The rapid growth and accessibility of artificial intelligence (AI) and machine learning (ML) have opened many avenues to revolutionize biomedical research, particularly in oncogenesis. Oncogenesis is a hallmark process in the development of cancer, involving the amplification of proto-oncogenes and the subsequent dysregulation of molecular signaling networks. These pathways-including the RAS/RAF/MEK/ERK, PI3K-AKT, JAK-STAT, TGF-β/Smad, Wnt/β-Catenin, and Notch cascades-have been studied extensively in isolation, with major strides achieved in understanding how they drive cancer. However, there are still many considerations regarding how these networks interact. Ongoing studies show that crosstalk among these pathways occurs through feedback loops, shared intermediates, and compensatory activation, creating a complex network that enables tumor cells to adapt and metastasize. New developments in AI and ML have enabled modeling and prediction of these interactions for pathway discovery, mapping oncogenic crosstalk, predicting drug resistance and therapeutic responses, and complex data analysis. Novel technologies such as feature selection algorithms and convolutional neural networks have demonstrated immense translational potential to bridge computational predictions in cancer genomics with clinical applications. Similar models have also proven useful for learning from genomic datasets and reducing multidimensionality in heterogeneous multiomics data. As current AI/ML approaches continue to develop, it is also important to consider the limitations of batch effects, model generalizability, and potential bias in training datasets. This review aims to integrate the most recent AI and ML applications in uncovering the hidden interactions within oncogenic networks that drive tumorigenesis, heterogeneity, and resistance to therapies. Moreover, this review aims to synthesize the functionality of emerging computational methods that elucidate these insights, as well as the transformative implications of AI-guided systems biology on precision oncology and combinatorial therapies.

BACKGROUND: Curcumin, a natural compound found in turmeric (Curcuma longa), demonstrates anticancer properties; however, it is characterized by poor bioavailability and stability. This study investigates the stability, antioxidant activity, and anticancer effects of two monocarbonyl analogs of curcumin (MACs), C66 and B2BrBC, in in vitro breast cancer models. METHODS: Stability and antioxidant activity of C66 and B2BrBC were assessed using spectrophotometric assays. Their effects on breast cancer cells (MCF-7, BT-474, MDA-MB-231) were evaluated through MTT assay, wound-healing assay, and caspase-3 fluorescence microscopy. EMT modulation was examined via RT-qPCR, Western blot, and immunofluorescence analyses. A MILLIPLEX protein assay was used to analyze cancer metastasis-related protein expression. RESULTS: C66 and B2BrBC demonstrated enhanced stability compared to curcumin. Both compounds significantly reduced breast cancer cell viability and migration, with B2BrBC showing higher potency. They effectively suppressed EMT, reversing EMT-inducer effects on epithelial and mesenchymal markers. C66 and B2BrBC modulated the expression of several metastasis-related proteins, including DKK1, OPG, and GDF15, in a cell line-dependent manner. CONCLUSIONS: C66 and B2BrBC exhibit improved stability and potent anticancer effects in breast cancer cells, effectively inhibiting cell viability, migration, and EMT. These compounds show promise as potential therapeutic agents for breast cancer, warranting further investigation in in vivo models.

Breast cancer is the most frequently diagnosed malignancy among women worldwide, with 2.3 million new cases and approximately 670,000 deaths reported in 2022 alone. Despite advances in therapy, metastasis and acquired drug resistance remain major clinical challenges. Reactive oxygen species (ROS) play a dual role in breast cancer biology: physiological levels sustain normal cellular signaling, moderately elevated levels promote tumorigenesis through DNA damage, proto-oncogene activation, and tumor suppressor inactivation, while excessive accumulation can trigger cancer cell death. This review examines how redox dysregulation contributes to breast cancer initiation and progression through key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2), as well as apoptotic cascades. We evaluate the evidence for dietary and synthetic antioxidants-melatonin, curcumin, vitamins C and E, and carotenoids-as chemopreventive and adjuvant agents, highlighting both their therapeutic promise and the conflicting data on their safety during cancer treatment. We further discuss emerging ROS-responsive nanoagents for targeted drug delivery and immunotherapy, and strategies to exploit redox vulnerabilities in multidrug-resistant breast cancer cells, including induction of ferroptosis, an iron-dependent cell death pathway driven by lipid peroxide accumulation that has emerged as a promising vulnerability in therapy-resistant and mesenchymal-phenotype tumors. Recent advances in machine learning and multi-omics integration, which have begun to identify redox-related gene signatures with prognostic and immunotherapy-predictive value, further point toward precision redox oncology as an emerging clinically actionable framework. By integrating molecular mechanisms with translational advances, this review identifies current gaps and future directions for ROS-targeted therapeutic strategies in breast cancer.

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (IKr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death.

Curcumin is a polyphenolic bio-compound derived from the rhizomes of the turmeric plant (Curcuma longa) that has proven anti-carcinogenic properties but poor bioavailability. By modifying its chemical structure, the monocarbonyl analogs of curcumin (MACs) possess improved stability, resorption, and circulation. This dataset presents RT-qPCR array analysis of 84 genes associated with Epithelial to Mesenchymal Transition (EMT), a key early event in cancer progression and metastasis, in human MCF-7 breast cancer cells. Cells were stimulated toward EMT reprogramming by treatment with a combination of EMT-inducing factors and co-treated with two experimental MACs, C66 or B2BrBC. Gene expression was measured using the human EMT QIAGEN RT2 Profiler kit, and results were obtained from three independent experiments. Gene expression changes are presented as both fold regulation and fold change values, with statistical significance determined by Student’s t-test (p < 0.05). This comprehensive dataset enables investigation into how MACs modulate the EMT transcriptome in breast cancer cells, with potential applications for understanding EMT mechanisms. The raw and processed data are publicly available and can be used for comparative analyses, validation studies, and bioinformatic analyses of EMT-related signaling pathways.

Purpose: We hypothesized that the curcumin analogs C66 and B2BrBC influenced inflammation in cancer cells by modulating free radical production and oxidative stress. Methods: We tested human breast cancer epithelial MDA-MB-231 and non-cancerous MCF-10 A cells. Results: The tested compounds significantly increased lipid peroxidation (TBARS) in both cell lines; curcumin induced a stronger effect in MDA-MB-231, C66 in MCF-10 A, and B2BrBC showed pronounced prooxidant activity in both cell lines. The baseline antioxidant activity (AOA) was higher in MCF-10 A cells. Curcumin exhibited limited or even suppressive effects, whereas C66 and B2BrBC markedly enhanced AOA in both cell lines, with a stronger effect observed in MCF-10 A cells. Curcumin and its analogs strongly enhanced superoxide dismutase (SOD) activity in MDA-MB-231 cancer cells but suppressed SOD activity in non-tumorigenic MCF-10 A cells. They exerted opposite effects on catalase (CAT) activity: strong suppression in MCF-10 A cells but a marked increase in MDA-MB-231 cells. Glutathione Reductase (GR) activity was substantially enhanced in both cell lines, with MCF-10 A showing the strongest response to B2BrBC, and MDA-MB-231 cells showing the strongest response to C66. Conclusions: Curcumin, C66, and B2BrBC modulated oxidative stress in a cell type-specific manner. MDA-MB-231 cells showed upregulation of the antioxidant enzyme activity. This highlights the potential of these analogs to regulate the redox balance in cancer cells.

Lipid metabolism and lipid-derived signaling together ensure cellular and systemic homeostasis. Their dysregulation causes obesity, type 2 diabetes, cardiovascular disease, NAFLD/MASH, and neurodegeneration throughout life. This review integrates central pathways, such as ACC-FASN-mediated de novo lipogenesis, lipid-droplet lipolysis, and mitochondrial and peroxisomal β-oxidation, and their regulation by insulin-PI3K-Akt, glucagon-cAMP-PKA, SREBPs, PPARs, and AMPK. We emphasize the mechanisms by which bioactive lipids like diacylglycerols, ceramides, eicosanoids, and endocannabinoids serve as second messengers linking nutrient state to insulin signaling, inflammation, and stress response; pathologic accumulation of these species enhances insulin resistance and lipotoxicity. Aging disrupts these axes via diminished catecholamine-stimulated lipolysis, defective fatty-acid oxidation, mitochondrial failure, and adipose depot redistribution, facilitating ectopic fat and postprandial dyslipidemia. We suggest a pathway-to-phenotype paradigm that connects lipid species and tissue environment to clinical phenotypes, allowing for mechanism-to-intervention alignment. Therapeutic avenues range from lipid lowering for atherogenic risk to novel agents targeting ACLY, ACC, FASN, CPT1, and nuclear receptors, with precision lifestyle intervention in diet and exercise. Translation is still heterogeneous because of isoform-dependent effects, safety trade-offs, and inconsistent adherence. We prioritize harmonization of lipidomics with multi-omics for stratifying patients, enriching responders, and bridging gaps between mechanistic understanding and clinical outcome, with focus on age-sensitive prevention and treatment for lipid-mediated metabolic disease.

Obesity and its related disorders, such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), represent a worldwide health challenge, which is driven primarily by the dysfunction of the adipose tissue–gut–liver axis. This article compiles mechanistic and translational data on curcumin and its analogs as multi-organ regulators targeting this axis. Curcumin plays a pleiotropic role by modulating adipogenesis, lipid metabolism, inflammation, fibrosis, and thermogenic remodeling in adipose tissue, tailoring gut microbial diversity, gut barrier integrity, and metabolic endotoxemia. Curcumin in the liver attenuates steatosis, oxidation, and fibrosis by inhibiting lipogenesis, increasing β-oxidation, and modulating the NF-κB and TGF-β signal pathways. These actions result in overall systemic insulin sensitivity and energy balance. On the contrary, the clinical application of curcumin is restricted due to its low solubility, instability, and poor bioavailability. New formulations (nanoparticles/liposomes/micelles) together with structurally enhanced analogs such as tetrahydrocurcumin and monocarbonyl analogs (C66, B2BrBC) exhibited superior pharmacokinetic and tissue-targeting properties in preclinical models. Pilot and randomized clinical trials suggest that curcumin supplementation enhances glucose and lipid metabolism, reduces liver fat content, and modulates inflammatory markers; however, results across studies remain heterogeneous. Large, high-quality multicenter trials using rigorously standardized, bioavailable curcumin formulations are still required to reliably establish the efficacy and safety of curcumin in metabolic diseases. Next steps involve comparing curcumin analogs, conducting multi-omics analyses to understand host–microbiota–organ crosstalk, and determining cooperative approaches with lifestyle and pharmacological interventions. Taken together, curcumin and its next-generation derivatives may offer a novel therapeutic approach to intervene in the adipose tissue–gut–liver axis for the treatment of obesity-related metabolic diseases.

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.

Recent studies in cardiac biology have identified a complex interplay between the Hippo, Wnt/β-catenin, and Notch signaling pathways, establishing an integrated regulatory network that influences cardiac growth and function. Deletion of MST1/2 activates the YAP/TAZ, STAT3, Wnt/β-catenin, and Notch pathways, highlighting the key role of YAP/TAZ in facilitating the crosstalk of these pathways. Activation of the Wnt/β-catenin pathway inhibits the positive feedback loop between Notch signaling and YAP/TAZ, elucidating the dynamic balance of these signaling systems. Communication between YAP and β-catenin in the nucleus regulates the expression of genes associated with cell proliferation and reprogramming, including Sox2 and Snai2. Although YAP forms a complex with the transcription factors TEAD/TEF while β-catenin with LEF/TCF, the two pathways exhibit distinct regulatory functions with partial overlap in gene targets. The Hippo pathway regulates heart size and cardiomyocyte proliferation by inhibiting Wnt/β-catenin signaling. Disruption of this balance can result in aberrant cardiac development and associated diseases, highlighting the need for a thorough understanding of these interactions. Therapeutics targeting of these signaling pathways have the potential to impact cardiac development and repair, creating new treatment options for heart disease.

Cancer is complex because of the critical imbalance in genetic regulation as characterized by both the overexpression of oncogenes (OGs), mainly through mutations, amplifications, and translocations, and the inactivation of tumor-suppressor genes (TSGs), which entail the preservation of genomic integrity by inducing apoptosis to counter the malignant growth. Reviewing the intricate molecular interplay between OGs and TSGs draws attention to their cell cycle, apoptosis, and cancer metabolism regulation. In the present review, we discuss seminal discoveries, such as Knudson’s two-hit hypothesis, which framed the field’s understanding of cancer genetics, leading to the next breakthroughs with next-generation sequencing and epigenetic profiling, revealing novel insights into OG and TSG dysregulation with opportunities for targeted therapy. The key pathways, such as MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin, are presented in the context of tumor progression. Importantly, we further highlighted the advances in therapeutic strategies, including inhibitors of KRAS and MYC and restoration of TSG function, despite which mechanisms of resistance and tumor heterogeneity pose daunting challenges. A high-level understanding of interactions between OG-TSGs forms the basis for effective, personalized cancer treatment—something to strive for in better clinical outcomes. This synthesis should integrate foundational biology with translation and, in this case, contribute to the ongoing effort against cancer.

The pathogenesis of type 1 diabetes mellitus (T1DM) involves oxidative stress and inflammation. Curcumin, a natural polyphenolic compound found in turmeric, known to exhibit antioxidative and anti-inflammatory properties, is characterized by poor chemical stability, low bioavailability, and rapid metabolism. Monocarbonyl analogs of curcumin (MACs) with a structural absence of β-diketone and enhanced stability and bioavailability present a potential solution to the challenges associated with the use of curcumin. This study aimed to evaluate the effect of two MACs, C66 and B2BrBC, on oxidative stress markers, antioxidant enzyme activity, expression of diabetes-associated genes, and signaling pathway proteins in the context of T1DM. Streptozotocin (STZ)-induced male Wistar rats or rat pancreatic RIN-m cells were used for in vivo and in vitro experiments, respectively. C66 or B2BrBC were given either before or after STZ treatment. Oxidative stress markers and antioxidant enzyme activities were determined in various tissues. Expression of diabetes-associated genes was assessed using RT-qPCR, and the activity of signaling pathway proteins in the pancreas was determined through Western blot analysis. Treatment with C66 and B2BrBC significantly reduced oxidative stress markers and positively influenced antioxidant enzyme activities. Moreover, both compounds inhibited JNK activity in the pancreas while enhancing the expression of genes crucial for β-cell survival and glucose and redox homeostasis. The findings highlight the multifaceted potential of C66 and B2BrBC in ameliorating oxidative stress, influencing gene expression patterns linked to diabetes, and modulating key signaling pathways in the pancreas. The findings suggest that these compounds can potentially address diabetes-related pathological processes

Obesity, a global pandemic, poses a major threat to healthcare systems worldwide. Adipose tissue, the energy-storing organ during excessive energy intake, functions as a thermoregulator, interacting with other tissues to regulate systemic metabolism. Specifically, brown adipose tissue (BAT) is positively associated with an increased resistance to obesity, due to its thermogenic function in the presence of uncoupled protein 1 (UCP1). Recently, studies on climate change and the influence of environmental pollutants on energy homeostasis and obesity have drawn increasing attention. The reciprocal relationship between increasing adiposity and increasing temperatures results in reduced adaptive thermogenesis, decreased physical activity, and increased carbon footprint production. In addition, the impact of climate change makes obese individuals more prone to developing type 2 diabetes mellitus (T2DM). An impaired response to heat stress, compromised vasodilation, and sweating increase the risk of diabetes-related comorbidities. This comprehensive review provides information about the effects of climate change on obesity and adipose tissue, the risk of T2DM development, and insights into the environmental pollutants causing adipose tissue dysfunction and obesity. The effects of altered dietary patterns on adiposity and adaptation strategies to mitigate the detrimental effects of climate change are also discussed.

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.

This paper presents a dataset obtained from an RT2-qPCR array analysis of rat pancreatic RIN-m cells treated with two monocarbonyl analogs of curcumin (MACs), C66 and B2BrBC in the presence or absence of streptozotocin (STZ). The array quantified the expression of 84 genes associated with the onset, development, and progression of diabetes. This dataset provides information on the gene expression profiles of pancreatic cells modulated by two specific MACs in a diabetic context. The data can serve as a foundation for developing new hypotheses, designing follow-up experiments, and identifying novel targets for treatment. It can be used to investigate further the molecular mechanisms underlying the therapeutic effects of these MACs and in comparative studies using other experimental antidiabetic compounds.

Monocarbonyl analogs of curcumin (MACs) lacking a β-diketone moiety have been shown to exhibit improved stability and better bioavailability than curcumin. This study aimed to evaluate the effects of two MACs (C66 and B2BrBC) on the expression of genes related to the onset, development, and progression of diabetes in rat pancreatic RIN-m cells. The cells were cultured in complete RPMI 1640 medium and treated with C66 or B2BrBC (50 μM) or vehicle for 72 h, followed by treatment with streptozotocin (STZ) (1.5 mM) or vehicle for an additional 24 h. Quantitative PCR array analysis was performed using a rat diabetes panel comprising 84 genes. The data demonstrated that C66 and B2BrBC significantly modulated the expression of 16 genes involved in growth regulation in RIN-m cells and genes associated with inflammation, immune response, and energy metabolism. Notably, C66 and B2BrBC inhibited the STZ-induced expression of pro-inflammatory Tnf and Icam1 while increasing the expression of Ins1. Moreover, C66 pretreatment influenced Ctla4 and Serpine1 expression, and B2BrBC pretreatment affected Mapk8, Serpine1, and Igfbp5 levels compared to STZ treatment alone. Cells treated with MACs and STZ showed a different pattern of gene expression for Igfbp5, Gpd1, Agt, Serpine1, Cebpa, Retn, Ccl5, and Srebf1 compared to vehicle-treated cells. Our findings show that C66 and B2BrBC modulate the expression of essential diabetes-related genes, which may serve as a basis for further research on MACs and contribute to the development of novel therapeutic targets and strategies. Disclosure R. Stojchevski: None. J.B. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D. Avtanski: None. Funding Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research

Purpose Resistin is an inflammatory cytokine secreted mostly by adipocytes and immune cells that plays a role in the development of insulin resistance, diabetes, and cancer. We hypothesized that resistin’s inflammatory activity influences the free radical and oxidative stress pathways. Methods We used human breast carcinogenic (MCF-7 and MDA-MB-231) and non-carcinogenic (MCF-10A) cells in this investigation and correlated the absorbed resistin concentration with the change in oxidative stress (TBARS, carbonated proteins) and antioxidant activity (Antioxidant Capacity, SuperOxideDismutase, CATalase, Glutathione Peroxidase). Results Resistin was substantially more effective as a prooxidant at lower (12.5 ng/ml) concentrations, than at higher concentrations (25.0 ng/ml). Vitamin C did not appear to be an effective oxidative stress protector at antioxidant concentrations of 5.10 –4 M. Leptin, at 100 ng/ml, did not result in conclusive oxidative stress or antioxidant defence stimulation, as expected. Conclusion Taken together, the findings support resistin’s role as a non-oxidative stress marker and a metabolic signaling molecule.