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Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2–65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin–piperaquine or dihydroartemisinin–piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate–mefloquine or dihydroartemisinin–piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether–lumefantrine or artemether–lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin–piperaquine (183 [17%]), dihydroartemisinin–piperaquine plus mefloquine (269 [24%]), artesunate–mefloquine (73 [7%]), artemether–lumefantrine (289 [26%]), or artemether–lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin–piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin–piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin–piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin–piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin–piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate–mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI −6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether–lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether–lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI −1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin–piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin–piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether–lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether–lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether–lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin–piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin–piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin–piperaquine plus mefloquine; p=0·50). Dihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Anthraquinones are bioactive natural products, which are often found in medicinal herbs. These compounds exert antioxidant-related pharmacological actions including neuroprotective effects, anti-inflammation, anticancer, hepatoprotective effects and anti-aging, etc. Considering the benefits from their pharmacological use, recently, there was an upsurge in the development and utilization of anthraquinones as reactive oxygen species (ROS) regulators. In this review, a deep discussion was carried out on their antioxidant activities and the structure-activity relationships. The antioxidant mechanisms and the chemistry behind the antioxidant activities of both natural and synthesized compounds were furtherly explored and demonstrated. Due to the specific chemical activity of ROS, antioxidants are essential for human health. Therefore, the development of reagents that regulate the imbalance between ROS formation and elimination should be more extensive and rational, and the exploration of antioxidant mechanisms of anthraquinones may provide new therapeutic tools and ideas for various diseases mediated by ROS.

This work was partially supported through national funds provided by the FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF) and COMPETE, under the projects PEst-C/MAR/LA0015/2013, PTDC/MAR-BIO/4694/2014, as well as by the project INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR/INSEAFOOD /ECOSERVICES), supported by the North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). J. Noitnart thanks the ALFABET project under the ERASMUS MUNDUS ACTION 2 with South East Asia, for a scholarship. We thank J?lia Bessa and Sara Cravo for technical support.

Senna tora is a widely used medicinal plant. Its health benefits have been attributed to the large quantity of anthraquinones, but how they are made in plants remains a mystery. To identify the genes responsible for plant anthraquinone biosynthesis, we reveal the genome sequence of S. tora at the chromosome level with 526 Mb (96%) assembled into 13 chromosomes. Comparison among related plant species shows that a chalcone synthase-like (CHS-L) gene family has lineage-specifically and rapidly expanded in S. tora . Combining genomics, transcriptomics, metabolomics, and biochemistry, we identify a CHS-L gene contributing to the biosynthesis of anthraquinones. The S. tora reference genome will accelerate the discovery of biologically active anthraquinone biosynthesis pathways in medicinal plants. Anthraquinones are aromatic polyketides and have been used for treating various diseases, but the biosynthetic pathway is unclear. Here, the authors assemble the genome of an anthraquinone-producing medicinal plant Senna tora and show the evidences that CHS-like genes may be involved in anthraquinone biosynthesis.

P2X receptors are trimeric ATP-gated ion channels. The P2X4 receptor subtype is a promising drug target for the treatment of inflammatory diseases, neuropathic pain, and cancer. Here, the water-soluble anthraquinone derivative Cibacron Blue, previously described as a P2X4 receptor modulator, is selected as a lead structure, and structure-activity relationships are investigated. A chimeric receptor approach, combined with mutagenesis and docking studies, is applied to identify the allosteric binding site and the interacting amino acid residues. We discover that Glu307, located in the upper body of the receptor, is prone to form an intermolecular “ionic lock” with basic amino acid residues, thereby preventing high-affinity binding of anthraquinone derivatives. Exchange of Glu307 for threonine leads to a dramatic potency increase for anthraquinones in blocking P2X4 receptor function. The structure of the human P2X4-E307T receptor in complex with the anthraquinone derivative PSB-0704 is determined by cryo-electron microscopy at a resolution of 3.35 Å. This reveals an allosteric binding site in the upper body at the interface of the receptor trimer subunits, which differs from previously described allosteric sites on P2X receptors. Our results provide a rational basis for structure-based drug design towards potent and selective P2X4 receptor antagonists. The P2X4 receptor, an ATP-activated ion channel, plays a role in chronic pain, inflammation, and cancer. Authors in this work discover an extracellular allosteric binding site that interacts with anthraquinone derivatives, and is narrowed by ionic lock formation.

Several natural products have been demonstrated to both enhance the anti-tumor efficacy and alleviate the side effects of conventional chemotherapy drugs. Rhein, a main constituent of the Chinese herb rhubarb, has been shown to induce apoptosis in various cancer types. However, the exact pharmacological mechanisms controlling the influence of Rhein on chemotherapy drug effects in pancreatic cancer (PC) remain largely undefined. In this study, we found that Rhein inhibited the growth and proliferation of PC cells through G1 phase cell cycle arrest. Moreover, Rhein induced caspase-dependent mitochondrial apoptosis of PC cells through inactivation of the PI3K/AKT pathway. Combination treatment of Rhein and oxaliplatin synergistically enhanced apoptosis of PC cells through increased generation of intracellular reactive oxygen species (ROS) and inactivation of the PI3K/AKT pathway. Pre-treatment with the ROS scavenger N-acetyl-L-cysteine attenuated the combined treatment-induced apoptosis and restored the level of phosphorylated AKT, indicating that ROS is an upstream regulator of the PI3K/AKT pathway. The combination therapy also exhibited stronger anti-tumor effects compared with single drug treatments . Taken together, these data demonstrate that Rhein can induce apoptosis and enhance the oxaliplatin sensitivity of PC cells, suggesting that Rhein may be an effective strategy to overcome drug resistance in the chemotherapeutic treatment of PC.

Anthraquinone dyes, which include an anthraquinone chromophore group, are the second-largest among dye classes, which is often employed in textile manufacturing. A significant number of anthraquinone dyes get into the environment, creating severe pollution since many of these dyes have intricate and stable structures. Currently, microbiological treatment of wastewater is an economically and feasibly viable solution for treating printing and dyeing wastewater, and there are growing reports of biodegradation of anthraquinone dyes. In this review, we outline the current advances in the biodegradation of anthraquinone dyes, summarizes dyes biodegradation by bacterial, fungal, and algae strains, factors influencing dyes biodegradation, current methods in enhancing dyes biodegradation, resuscitation of viable but non-culturable (VBNC) bacteria for better microbial performance, and potentials of VBNC bacteria in degrading dyes. Finally, future directions and important areas for study are given, and such efforts are anticipated to improve the anaerobic degradation process.

Electrocatalytic hydrogen peroxide (H 2 O 2 ) production via the two-electron oxygen reduction reaction is a promising alternative to the energy-intensive and high-pollution anthraquinone oxidation process. However, developing advanced electrocatalysts with high H 2 O 2 yield, selectivity, and durability is still challenging, because of the limited quantity and easy passivation of active sites on typical metal-containing catalysts, especially for the state-of-the-art single-atom ones. To address this, we report a graphene/mesoporous carbon composite for high-rate and high-efficiency 2e − oxygen reduction catalysis. The coordination of pyrrolic-N sites -modulates the adsorption configuration of the *OOH species to provide a kinetically favorable pathway for H 2 O 2 production. Consequently, the H 2 O 2 yield approaches 30 mol g −1 h −1 with a Faradaic efficiency of 80% and excellent durability, yielding a high H 2 O 2 concentration of 7.2 g L −1 . This strategy of manipulating the adsorption configuration of reactants with multiple non-metal active sites provides a strategy to design efficient and durable metal-free electrocatalyst for 2e − oxygen reduction. A graphene/mesoporous carbon composite presents rapid and efficient H2O2 electrosynthesis capability by two-electron oxygen reduction catalysis which is facilitated by the presence of multiple pyrrolic nitrogen dopants within the material.

Endophytic fungi represent a significant renewable resource for the discovery of pharmaceutically important compounds, offering substantial potential for new drug development. Their ability to address the growing issue of drug resistance has drawn attention from researchers seeking novel, nature-derived lead molecules that can be produced on a large scale to meet global demand. Recent advancements in genomics, metabolomics, bioinformatics, and improved cultivation techniques have significantly aided the identification and characterization of fungal endophytes and their metabolites. Current estimates suggest there are approximately 1.20 million fungal endophytes globally, yet only around 16% (190,000) have been identified and studied in detail. This underscores the vast untapped potential of fungal endophytes in pharmaceutical research. Research has increasingly focused on the transformation of bioactive compounds by fungal endophytes through chemical and enzymatic processes. A notable example is the anthraquinone derivative 6-O-methylalaternin, whose cytotoxic potential is enhanced by the addition of a hydroxyl group, sharing structural similarities with its parent compound macrosporin. These structure-bioactivity studies open up new avenues for developing safer and more effective therapeutic agents by synthesizing targeted derivatives. Despite the immense promise, challenges remain, particularly in the large-scale cultivation of fungal endophytes and in understanding the complexities of their biosynthetic pathways. Additionally, the genetic manipulation of endophytes for optimized metabolite production is still in its infancy. Future research should aim to overcome these limitations by focusing on more efficient cultivation methods and deeper exploration of fungal endophytes’ genetic and metabolic capabilities to fully harness their therapeutic potential. Graphical Abstract

Anthraquinones (AQs) are found in a variety of consumer products, including foods, nutritional supplements, drugs, and traditional medicines, and have a wide range of pharmacological actions. Rubiadin, a 1,3-dihydroxy-2-methyl anthraquinone, primarily originates from Linn (Rubiaceae). It was first discovered in 1981 and has been reported for many biological activities. However, no review has been reported so far to create awareness about this molecule and its role in future drug discovery. Therefore, the present review aimed to provide comprehensive evidence of Rubiadin's phytochemistry, biosynthesis, physicochemical properties, biological properties and therapeutic potential. Relevant literature was gathered from numerous scientific databases including PubMed, ScienceDirect, Scopus and Google Scholar between 1981 and up-to-date. The distribution of Rubiadin in numerous medicinal plants, as well as its method of isolation, synthesis, characterisation, physiochemical properties and possible biosynthesis pathways, was extensively covered in this review. Following a rigorous screening and tabulating, a thorough description of Rubiadin's biological properties was gathered, which were based on scientific evidences. Rubiadin fits all five of Lipinski's rule for drug-likeness properties. Then, the in depth physiochemical characteristics of Rubiadin were investigated. The simple technique for Rubiadin's isolation from and the procedure of synthesis was described. Rubiadin is also biosynthesized via the polyketide and chorismate/o-succinylbenzoic acid pathways. Rubiadin is a powerful molecule with anticancer, antiosteoporotic, hepatoprotective, neuroprotective, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antimalarial, antifungal, and antiviral properties. The mechanism of action for the majority of the pharmacological actions reported, however, is unknown. In addition to this review, an in silico molecular docking study was performed against proteins with PDB IDs: 3AOX, 6OLX, 6OSP, and 6SDC to support the anticancer properties of Rubiadin. The toxicity profile, pharmacokinetics and possible structural modifications were also described. Rubiadin was also proven to have the highest binding affinity to the targeted proteins in an in silico study; thus, we believe it may be a potential anticancer molecule. In order to present Rubiadin as a novel candidate for future therapeutic development, advanced studies on preclinical, clinical trials, bioavailability, permeability and administration of safe doses are necessary.