Mashreq University

Acute pancreatitis (AP) is one of the most common gastrointestinal disorders requiring hospitalization worldwide and is characterized by excessive inflammatory and oxidative responses that contribute to pancreatic tissue injury. Dapagliflozin (DAPA), a selective sodium–glucose co-transporter 2 inhibitor, has demonstrated pleiotropic anti-inflammatory and antioxidant properties beyond its glucose-lowering effects. To investigate the protective effect of DAPA against L-arginine–induced AP and to elucidate the underlying molecular mechanisms. Twenty-four Wistar rats were randomly divided into three groups (n = 8): control, AP, and DAPA-treated AP. AP was induced by L-arginine administration. DAPA (1 mg/kg, orally) was administered for three consecutive days starting 1 h after AP induction. Markers of pancreatic injury, inflammation, and oxidative stress were assessed. Pancreatic histopathology and immunohistochemical analyses were performed. Furthermore, molecular docking analyses were conducted to evaluate the potential inhibitory interactions of DAPA with toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and NLR family pyrin domain–containing 3 (NLRP3). DAPA treatment significantly reduced α-amylase, lipase levels and preserved pancreatic histoarchitecture compared with the untreated AP group. It markedly decreased pancreatic levels of interleukin (IL)-1β, IL-18, tumor necrosis factor-α (TNF-α), TLR4, NLRP3, myeloperoxidase, and malondialdehyde, while significantly increasing superoxide dismutase activity. Immunohistochemical analysis revealed negative expression of NF-κB and caspase-1 in pancreatic tissues from DAPA-treated rats, in contrast to their pronounced expression in the L-arginine–induced AP group. Molecular docking studies demonstrated favorable binding affinities and interactions between DAPA and TLR4, NF-κB, and NLRP3. DAPA attenuates L-arginine–induced acute pancreatitis by suppressing inflammatory, oxidative, and inflammasome-related pathways through modulation of the TLR4/NF-κB/NLRP3 signaling axis.

This study aimed to synthesize, characterize, and test new drug-polymer composites to address microbial resistance. Several new composites (Z2-Z7) were created by building a strong polymer backbone (a chain of large, repeating units) and attaching polyvinylpyrrolidone (PVP), a water-soluble polymer, to provide a stable platform for drug loading. Successful drug inclusion was confirmed using Fourier Transform Infrared spectroscopy (FT-IR), Proton Nuclear Magnetic Resonance (1H NMR), Thermogravimetric Analysis (TGA), X-ray Diffraction studies (XRD), and Scanning Electron Microscopy (SEM). Biological assays demonstrated that the thymine-based polymer (Z5) exhibited the strongest broad-spectrum antimicrobial activity according to the zone inhibition diameter in mm, with effects against Gram-positive bacteria (Staphylococcus aureus (S. aureus), 19 mm), (Enterococcus faecalis (E. faecalis), 18 mm), Gram-negative bacteria (Escherichia coli (E. coli), 23 mm), (Pseudomonas aeruginosa (P. aeruginosa), 21 mm), and fungi Candida albicans (C. albicans), 16 mm), (Candida tropicalis (C. tropicalis), 26 mm). Molecular docking studies clarified the strong binding of the composites, supporting their bioactivity. The thymine-based polymer (Z5) showed the highest binding affinity: -10.073 kcal/mol for Gram-positive bacteria, -7.740 kcal/mol for Gram-negative bacteria, and -7.461 kcal/mol for fungi. Composites containing chloramphenicol and sulfamethoxazole also showed notable antimicrobial activity and strong molecular interactions. Collectively, these findings demonstrate that drug-polymer composites represent a promising strategy. In particular, the thymine-based variant (Z5) showed superior performance. Meanwhile, both the chloramphenicol-based (Z3) and sulfamethoxazole-based polymer (Z6) independently exhibited significant potential as potent antimicrobial agents. Looking ahead, future work will focus on optimizing these compounds. Additionally, upcoming studies will evaluate their controlled-release characteristics to enhance therapeutic efficacy.

This study reports the biological evaluation of novel Schiff base-tethered organoselenium (OSe) compounds as potential anticancer agents. New derivatives (HB178, HB179, HB181, HB183, HB208, HB209, and HB210) were synthesized and screened for cytotoxicity against eight cancer cell lines (including HN9, FaDu, MCF7, A375, HEPG2, HuH7, A549, and HCT116) and two normal cell lines (OEC and HSF). Among them, HB183, HB209, and HB210 exhibited the most potent growth inhibition (GI) activity, with average values of 78.25%, 76.34%, and 79.14%, respectively-surpassing the reference drug doxorubicin (61.89%). HB183 demonstrated the strongest cytotoxic effects, with IC50 values of 9.72 µM (MCF7), 13.28 µM (HCT116), 13.50 µM (A549), and 31.28 µM (HEPG2), significantly outperforming doxorubicin across multiple cell lines. Importantly, HB183 showed selective cytotoxicity with lower GI% values against normal OEC (53.90%) and HSF (42.27%) cells. Mechanistic investigations revealed that HB183 upregulated key pro-apoptotic proteins-BAX (1.39-fold), caspase-3 (1.18-fold), caspase-7 (1.20-fold), and caspase-9 (1.45-fold)-while downregulating anti-apoptotic markers such as BCL-2 (1.22-fold), MMP2 (1.15-fold), and MMP9 (1.30-fold). Furthermore, flow cytometry analysis indicated that HB183 induced cell cycle arrest at the pre-G1 phase in MCF7 cells, increasing the population from 94.32% to 98.84%. Molecular docking, molecular dynamics simulation (for 500 ns), and MM-GBSA calculations for the lead analogue (HB183) towards the BCL-2 target, as a crucial one in the pathway of apoptosis induction, were performed to support the mechanistic investigation. These findings suggest that HB183 is a promising lead for further development as a selective and potent anticancer agent, particularly in the treatment of breast cancer.

This study examined the renoprotective effect of Piribedil against cyclophosphamide (CP)-induced nephrotoxicity through modulation of adenosine monophosphate–activated protein kinase (AMPK)/sirtuin-1 (SIRT1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinases (MAPKs), and Toll-like receptor-4 (TLR4)/NOD-like receptor protein-3 (NLRP3) pathways, as well as renal injury markers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase–associated lipocalin (NGAL). Male rats were divided into four groups (n = 8). Controls received distilled water plus saline; the CP group received a single CP dose (200 mg/kg, i.p.) on day 7; Piribedil groups received 15 or 40 mg/kg/day for 10 days with CP on day 7. Renal function, oxidative stress, inflammation, and injury markers (KIM-1 and NGAL) were assessed via biochemical assays, histopathology, immunohistochemistry, and quantitative real-time PCR (qRT-PCR). CP caused significant renal dysfunction, elevating blood urea nitrogen (BUN), serum creatinine (SCr), NGAL, and KIM-1, increasing oxidative stress (malondialdehyde [MDA], inducible nitric oxide synthase [iNOS]) and reducing nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione (GSH). CP also upregulated inflammatory mediators (interleukin-1β [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α], nuclear factor-κB p65 [NF-κB p65]) and enhanced TLR4, NLRP3, and MAPKs, while suppressing AMPK, SIRT1, and PI3K/Akt signaling. Piribedil reversed these changes, improving renal function, lowering oxidative and inflammatory markers, and normalizing BUN, SCr, KIM-1, and NGAL. Histology confirmed reduced renal damage. Piribedil effectively protects against CP-induced nephrotoxicity by modulating AMPK/SIRT1 and related oxidative and inflammatory pathways, supporting its potential use in drug-induced kidney injury.

Casein Kinase-2 (CK2) and Proviral Integration site for Moloney murine leukemia virus-1 (PIM-1) are kinases that are continuously active and work together to promote oncogenesis, thus becoming an important target for anti-cancer drugs. This research highlights the design, synthesis, and in silico evaluation of a new class of azo-Schiff bases bearing benzimidazole moieties (A1-A7) as potential dual inhibitors of CK2/PIM-1 targets. The compounds were synthesized using diazotization/azocoupling reaction and Schiff's base condensation reactions, where structural elucidation was accomplished through FT-IR, 1H NMR, and 13C NMR analyses. The molecular docking process was performed using the GOLD docking program against ATP-binding sites on CK2 (PDB: 4DTK) and PIM-1 (PDB: 4KWP), followed by MD simulation for 100 ns using GROMACS software. Through computational screening, molecules A4 and A6 were found to be the most potent dual inhibitors. Compound A6 displayed the greatest affinity to CK2 with a PLP fitness value of 81.33, whereas compound A4 displayed the highest affinity to PIM-1 with a PLP fitness value of 86.80. The interesting thing is that both compounds revealed very good cross-reactivity to both enzymes and were superior to other compounds in the series concerning dual-target PLP fitness. The MD simulation results showed that A4 and A6 exhibit high stability in their interactions with minimal structural fluctuations, attributed to hydrogen bonds formed consistently within the active site regions. In contrast, A7 has been shown to be a PIM-1 selective inhibitor. The attachment of azo-Schiff base groups to the benzimidazole core results in an interesting structure with a potential for multi-kinase inhibitory activity. The current study has identified molecules A4 and A6 as potential leads that require further in vitro and in vivo validation.