Bintul Huda

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)–extracellular signal-regulated kinase (ERK)–tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2–ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy.

The global burden of heart failure (HF) continues to escalate, with a lifetime risk approaching one in four adults in the United States. Concurrently, advances in cancer therapeutics have created a burgeoning population of long-term survivors, who now face the significant morbidity and mortality of chemotherapy-induced cardiovascular disease (CVD). This review addresses the critical overlap of these two pathologies, which share fundamental drivers such as oxidative stress, inflammation, and metabolic dysregulation. Epigallocatechin gallate (EGCG), the most abundant and biologically active polyphenol in green tea, has demonstrated pleiotropic bioactivity in preclinical models, encompassing potent antioxidant, anti-inflammatory, and anti-apoptotic properties. The central aim of this review is to provide a critical and comprehensive synthesis of the evidence supporting EGCG’s dual protective role. This review dissects its molecular mechanisms in modulating key pathways in HF and cardio-oncology, evaluates its translational potential, and importantly, delineates the significant gaps that must be addressed for its clinical application. This analysis uniquely positions EGCG not merely as a nutraceutical, but as a multi-target molecular therapeutic capable of simultaneously addressing the convergent pathological cascades of heart failure and cancer-related cardiotoxicity. The synthesis of preclinical evidence with a critical analysis of its translational barriers offers a novel perspective and a strategic roadmap for future research.

Statins, primarily prescribed for their lipid-lowering effects, have garnered significant attention for their potent anti-inflammatory effects. This review explores the underlying molecular pathways and clinical relevance of statins’ anti-inflammatory actions, extending beyond cardiovascular disease management to chronic inflammatory conditions and oncological applications. The lipid-lowering effect of statins stems from their ability to suppress HMG-CoA reductase, a crucial enzyme in cholesterol synthesis; however, their pleiotropic effects include modulation of critical inflammatory pathways such as the inhibition of NF-κB signalling, a reduction in pro-inflammatory cytokine production, and enhancement of endothelial function. We delve into the molecular pathways influenced by statins, including their effects on inflammatory mediators like C-reactive protein (CRP), interleukins (IL-6, IL-1β), and tumour necrosis factor-alpha (TNF-α). Clinical evidence supporting the efficacy of statins in managing chronic inflammatory diseases, such as rheumatoid arthritis, chronic obstructive pulmonary disease, diabetes, and osteoarthritis, is critically reviewed. Additionally, we investigate the emerging role of statins in oncology, examining their impact on inflammation-driven carcinogenesis, tumour microenvironment modulation, and cancer progression. Despite their broad therapeutic potential, the safety profile of statins, particularly concerning adverse effects such as myopathy, hepatotoxicity, and potential diabetes risk, is discussed. Controversies surrounding the extent of their anti-inflammatory benefits and the variability in patient responses are also addressed. This review consolidates the current literature, elucidating the biochemical mechanisms underlying the anti-inflammatory properties of statins and evaluating their clinical applications and associated controversies. Future research directions are identified, including the development of novel statin analogues with enhanced anti-inflammatory effects and the investigation of new therapeutic indications in inflammatory diseases and cancer. By providing an in-depth analysis, this review underscores the expanding therapeutic scope of statins and advocates for their integration into broader clinical strategies for the management of inflammation and cancer.

Background/Objectives: Colorectal cancer (CRC) remains a major global health burden, marked by complex tumor–microenvironment interactions, genetic heterogeneity, and varied treatment responses. Effective preclinical models are essential for dissecting CRC biology and guiding personalized therapeutic strategies. This review aims to critically evaluate current experimental CRC models, assessing their translational relevance, limitations, and potential for integration into precision oncology. Methods: A systematic literature search was conducted across PubMed, Scopus, and Web of Science, focusing on studies employing defined in vitro, in vivo, and emerging integrative CRC models. Studies were included based on experimental rigor and relevance to therapeutic or mechanistic investigation. Models were compared based on molecular fidelity, tumorigenic capacity, immune interactions, and predictive utility. Results: CRC models were classified into in vitro (2D cell lines, spheroids, patient-derived organoids), in vivo (murine, zebrafish, porcine, canine), and integrative platforms (tumor-on-chip systems, humanized mice, AI-augmented simulations). Traditional models offer accessibility and mechanistic insight, while advanced systems better mimic human tumor complexity, immune landscapes, and treatment response. Tumor-on-chip and AI-driven models show promise in simulating dynamic tumor behavior and predicting clinical outcomes. Cross-platform integration enhances translational validity and enables iterative model refinement. Conclusions: Strategic deployment of complementary CRC models is critical for advancing translational research. This review provides a roadmap for aligning model capabilities with specific research goals, advocating for integrated, patient-relevant systems to improve therapeutic development. Enhancing model fidelity and interoperability is key to accelerating the bench-to-bedside translation in colorectal cancer care.

Background: Colorectal cancer (CRC) is a growing health concern globally and in regions such as the United Arab Emirates, where risk factors like obesity and hyperlipidaemia are prevalent. Chronic inflammation, driven by pathways involving protease-activated receptor 2 (PAR-2), plays a pivotal role in CRC progression, creating a tumour-promoting microenvironment. The overexpression of PAR-2 has been associated with increased tumour aggressiveness and drug resistance. While previous studies have focused on broad inflammatory modulation, this study explores the selective targeting of PAR-2 by atorvastatin (ATV) and rosuvastatin (RSV), highlighting their specificity by assessing minimal impact on PAR-1 expression, which serves as a control. Methods: HT-29 and Caco-2 CRC cell lines were employed to investigate the anti-inflammatory effects of ATV and RSV. Inflammation was induced with lipopolysaccharide (LPS), followed by treatment with varying concentrations of ATV and RSV. Western blotting and real-time polymerase chain reaction for quantification (qPCR) were performed to quantify PAR-2 and TNF-α at both the protein and mRNA levels. Enzyme linked immunosorbent assay (ELISA) was used to measure the secretion of TNF-α. Calcium signalling, which plays a crucial role in inflammation, was analysed using Fluo-4 AM dye, with fluorescence imaging capturing the effects of statin treatment on intracellular calcium influx. Results: LPS treatment significantly upregulated PAR-2 and TNF-α expression in both cell lines, validating the inflammatory model. Co-treatment with ATV or RSV reduced PAR-2 and TNF-α expression in a dose-dependent manner. The higher concentrations of ATV (50 µg/mL) and RSV (20 µg/mL) produced the most significant reduction in these inflammatory markers at both the protein and mRNA levels. Importantly, the treatment did not substantially alter PAR-1 expression, underlining the specificity of ATV and RSV in modulating PAR-2-mediated pathways. Additionally, statin treatment attenuated LPS-induced calcium influx, with fluorescence intensity decreasing markedly at higher concentrations of both statins. Conclusions: This study provides novel insights into the selective targeting of PAR-2 by ATV and RSV, distinguishing their effects from PAR-1. The reduction in PAR-2 expression and TNF-α secretion, along with the suppression of calcium signalling, underscores the potential of these statins as targeted anti-inflammatory agents in CRC. The findings highlight the therapeutic value of ATV and RSV in modulating inflammation through PAR-2-specific pathways, which may contribute to reduced cancer progression. These results pave the way for further preclinical and clinical evaluations to explore statins as adjunctive therapies in the management of CRC.