Malaria elimination urgently needs novel antimalarial therapies that transcend resistance, toxicity, and high costs. Our multicentric international collaborative team focuses on developing multistage antimalarials that exhibit novel mechanisms of action. Here, we describe the design, synthesis, and evaluation of a novel multistage antimalarial compound, ‘Calxinin’. A compound that consists of hydroxyethylamine (HEA) and trifluoromethyl-benzyl-piperazine. Calxinin exhibits potent inhibitory activity in the nanomolar range against the asexual blood stages of drug-sensitive (3D7), multidrug-resistant (Dd2), artemisinin-resistant (IPC4912), and fresh Kenyan field isolated Plasmodium falciparum strains. Calxinin treatment resulted in diminished maturation of parasite sexual precursor cells (gametocytes) accompanied by distorted parasite morphology. Further, in vitro liver-stage testing with a mouse model showed reduced parasite load at an IC₅₀ of 79 nM. A single dose (10 mg/kg) of Calxinin resulted in a 30% reduction in parasitemia in mice infected with a chloroquine-resistant strain of the rodent parasite P. berghei. The ex vivo ookinete inhibitory concentration within mosquito gut IC₅₀ was 150 nM. Cellular in vitro toxicity assays in the primary and immortalized human cell lines did not show cytotoxicity. A computational protein target identification pipeline identified a putative P. falciparum membrane protein (Pf3D7_1313500) involved in parasite calcium (Ca²⁺) homeostasis as a potential Calxinin target. This highly conserved protein is related to the family of transient receptor potential cation channels (TRP-ML). Target validation experiments showed that exposure of parasitized RBCs (pRBCs) to Calxinin induces a rapid release of intracellular Ca²⁺ from pRBCs; leaving de-calcinated parasites trapped in RBCs. Overall, we demonstrated that Calxinin is a promising antimalarial lead compound with a novel mechanism of action and with potential therapeutic, prophylactic, and transmission-blocking properties against parasites resistant to current antimalarials.

Pathogenic forms of α-synuclein (α-syn) are transferred to and from neurons, astrocytes, and microglia, which spread α-syn pathology in the olfactory bulb and the gut and then throughout the Parkinson’s disease (PD) brain and exacerbate neurodegenerative processes. Here, we review attempts to minimize or ameliorate the pathogenic effects of α-syn or deliver therapeutic cargo into the brain. Exosomes (EXs) have several important advantages as carriers of therapeutic agents including an ability to readily cross the blood–brain barrier, the potential for targeted delivery of therapeutic agents, and immune resistance. Diverse cargo can be loaded via various methods, which are reviewed herein, into EXs and delivered into the brain. Genetic modification of EX-producing cells or EXs and chemical modification of EX have emerged as powerful approaches for the targeted delivery of therapeutic agents to treat PD. Thus, EXs hold great promise for the development of next-generation therapeutics for the treatment of PD.

Parkinson’s disease (PD) is an aging-related neurodegenerative disease characterized by a progressive loss of dopamine (DA)-secreting neurons in the substantia nigra. Most of the currently available treatments attempt to alleviate the disease symptoms by increasing DA transmission in the brain and are associated with unpleasant side effects. Since there are no treatments that modify the course of PD or regenerate DA neurons, identifying therapeutic strategies that slow, stop, or reverse cell death in PD is of critical importance. Here, factors that confer vulnerability of substantia nigra DA neurons to cell death and the primary mechanisms of PD pathogenesis, including cellular senescence, a cellular stress response that elicits a stable cell cycle arrest in mitotic cells and profound phenotypic changes including the implementation of a pro-inflammatory secretome, are reviewed. Additionally, a discussion of the characteristics, mechanisms, and markers of cellular senescence and the development of approaches to target senescent cells, referred to as senotherapeutics, is included. Although the senotherapeutics curcumin, fisetin, GSK-650394, and astragaloside IV had disease-modifying effects in in vitro and in vivo models of PD, the potential long-term side effects of these compounds remain unclear. It remains to be elucidated whether their beneficial effects will translate to non-human primate models and/or human PD patients. The enhanced selectivity, safety, and/or efficacy of next generation senotherapeutic strategies including senolytic peptides, senoreverters, proteolysis-targeting chimeras, pro-drugs, immunotherapy, and nanoparticles will also be reviewed. Although these next generation senotherapeutics may have advantages, none have been tried in models of PD.

Membrane-enclosed particles, known as extracellular vesicles (EVs), are ubiquitously present in organisms, including animals, plants, and microorganisms

Cardiovascular diseases remain a major cause of death and disability, and the limited regenerative capacity of the adult myocardium continues to constrain recovery after myocardial infarction, ischemia/reperfusion injury, cardiomyopathy, and heart failure. Small extracellular vesicles (sEVs), often described as exosome-enriched vesicle preparations, have emerged as promising cell-free mediators of cardioprotection and cardiac repair. This review evaluates the current experimental and translational evidence on sEVs in cardiac injury, including regulatory RNA and non-RNA cargo mechanisms, producer cell sources, preclinical injury models, engineered and biomaterial-assisted delivery strategies, and the development of clinically viable cell-free therapies. Across preclinical models, sEVs derived from mesenchymal stem cells, induced pluripotent stem cell-derived cardiac cells, cardiac progenitor cells, endothelial cells, cardiomyocytes, immune cells, and other sources have been associated with improved ventricular function, reduced infarct or scar size, enhanced angiogenesis, lower apoptosis, attenuated fibrosis, and modulation of post-injury inflammation. These effects are frequently associated with changes in, or enrichment of, microRNAs, long non-coding RNAs, and circular RNAs that regulate survival signaling, immune polarization, extracellular matrix remodeling, and endothelial recovery. Emerging evidence further suggests that proteins, lipids, and organelle-associated cargo, including mitochondrial components, also contribute to stress adaptation, vesicle biogenesis, mitochondrial homeostasis, and metabolic repair. However, the field remains limited by inconsistent nomenclature, variable isolation and characterization methods, heterogeneous producer cell sources, uncertain potency assays, incomplete biodistribution data, and unresolved regulatory classification. Overall, sEV-based therapy represents a compelling but still developing approach to cardiac repair. Within this framework, functional recovery is treated as an outcome of cardioprotection, cardiac repair, or, where supported, myocardial regeneration; regeneration is reserved for evidence of newly formed and functionally integrated myocardium. Future progress will depend on better product definition, mechanism-linked potency testing, scalable manufacturing, and delivery strategies matched to specific cardiac indications.