidation,” “inflammatory injury,” “effects of AS on organ protection,” and “clinical effectiveness,” we conducted an extensive literature search of several databases, including PubMed, Web of Science, and Google Scholar; the collected articles were categorized by topic and incorporated into this review. A comprehensive understanding of AS’s organ and tissue-protective effects and underlying mechanisms will enhance its capacity to serve as an effective organ and tissue protector and facilitate its clinical application. Furthermore, it may introduce novel perspectives on organ and tissue protection.

AS demonstrates remarkable protective effects across a spectrum of organs and tissues, suggesting promising prospects for its clinical application. Oxidative stress has been a hot spot in basic research. The accumulation of a large amount of information has proved that oxidative stress is a key factor indirectly or directly involved in the development of many human diseases. In addition, human organs and tissues are susceptible to the damage caused by oxidative stress. Therefore, the search for effective antioxidants has become a long-term goal in biology, medicine, and other fields. In recent years, AS has received widespread attention due to its significant antioxidant properties.

The antioxidant activity of AS is a very crucial step in exerting organ and tissue protection, and it can effectively mitigate excessive oxidative stress, inhibit the expression of multiple oxidative damage markers, enhancing tissue and organ repair. The Nrf2/HO-1 pathway is a key signaling pathway for cellular antioxidative stress. AS can significantly up-regulate the expression of Nrf2 and HO-1, regulate the related antioxidant enzymes to eliminate reactive oxygen species and scavenge free radicals, and exert antioxidative stress, thus alleviating the damage of organs and tissues. In addition, large amounts of ROS and lipid oxidation products can disrupt the operation of the mitochondrial electron transport chain, leading to mitochondrial dysfunction, whereas AS has been found to improve mitochondrial function and dynamics. Continuing to understand the antioxidant mechanism of AS and its modulation of oxidative stress-related genes and signaling pathways may be a useful attempt to broaden the spectrum of antioxidant activity of AS and help us to fight against many human diseases in a more precise way.

Verification of the biological relevance of AS in humans is a crucial step in its clinical application. However, research into the organ and tissue-protective mechanisms of AS remains primarily at the stage of in vitro and animal experiments. The results of experiments in cells and animal models may not be fully representative of the actual effects of AS in humans. There is a clear need for further investment in combining basic research with high-quality clinical translation. Currently, there is insufficient evidence to assess comprehensively the preclinical safety of AS. To ensure safer utilization of AS, it is imperative to employ modern technology to delve deeper into its toxicity mechanisms and determine both safe and toxic doses.

The multifaceted nature of diseases marked by diverse pathological changes requires a compound capable of addressing various mechanisms simultaneously. Natural products have shown potential in this regard, with AS standing out due to its multi-targeted actions. AS has demonstrated protective effects against various types of organ and tissue damage, such as fibrosis, inflammation, oxidative stress, and metabolic disorders. For instance, in models of liver fibrosis, AS has been shown to modulate pathways such as TGF-β1/SMAD2/3, PI3K/Akt, and LPS/TLR4/NF-κB, thereby reducing fibrosis and promoting tissue repair. In the context of cardiovascular diseases, AS’s effects on myocardial protection are linked to its ability to modulate signaling pathways like NF-κB, NLRP3, and TLR4, which are involved in inflammatory responses. Additionally, AS has been found to improve mitochondrial function and dynamics, essential for maintaining cellular homeostasis and preventing damage due to oxidative stress.

Inflammation and oxidative stress are closely linked processes that play significant roles in the pathogenesis of various diseases. AS has shown potent anti-inflammatory and antioxidant properties, which contribute to its protective effects on organs and tissues. By modulating signaling pathways such as Nrf2/HO-1, AS can up-regulate the expression of antioxidant enzymes, reduce the production of reactive oxygen species, and mitigate oxidative damage. This, in turn, helps in reducing inflammation and promoting tissue repair. Furthermore, AS’s ability to modulate pathways involved in apoptosis and autophagy, such as PI3K/AKT/mTOR, Wnt/β-catenin, and AMPK/SIRT1, further enhances its protective effects by promoting cell survival and reducing cell death.

The therapeutic potential of AS extends beyond its anti-malarial properties. Its efficacy in treating various diseases and conditions has been explored in numerous studies. For instance, AS has been investigated for its potential in treating cancer, with studies showing its ability to inhibit tumor growth and induce apoptosis in cancer cells. Additionally, AS has been found to have neuroprotective effects, making it a potential candidate for treating neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Its anti-inflammatory and antioxidant properties also make it a promising agent for treating respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma.

Clinical translation of AS’s protective effects requires rigorous evaluation of its safety and efficacy in human studies. While preclinical studies have shown promising results, there is a need for well-designed clinical trials to confirm these findings in humans. Additionally, understanding the pharmacokinetics and pharmacodynamics of AS in humans is crucial for optimizing its therapeutic use. Advances in drug delivery systems, such as nanoparticle-based delivery, could enhance the bioavailability and targeting of AS to specific tissues and organs, thereby improving its therapeutic potential.

In conclusion, AS demonstrates remarkable protective effects across a spectrum of organs and tissues, suggesting promising prospects for its clinical application. Its ability to modulate various signaling pathways involved in inflammation, oxidative stress, fibrosis, apoptosis, and autophagy makes it a potent multi-targeted agent for treating diverse pathological conditions. Further research is needed to fully understand the mechanisms underlying AS’s protective effects and to translate these findings into clinical practice. As scientific knowledge advances, the value of AS’s development and application will continue to grow, benefiting mankind across a broader spectrum of fields.


reference link : https://www.mdpi.com/2076-3921/13/6/686

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