Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cance Show more
Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cancer development, progression, and resistance to therapy. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-antioxidant response element (ARE) signaling pathway is central to maintaining redox balance by regulating the expression of antioxidant and detoxification genes. Under physiological conditions, this pathway protects cells from oxidative damage, however, sustained activation of NRF2 in cancer, often due to mutations in KEAP1, supports tumor cell survival, drug resistance, and metabolic reprogramming. Recent studies demonstrate that NRF2 enhances glutathione (GSH) synthesis, induces detoxifying enzymes, and upregulates drug efflux transporters, collectively contributing to resistance against chemotherapy and targeted therapies. The inhibition of NRF2 using small molecules or dietary phytochemicals has shown promise in restoring drug sensitivity in preclinical cancer models. This review highlights the dual role of NRF2 in redox regulation and cancer therapy, emphasizing its potential as a therapeutic target. While targeting NRF2 offers a novel approach to overcoming treatment resistance, further research is needed to enhance specificity and facilitate clinical translation. Show less
Abstract Transition metal complexes have been widely utilized as cellular imaging tools. To impart organelle specificity, ligand architecture is usually modified to modulate properties like overall ch Show more
Abstract Transition metal complexes have been widely utilized as cellular imaging tools. To impart organelle specificity, ligand architecture is usually modified to modulate properties like overall charge and lipophilicity. In many such designs, the metal identity and its intrinsic properties are often ignored. To address this gap, in this study, we explored the effects of changing the metal center on the localization patterns of isostructural complexes. To this end, we employed the thiosemicarbazone Dp44mT to synthesize coumarinâconjugated complexes of Au(III), Pt(II), and Pd(II). Although the metal centers in these compounds share a formal d 8 configuration, they differ in properties such as ionic radius, charge density, and ligand exchange rates, which can affect their subcellular localization patterns. In addition, we synthesized a second set of analogous complexes using BODIPY as the conjugating fluorophore to assess the influence of using a different dye on the cellular distribution. Confocal imaging revealed that the complexes exhibited distinct intracellular distributions. For instance, while the coumarinâconjugated Pt(II) complex localized specifically in lysosomes, the corresponding lipophilic Pd(II) complex lacked this specificity and instead followed a diffusely cytosolic distribution. Similarly, the more lipophilic BODIPY conjugated complexes were nonâspecific in their cellular distribution as well. Overall, the findings of this study highlight the interplay of metal identity and lipophilicity in determining the localization patterns of Dp44mTâbased metal complexes, offering fresh insights into the design of new metalâbased imaging tools. Show less
Tumor metastases account for nearly 90% of cancer-related fatalities. To tackle this issue, chemotherapeutic agents that induce immunogenic cell death (ICD) are being investigated as promising candida Show more
Tumor metastases account for nearly 90% of cancer-related fatalities. To tackle this issue, chemotherapeutic agents that induce immunogenic cell death (ICD) are being investigated as promising candidates for metastatic cancer treatment. Herein, the chemical synthesis and biological evaluation of a novel Ga(III) complex with Schiff bases, [Ga((E)-1-((quinolin-8-ylimino)methyl)naphthalen-2-olato)2][Cl], for potential use in combined chemotherapy and immunotherapy are reported. This compound exhibited broad cytotoxicity against human breast cancer, pancreatic cancer, cervical cancer cell lines, and the noncancerous human fibroblast cell line. Mechanistic investigations revealed that the compound triggers apoptosis and ICD hallmarks, such as translocation of calreticulin, phosphorylation of eIF2α, migration of high mobility group protein 1, and release of adenosine triphosphate. Deeper biological assessment using multicellular tumor spheroids of cervical cancer cell lines, a solid tumor model, demonstrated successful eradication at micromolar concentrations. This study presents one of the few reported Ga(III) complexes capable of inducing immunogenic cell death. Show less
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism t Show more
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Show less
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potenti Show more
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation â and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration. Show less