Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action

Copper is an endogenous metal ion that has been studied to prepare a new antitumoral agent with less side-effects. Copper is involved as a cofactor in several enzymes, in ROS production, in the promotion of tumor progression, metastasis, and angiogenesis, and has been found at high levels in serum and tissues of several types of human cancers. Under these circumstances, two strategies are commonly followed in the development of novel anticancer Copper-based drugs: the sequestration of free Copper ions and the synthesis of Copper complexes that trigger cell death. The latter strategy has been followed in the last 40 years and many reviews have covered the anticancer properties of a broad spectrum of Copper complexes, showing that the activity of these compounds is often multi factored. In this work, we would like to focus on the anticancer properties of mixed Cu(II) complexes bearing substituted or unsubstituted 1,10-phenanthroline based ligands and different classes of inorganic and organic auxiliary ligands. For each metal complex, information regarding the tested cell lines and the mechanistic studies will be reported and discussed. The exerted action mechanisms were presented according to the auxiliary ligand/s, the metallic centers, and the increasing complexity of the compound structures.

Apoplastic effector candidates of a foliar forest pathogen trigger cell death in host and non-host plants

Forests are under threat from pests, pathogens, and changing climate. A major forest pathogen worldwide is the hemibiotroph Dothistroma septosporum, which causes dothistroma needle blight (DNB) of pines. While D. septosporum uses effector proteins to facilitate host infection, it is currently unclear whether any of these effectors are recognised by immune receptors to activate the host immune system. Such information is needed to identify and select disease resistance against D. septosporum in pines. We predicted and investigated apoplastic D. septosporum candidate effectors (DsCEs) using bioinformatics and plant-based experiments. We discovered DsCEs that trigger cell death in the angiosperm Nicotiana spp., indicative of a hypersensitive defence response and suggesting their recognition by immune receptors in non-host plants. In a first for foliar forest pathogens, we developed a novel protein infiltration method to show that tissue-cultured pine shoots can respond with a cell death response to a DsCE, as well as to a reference cell death-inducing protein. The conservation of responses across plant taxa suggests that knowledge of pathogen–angiosperm interactions may also be relevant to pathogen–gymnosperm interactions. These results contribute to our understanding of forest pathogens and may ultimately provide clues to disease immunity in both commercial and natural forests.

Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells

Continuous treatment of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist of the anti-apoptotic protein Bcl-2, can result in resistance, which highlights the need for novel targets to trigger cell death in CLL. Venetoclax also induces autophagy by perturbing the Bcl-2/Beclin-1 complex, so autophagy might represent a target in CLL. Diverse autophagy inhibitors were assessed for cytotoxic activities against patient-derived CLL cells. The AMPK inhibitor dorsomorphin, the ULK1/2 inhibitor MRT68921, and the autophagosome–lysosome fusion inhibitor chloroquine demonstrated concentration-dependent and time-dependent cytotoxicity against CLL cells, even in those from hard-to-treat patients who carried del(11q) and del(17p). Dorsomorphin and MRT68921 but not chloroquine triggered caspase-dependent cell death. According to the metabolic activities of CLL cells and PBMCs following treatments with 10 µM dorsomorphin (13% vs. 84%), 10 µM MRT68921 (7% vs. 78%), and 25 µM chloroquine (41% vs. 107%), these autophagy inhibitors are selective toward CLL cells. In these CLL cells, venetoclax induced autophagy, and addition of dorsomorphin, MRT68921, or chloroquine showed potent synergistic cytotoxicities. Additionally, MRT68921 alone induced G2 arrest, but when combined with venetoclax, it triggered caspase-dependent cytotoxicity. These data provide the rationale to target autophagy and for autophagy inhibitors as potential treatments for patients with CLL.

Apoplastic effector candidates of a foliar forest pathogen trigger cell death in host and non-host plants

Forests are under threat from pests, pathogens, and changing climate. One of the major forest pathogens worldwide is Dothistroma septosporum, which causes dothistroma needle blight (DNB) of pines. D. septosporum is a hemibiotrophic fungus related to well-studied Dothideomycete pathogens, such as Cladosporium fulvum. These pathogens use small secreted proteins, termed effectors, to facilitate the infection of their hosts. The same effectors, however, can be recognised by plants carrying corresponding immune receptors, resulting in resistance responses. Hence, effectors are increasingly being exploited to identify and select disease resistance in crop species. In gymnosperms, however, such research is scarce. We predicted and investigated apoplastic D. septosporum candidate effectors (DsCEs) using bioinformatics and plant-based experiments. We discovered secreted proteins that trigger cell death in the angiosperm Nicotiana spp., suggesting their recognition by immune receptors in non-host plants. In a first for foliar forest pathogens, we also developed a novel protein infiltration method to show that tissue-cultured pine shoots can respond with a cell death response to one of our DsCEs, as well as to a reference cell death-inducing protein. These results contribute to our understanding of forest pathogens and may ultimately provide clues to disease immunity in both commercial and natural forests.

The Immunopathogenesis of Neuroinvasive Lesions of SARS-CoV-2 Infection in COVID-19 Patients

The new coronavirus disease COVID-19 was identified in December 2019. It subsequently spread across the world with over 125 M reported cases and 2.75 M deaths in 190 countries. COVID-19 causes severe respiratory distress; however, recent studies have reported neurological consequences of infection by the COVID-19 virus SARS-CoV-2 even in subjects with mild infection and no initial neurological effects. It is likely that the virus uses the olfactory nerve to reach the CNS and that this transport mechanism enables virus access to areas of the brain stem that regulates respiratory rhythm and may even trigger cell death by alteration of these neuronal nuclei. In addition, the long-term neuronal effects of COVID-19 suggest a role for SARS-CoV-2 in the development or progression of neurodegerative disease as a result of inflammation and/or hypercoagulation. In this review recent findings on the mechanism(s) by which SARS-CoV-2 accesses the CNS and induces neurological dysregulation are summarized.

The Role of Macrophages During Mammalian Tissue Remodeling and Regeneration Under Infectious and Non-Infectious Conditions

Several infectious pathologies in humans, such as tuberculosis or SARS-CoV-2, are responsible for tissue or lung damage, requiring regeneration. The regenerative capacity of adult mammals is limited to few organs. Critical injuries of non-regenerative organs trigger a repair process that leads to a definitive architectural and functional disruption, while superficial wounds result in scar formation. Tissue lesions in mammals, commonly studied under non-infectious conditions, trigger cell death at the site of the injury, as well as the production of danger signals favouring the massive recruitment of immune cells, particularly macrophages. Macrophages are also of paramount importance in infected injuries, characterized by the presence of pathogenic microorganisms, where they must respond to both infection and tissue damage. In this review, we compare the processes implicated in the tissue repair of non-infected versus infected injuries of two organs, the skeletal muscles and the lungs, focusing on the primary role of macrophages. We discuss also the negative impact of infection on the macrophage responses and the possible routes of investigation for new regenerative therapies to improve the recovery state as seen with COVID-19 patients.

Reactive Oxygen Species-Based Nanomaterials for Cancer Therapy

Nanotechnology advances in cancer therapy applications have led to the development of nanomaterials that generate cytotoxic reactive oxygen species (ROS) specifically in tumor cells. ROS act as a double-edged sword, as they can promote tumorigenesis and proliferation but also trigger cell death by enhancing intracellular oxidative stress. Various nanomaterials function by increasing ROS production in tumor cells and thereby disturbing their redox balance, leading to lipid peroxidation, and oxidative damage of DNA and proteins. In this review, we outline these mechanisms, summarize recent progress in ROS-based nanomaterials, including metal-based nanoparticles, organic nanomaterials, and chemotherapy drug-loaded nanoplatforms, and highlight their biomedical applications in cancer therapy as drug delivery systems (DDSs) or in combination with chemodynamic therapy (CDT), photodynamic therapy (PDT), or sonodynamic therapy (SDT). Finally, we discuss the advantages and limitations of current ROS-mediated nanomaterials used in cancer therapy and speculate on the future progress of this nanotechnology for oncological applications.