Rom. J. Prev. Med., Volume 4, Issue 1 (March 2026) – 2 articles

This critical integrative review reassesses the lipid paradigm by systematically mapping 380 influential trials and cohort studies on cholesterol, saturated fats, and statins in relation to cardiovascular and cognitive outcomes. The evidence base reveals a nearly even split between studies supporting and challenging LDL-centric causality, alongside pervasive methodological flaws, including reliance on surrogate lipid markers, ecological inferences, residual confounding, and industry-related reporting biases. Trial-generation comparisons and structured risk-of-bias assessment (ROB 2, ROBINS-I) repeatedly show that substantial pharmacological LDL reductions do not consistently yield proportional reductions in myocardial infarction, stroke, or all-cause mortality. Integrating Mendelian randomization with clinical and metabolomic data, the review advances a Critical Window Hypothesis in which LDL is necessary but not sufficient for atherogenesis, exerting dominant causal influence during early and midlife plaque initiation, while inflammatory, oxidative, and hemodynamic factors become primary drivers in advanced disease. Metabolomic studies of extreme longevity and late-life cohorts demonstrate that bile acids, steroid metabolites, and low-glycemic metabolic profiles—not total cholesterol—better predict survival and cognitive preservation, and that higher LDL in the oldest-old often associates with lower mortality and dementia risk. These findings challenge universal LDL-centric policies and support lifestyle medicine strategies prioritizing systemic metabolic optimization over isolated cholesterol targets. Full article

Tumor necrosis factor alpha (TNF-α) serves as a major regulator of inflammatory responses. The initial, critical release and activation of TNF-α in acute pancreatitis (AP) is primarily triggered within the pancreatic acinar cells through intracellular mechanisms in response to initial injury. This local, acinar cell-derived TNF-α recruits immune cells into the pancreas, which then produce more TNF-α, leading to the amplification of the inflammatory cascade. This opinion emphasises the role of TNF-α-mediated dysfunction of pancreatic β-cells and apoptosis induction through the Bax/Bcl-2/caspase-3 pathway. AP is often diagnosed by autodigestive pancreatic damage and systemic inflammatory response with transient or persistent hyperglycaemia. TNF-α signalling takes place through TNFR1, which initiates apoptotic events that weaken mitochondrial integrity leading to β-cell disruption and diminished insulin secretion. Studies reported TNF-α-mediated increases in Bax expression, anti-apoptotic Bcl-2 suppression and activation of caspase-3. Therapeutic strategies such as TNFR1 inhibitors, Bax/Bcl-2 modulators and BH3 mimetics possess great potential to preserve β-cell integrity. However, TNF-α inhibition requires a careful approach in order to avoid compromising immune defence in AP patients. TNF-α-driven β-cell apoptosis represents a strong link between inflammation and metabolic dysfunction that makes it a suitable target for AP. Future directions should prioritise translational research in human cohorts and developing receptor-specific interventions to balance immune modulation with β-cell preservation. Full article