Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine

Artemisinin and its derivatives represent the most important and influential class of drugs in the fight against malaria. Since the discovery of artemisinin in the early 1970s, the global community has made great strides in characterizing and understanding this remarkable phytochemical and its unique chemical and pharmacological properties. Today, even as artemisinin continues to serve as the foundation for antimalarial therapy, numerous challenges have surfaced in the continued application and development of this family of drugs. These challenges include the emergence of delayed treatment responses to artemisinins in malaria and efforts to apply artemisinins for non-malarial indications. Here, we provide an overview of the story of artemisinin in terms of its past, present, and future. In particular, we comment on the current understanding of the mechanism of action (MOA) of artemisinins, and emphasize the importance of relating mechanistic studies to therapeutic outcomes, both in malarial and non-malarial contexts.

Flow behavior of liquid metal in the connected fascial space： Intervaginal space injection in the rat wrist and mice with tumor

The fascia and the fascial space can help provide a better understanding of the body. An intervaginal space injection （ISI） provides unique advantages that require further investigation. An upper limb model including physiological conditions and the tumor process was chosen to determine the flow behavior of liquid metal after ISI. In normal rats, after the injection of liquid metal into the intervaginal space comprising tendons, vessels, and nerves, magnetic resonance imaging and an anatomy experiment indicated that the liquid metal wrapped around the fascial space and finally reached the fingertip downstream and the armpit upstream in addition to the neurovascular bundle without vessels or lymph nodes. Using environmental scanning electron microscopy （ESEM） images, we discovered that the liquid metal was wrapped around the fibers of the fascia and moved forward in microscale or nanoscale areas. These data confirmed a fascia-based pathway. In tumors, the liquid metal moved to the tumor capsule through the damaged spot, where cancer cells destroy the integrity of the fascia between the normal cells and cancer cells. The liquid metal partly wrapped around the tumor and separated the tumor from the surrounding normal muscle. The ESEM images showed that fibers of the fascia penetrated the tumor, thus forming a network through which the liquid metal penetrated the tumor. Our study illustrated the physiological and pathological flow behavior of liquid metal in the upper limb after ISI and demonstrated a nonvascular pathway in the fascia. ISI may be useful for clinical treatment in the fascial pathway.

Discovery and repurposing of artemisinin

Malaria is an ancient infectious disease that threatens millions of lives globally even today.The discovery of artemisinin,inspired by traditional Chinese medicine(TCM),has brought in a paradigm shift and been recognized as the“best hope for the treatment of malaria”by World Health Organization.With its high potency and low toxicity,the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries,including China,to eventually eradicate malaria.Here,we will first review the initial discovery of artemisinin,an extraordinary journey that was in stark contrast with many drugs in western medicine.We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer,inflammation,immunoregulation-related diseases,and COVID-19.Finally,we will discuss the implications of the“artemisinin story”and how that can better guide the development of TCM today.We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.

Stiffness heterogeneity-induced double-edged sword behaviors of carcinoma-associated fibroblasts in antitumor therapy

Carcinoma-associated fibroblasts(CAFs) function as a double-edged sword in tumor progression. However,factors affecting the transition between tumor promotion and inhibition remain to be investigated. Here, we found that the transition was determined by stiffness heterogeneity of the tumor stroma in which tumor cells and CAFs were grown.When tumor cells were grown on a rigid plastic substrate,supernatants from CAFs inhibited the cytotoxic effects of 5-fluorouracil. In contrast, when tumor cells were grown on a soft substrate(5.3 kPa), supernatants from CAFs grown on a soft substrate increased the cytotoxicity of 5-fluorouracil. The diverse effects of CAFs were mediated by mechanotransduction factors, including stroma stiffness-induced cytokine expression in CAFs and signal transduction associated with stress fiber formation of CAFs. Moreover, we found that the cytokine expression in CAFs was regulated by nuclear Yesassociated protein, which changed according to cell stiffness,as characterized by atomic force microscopy. Overall, these findings suggested that modulating the mechanotransduction of the stroma together with CAFs might be important for increasing the efficacy of chemotherapy.

Neglected interstitial space in malaria recurrence and treatment

The interstitial space, a widespread fluid-filled compartment throughout the body, is related to many pathophysiological alterations and diseases, attracting increasing attention. The vital role of interstitial space in malaria infection and treatment has been neglected current research efforts. We confirmed the reinfection capacity of parasites sequestrated in interstitial space, which replenish the mechanism of recurrence. Malaria parasite-infected mice were treated with artemisinin-loaded liposomes through the interstitial space and exhibited a better therapeutic response. Notably, compared with oral administration, interstitial administration showed an unexpectedly high activation and recruitment of immune cells, and resulted in better clearance of sequestered parasites from organs, and enhanced pathological recovery. The interstitial route of administration prolongs the blood circulation time of artemisinin and increases its plasma concentration, and may compensate for the inefficiency of oral administration and the nanotoxicity of intravenous administration, providing a potential strategy for infectious disease therapy.

Qingjin Huatan decoction attenuates lipopolysaccharide-induced acute lung injury in mice by controlling platelet-associated formation of neutrophil extracellular traps

Background:Acute lung injury(ALI)is a severe and life-threatening lung inflammation with high morbidity and mortality,underscoring the importance to develop effective drugs.Qingjin Huatan decoction(QJHTD),as a classic ancient prescription,has been widely used for treating respiratory diseases.However,the role and mechanism of QJHTD against ALI remain unclear.Objective:This study aimed to explore the therapeutic effect of QJHTD on lipopolysaccharide(LPS)-induced ALI in mice and uncover its mechanism.Methods:The therapeutic effect of QJHTD on LPS-induced ALI in mice was evaluated by the histopathological changes in the lung tissue,the lung wet/dry weight ratio,and the levels of inflammatory cytokines and thrombin-antithrombin complexes.Transcriptomics was used to predict the mechanism of QJHTD in treating ALI.The expression levels of citrullinated histone 3 in the lung tissue,the content of cell-free DNA in the bronchoalveolar lavage fluid(BALF),and the platelet-associated formation of neutrophil extracellular traps(NETs)in vitro were determined.Results:Qingjin Huatan decoction exerted protective effect against LPS-induced ALI by suppressing interstitial edema,maintaining the alveolar-capillary barrier,inhibiting the infiltration of neutrophils and platelets in the lung tissue,and lowering the levels of tumor necrosis factorα,interleukin 1β,interleukin 6,and thrombin-antithrombin complexes in BALF.Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the formation of NETs was the main regulatory pathway for QJHTD against ALI.Qingjin Huatan decoction could treat ALI by inhibiting the release of NETs via reducing the content of citrullinated histone 3 in lung tissue and cell-free DNA in BALF in vivo,and suppressing the NETs formation induced by LPS-stimulated platelets under flow and static conditions in vitro.The formation of NETs was considered to bridge the interactions between neutrophils and platelets.Conclusions:This research demonstrated the effects of QJHTD in treating ALI and provided new insights for clarifying the complex regulation of neutrophils,platelets,and NETs in ALI.