Triple-negative breast cancer (TNBC) stands out as the most formidable variant of breast cancer, predominantly affecting younger women and characterized by a bleak outlook and a high likelihood of spreading. The absence of safe and effective targeted treatments leaves standard cytotoxic chemotherapy as the primary option. The role of protein kinases, frequently altered in many cancers, is significant in the advancement and drug resistance of TNBC, making them a logical target for creating new, potent therapies against TNBC. Recently, an array of promising small molecules aimed at various kinases have been developed specifically for TNBC, with combination studies showing a synergistic improvement in combatting this condition. This review underscores the effectiveness of small molecule kinase inhibitors in battling the most lethal form of breast cancer and sheds light on prospective pathways for crafting novel treatments.

The complex process known as epithelial to mesenchymal transition (EMT) plays a fundamental role in several biological settings, encompassing embryonic development, wound healing, and pathological conditions such as cancer and fibrosis. In recent years, a bulk of research has brought to light the key role of copper, a trace element with essential functions in cellular metabolism, cancer initiation and progression. Indeed, copper, besides functioning as cofactor of enzymes required for essential cellular processes, such as energy production and oxidation reactions, has emerged as an allosteric regulator of kinases whose activity is required to fulfill cancer dissemination through the EMT. In this comprehensive review, we try to describe the intricate relationship between the transition metal copper and EMT, spanning from the earliest foundational studies to the latest advancements. Our aim is to shed light on the multifaceted roles undertaken by copper in EMT in cancer and to unveil the diverse mechanisms by which copper homeostasis exerts its influence over EMT regulators, signaling pathways, cell metabolic reprogramming and transcription factors ultimately contributing to the spread of cancer. Therefore, this review not only may contribute to a deeper comprehension of copper-mediated mechanisms in EMT but also supports the hypothesis that targeting copper may contribute to counteract the progression of EMT-associated pathologies.

The accuracy of cell division requires precise regulation of the cellular machinery governing DNA/genome duplication, ensuring its equal distribution among the daughter cells. The control of the centrosome cycle is crucial for the formation of a bipolar spindle, ensuring error-free segregation of the genome. The cell and centrosome cycles operate in close synchrony along similar principles. Both require a single duplication round in every cell cycle, and both are controlled by the activity of key protein kinases. Nevertheless, our comprehension of the precise cellular mechanisms and critical regulators synchronizing these two cycles remains poorly defined. Here, we present our hypothesis that the spatiotemporal regulation of a dynamic equilibrium of mitotic kinases activities forms a molecular clock that governs the synchronous progression of both the cell and the centrosome cycles.

Since the initial identification of oncogenic Wnt in mice and Drosophila, the Wnt signaling pathway has been subjected to thorough and extensive investigation. Persistent activation of Wnt signaling exerts diverse cancer characteristics, encompassing tumor initiation, tumor growth, cell senescence, cell death, differentiation, and metastasis. Here we review the principal signaling mechanisms and the regulatory influence of pathway-intrinsic and extrinsic kinases on cancer progression. Additionally, we underscore the divergences and intricate interplays of the canonical and non-canonical Wnt signaling pathways and their critical influence in cancer pathophysiology, exhibiting both growth-promoting and growth-suppressing roles across diverse cancer types.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine secreted by the pineal gland during the dark phase of the photoperiod. Its main function is the synchronization of different body rhythms with the dark-light cycle. Research on melatonin has significantly advanced since its discovery and we now know that it has considerable significance in various physiological processes, including immunity, aging, and reproduction. Moreover, in recent years evidence of the pharmacological possibilities of melatonin has increased. Indoleamine, on the other hand, has antidepressant-like effects in rodents, which may be mediated by the activation of calcium-calmodulin-dependent kinase II (CaMKII) and are also related to the regulation of neuroplasticity processes, including neurogenesis, synaptic maintenance, and long-term potentiation. Remarkably, patients with major depression show decreased levels of circulating melatonin in plasma. This review presents evidence of the antidepressant-like effects of melatonin in preclinical models and the participation of CaMKII in these actions. CaMKII\'s role in cognition and memory processes, which are altered in depressive states, are part of the review, and the effects of melatonin in these processes are also reviewed. Furthermore, participation of CaMKII on structural and synaptic plasticity and the effects of melatonin are also described. Finally, the advantages of using melatonin in combination with other antidepressants such as ketamine for neuroplasticity are described. Evidence supports that CaMKII is activated by melatonin and downstream melatonin receptors and may be the common effector in the synergistic effects of melatonin with other antidepressants. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin causes antidepressant-like effects in mice through calmodulin kinase II stimulation of downstream melatonin receptors as well as the participation of this enzyme in neuroplasticity, memory, and cognition. Finally, we describe evidence about the effectiveness of antidepressant-like effects of melatonin in combination with ketamine.

Protein S-acylation or palmitoylation is a reversible post-translational modification that influences many proteins encoded in plant genomes. Exciting progress in the past 3 years demonstrates that S-acylation modulates subcellular localization, interacting profiles, activity, or turnover of substrate proteins in plants, participating in developmental processes and responses to abiotic or biotic stresses. In this review, we summarize and discuss the role of S-acylation in the targeting of substrate proteins. We highlight complex roles of S-acylation in receptor signaling. We also point out that feedbacks of protein S-acyl transferase by signaling initiated from their substrate proteins may be a recurring theme. Finally, the reversibility of S-acylation makes it a rapid and efficient way to respond to environmental cues. Future efforts on exploring these important aspects of S-acylation will give a better understanding of how plants enhance their fitness under ever changing and often harsh environments.

Cyclin-dependent kinase 7 is an attractive therapeutic target for the treatment of cancers, and a previous report suggested that Plasmodium falciparum CDK7 is a potential drug target for developing new anti-malarial drugs. In this study, we aimed to characterize and evaluate the drug target potential of Theileria annulata CDK7. Theileria annulata is responsible for tropical theileriosis, which induces a phenotype similar to cancerous cells like immortalization, hyperproliferation, and dissemination. Virtual screening of the MyriaScreen II library predicted 14 compounds with high binding energies to the ATP-binding pocket of TaCDK7. Three compounds (cimicifugin, ST092793, and ST026925) of these 14 compounds were non-cytotoxic to the uninfected bovine cells (BoMac cells). Cimicifugin treatment led to the activation of the extrinsic apoptosis pathway and induced autophagy in T. annulata-infected cells. Furthermore, cimicifugin also inhibited the growth of P. falciparum, indicating that it has both anti-theilerial and anti-malarial activities and that TaCDK7 and PfCDK7 are promising drug targets.

Integration of the DNA copy of HIV-1 genome into the cellular genome results in series of damages, repair of which is critical for successful replication of the virus. We have previously demonstrated that the ATM and DNA-PK kinases, normally responsible for repairing double-strand breaks in the cellular DNA, are required to initiate the HIV-1 DNA postintegrational repair, even though integration does not result in DNA double-strand breaks. In this study, we analyzed changes in phosphorylation status of ATM (pSer1981), DNA-PK (pSer2056), and their related kinase ATR (pSer428), as well as their targets: Chk1 (pSer345), Chk2 (pThr68), H2AX (pSer139), and p53 (pSer15) during the HIV-1 DNA postintegrational repair. We have shown that ATM and DNA-PK, but not ATR, undergo autophosphorylation during postintegrational DNA repair and phosphorylate their target proteins Chk2 and H2AX. These data indicate common signaling mechanisms between the double-strand DNA break repair and postintegrational repair of HIV-1 DNA.

The prevalence of diabetes is increasing worldwide. Massive death of pancreatic beta-cells causes type 1 diabetes. Progressive loss of beta-cell function and mass characterizes type 2 diabetes. To date, none of the available antidiabetic drugs promotes the maintenance of a functional mass of endogenous beta-cells, revealing an unmet medical need. Dysfunction and apoptotic death of beta-cells occur, in particular, through the activation of intracellular protein kinases. In recent years, protein kinases have become highly studied targets of the pharmaceutical industry for drug development. A number of drugs that inhibit protein kinases have been approved for the treatment of cancers. The question of whether safe drugs that inhibit protein kinase activity can be developed and used to protect the function and survival of beta-cells in diabetes is still unresolved. This review presents arguments suggesting that several protein kinases in beta-cells may represent targets of interest for the development of drugs to treat diabetes.

Endothelial dysfunction has been associated with devastating outcomes which can eventually lead to permanent disability and death. Elucidation of the meticulously devised network orchestrating endothelial responses, provides information to develop new therapies towards endothelial-related disorders. NEK kinases - which have been involved in the development of human disease - promote vascular leak; suggesting the possibility that their inhibition may ameliorate medical conditions related to barrier derangement.