The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6′-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of −7.526 kcal/mol, −7.438 kcal/mol, and −7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (−6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.

Background: Acute pancreatitis (AP) is a severe inflammation of the pancreas, marked by elevated enzyme levels, cellular inflammation, and necrosis. Recent studies emphasize the critical role of inflammation in AP progression. Tirzepatide, a multi‐target agonist of glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors, has demonstrated notable anti‐inflammatory and metabolic benefits. Methods: This study explores the therapeutic potential of Tirzepatide in pancreatitis induced by L‐arginine in rats, focusing on enzymatic markers, cytokine profiles, oxidative stress, and histological outcomes. Over 27 days, rats were distributed into Control, Tirzepatide, L‐Arginine, and L‐Arginine + Tirzepatide groups, with the latter receiving L‐Arginine to induce pancreatitis followed by Tirzepatide administration. Results: L‐Arginine significantly elevated serum amylase, lipase, and inflammatory mediators (IL‐6, IL‐4, and IL‐10), alongside oxidative stress markers and histopathological deterioration. Conversely, the L‐Arginine + Tirzepatide group exhibited reduced lipase and IL‐6 levels, suppressed reactive oxygen species (ROS) generation, and enhanced anti‐inflammatory cytokines IL‐4 and IL‐10. Histopathological analysis revealed reduced necrosis and tissue damage in the L‐Arginine + Tirzepatide group compared to the L‐Arginine group, indicating Tirzepatide's possible protective effects. Immunofluorescence studies further demonstrated increased p‐Akt expression, supporting the role of Tirzepatide in cellular repair and recovery. Conclusion: These findings highlight Tirzepatide's ability to mitigate pancreatic damage through antioxidant and anti‐inflammatory mechanisms, underscoring its potential as a pharmacological agent for acute pancreatitis.

Type 2 Diabetes Mellitus (T2DM) is a widespread metabolic disorder that can affect brain health, primarily through the damaging effects of prolonged hyperglycemia. This condition increases oxidative stress (OS), neuroinflammation, and neuroapoptosis, ultimately impairing cognitive function. Acrylamide (ACY), a neurotoxicant formed during high-temperature food processing and present in cigarette smoke, may further aggravate these neurological disturbances. The present experiment examined the exacerbating effects of T2DM and ACY exposure on cognitive function, neurodegeneration, OS, neuroinflammation, and neuroapoptosis in diabetic rats. T2DM was induced via intraperitoneal injections of nicotinamide and streptozotocin, followed by daily oral doses of ACY for a month. Behavioral assessments (EPM, NOR, and Y-maze) evaluated cognitive performance. Brain tissues were analyzed for biochemical markers of neurodegeneration (GSK-3β, AChE, BACE1), OS (MDA, GSH, Catalase), neuroinflammation (NF-κB, TNF-α, PGE2, COX-2), and neuroapoptosis (Bcl-2, Bax, Caspase-3). Immunohistochemistry of Bcl-2, Bcl-6, CD138, and NF assessed structural brain changes. Results indicated that T2DM and ACY exposure significantly increased the incidence of neurological disturbances. Notably, through increased COX-2, PGE2, MDA, Bax, Bcl-6, Caspase-3, and cognitive decline deficits. This study highlights the harmful neurotoxic amplification of T2DM and ACY exposure, emphasizing the importance of public health measures to reduce ACY exposure through dietary and lifestyle changes, particularly among T2DM populations. Further research into neuroprotective strategies and underlying mechanisms is necessary.