Theodore Lemuel Mathuram

Aquaporins (AQPs) are a conserved family of transmembrane channel proteins that facilitate the selective transport of water, glycerol, and small solutes, thereby playing a pivotal role in maintaining cellular homeostasis. Beyond their classical role in fluid regulation, AQPs have emerged as key modulators of redox biology and cancer progression through their ability to transport hydrogen peroxide (H2O2), a central signaling molecule in oxidative stress. This redox-regulatory function, mediated predominantly by peroxiporins such as AQP3, AQP5, AQP8, and AQP9, influences diverse cellular outcomes including proliferation, apoptosis, migration, and stress adaptation. In cancer, dysregulated expression of AQPs has been linked to enhanced invasiveness, angiogenesis, and stemness, positioning them as critical drivers of tumor progression and potential therapeutic targets. Recent evidence highlights the clinical relevance of AQPs, with pharmacological inhibitors such as AqB013, Bacopasides, and small-molecule blockers under investigation for attenuating tumor growth and redox imbalance. Additionally, corticosteroid-mediated regulation of AQP3 and vasopressininduced trafficking of AQP2 illustrate the broader integration of AQPs within hormonal and inflammatory signaling pathways. By mediating water and reactive oxygen species flux across membranes, AQPs serve as gatekeepers of osmotic and oxidative balance at both the cellular and organ levels. This review synthesizes emerging insights into the mechanistic roles of AQPs in oxidative stress mitigation and tumor biology, while evaluating their translational potential as therapeutic targets. Understanding the dual role of AQPs in maintaining redox homeostasis and driving oncogenic signaling offers new opportunities for clinical intervention in cancer and oxidative stress-related pathologies.

Protein kinases play a pivotal role in regulating cellular functions and signaling pathways, with over 530 kinase genes identified in the human genome. Traditional drug discovery targeting kinases is a lengthy and costly process, often exceeding 15 years and $1 billion. However, artificial intelligence (AI) offers transformative potential to streamline this pipeline by accelerating target identification, validation, and drug design. AI-driven methodologies such as machine learning, deep learning, and natural language processing have revolutionized preclinical drug discovery, enabling rapid identification of drug candidates, structural predictions, and binding affinity assessments. Tools such as AlphaFold2, OnionNet-2, and Deeply Tough illustrate AI’s role in structural and virtual screening of drugs. AI has also significantly impacted clinical trials through digital twinning, patient recruitment optimization, and real-time monitoring, enhancing trial efficiency and precision. Currently, 75 AI-powered drugs are in various clinical phases, with notable successes in novel target identification and drug repurposing. Despite its promise, AI in drug discovery faces challenges such as ethical concerns, data quality, and substantial investment requirements. Looking ahead, advances in organoid intelligence and biocomputing hold promise for a future where AI-driven innovation accelerates drug discovery, enhances precision medicine, and transforms the pharmaceutical landscape.

Background: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase known to participate in the regulation of β-catenin signaling ( Wnt signaling). This aids in the establishment of a multicomponent destruction complex that stimulates phosphorylation, leading to the destruction of β-catenin. Evidence about the role of increasingly active β-catenin signaling is involved in many forms of human cancer. The understanding of GSK-3 remains elusive as recent research aims to focus on developing potent GSK-3 inhibitors to target this kinase. Objective: This short review aims to highlight the regulation of GSK-3 with emphasis on Wnt signaling while highlighting its interaction with miRNAs corresponding to pluripotency and epithelial mesenchymal transition substantiating this kinase as an “Ace” among kinases in regulation of cellular processes. Result: Significant findings of miRNA regulation by GSK-3 exemplify the underpinnings of kinase-mediated transcriptional regulation in cancers. Conclusion: The review provides evidence on the role of GSK-3 as a possible master regulator of proteins and noncoding RNA, thereby implicating the fate of a cell.

Rationale: We showed that levels of a murine mitochondrial noncoding RNA, mito-ncR-LDL805 , increase in alveolar epithelial type 2 cells exposed to extracts from cigarette smoke. The transcripts translocate to the nucleus, upregulating nucleus-encoded mitochondrial genes and mitochondrial bioenergetics. This response is lost after chronic exposure to smoke in a mouse model of chronic obstructive pulmonary disease. Objectives: To determine if mito-ncR-LDL805 plays a role in human disease, this study aimed to (i) identify the human homologue, (ii) test if the smoke-induced response occurs in human cells, (ii) determine causality between the subcellular localization of the transcript and increased mitochondrial bioenergetics, and (iii) analyze mito-ncR-LDL805 transcript levels in samples from patients with chronic obstructive pulmonary disease. Methods: Levels and subcellular localization of the human homologue identified from an RNA transcript library were assessed in human alveolar epithelial type 2 cells exposed to smoke extract. Lipid nanoparticles were used for nucleus-targeted delivery of mito-ncR-LDL805 transcripts. Analyses included in situ hybridization, quantitative PCR, cell growth, and Seahorse mitochondrial bioenergetics assays. Measurements and Main Results: The levels of human homologue transiently increased and the transcripts translocated to the nuclei in human cells exposed to smoke extract. Targeted nuclear delivery of transcripts increased mitochondrial bioenergetics. Alveolar cells from humans with chronic obstructive pulmonary disease had reduced levels of the mito-ncR-LDL805 . Conclusions: mito-ncR-LDL805 mediates mitochondrial bioenergetics in murine and human alveolar epithelial type 2 cells in response to cigarette smoke exposure, but this response is likely lost in diseases associated with chronic smoking, such as chronic obstructive pulmonary disease, due to its diminished levels. Impact: This study describes a novel mechanism by which epithelial cells in the lungs adapt to the mitochondrial stress triggered by exposure to cigarette smoke. We show that a noncoding RNA in mitochondria is upregulated and translocated to the nuclei of alveolar epithelial type 2 cells to trigger expression of genes that restore mitochondrial bioenergetics. Mitochondria function and levels of the noncoding RNA decrease under conditions that lead to chronic obstructive pulmonary disease, suggesting that the mitochondrial noncoding RNA can serve as potential therapeutic target to restore function to halt disease progression.

REV-ERB agonists have shown antifibrotic effects in the heart and other organs. The function of REV-ERB in the cardiac fibroblasts remains unstudied. Here, we characterize the functional difference of REV-ERB in mouse embryonic fibroblasts and cardiac fibroblasts using genetic deletion of REV-ERBα and ß in vitro. We show that REV-ERB α/β double deleted cardiac fibroblasts have reduced viability and proliferation, but increased migration and myofibroblasts activation. Thus, REV-ERB α/β has essential cell-autonomous role in cardiac fibroblasts in maintaining them in a healthy, quiescent state. We also show that existing REV-ERB agonist SR9009 strongly suppresses cardiac fibroblasts activation but in a REV-ERB-independent manner highlighting the need to develop novel REV-ERB agonists for treating cardiac fibrosis.