Mitotic progression is regulated by co-ordinated action of several proteins and is crucial for the maintenance of genomic stability. CHFR (Check point protein with FHA and RING domains) is an E3 ubiquitin ligase and a checkpoint protein that regulates entry into mitosis. But the molecular players involved in CHFR mediated mitotic checkpoint are not completely understood. In this study, we identified TOPK/PBK, a serine/threonine kinase and PTEN, a lipid phosphatase to play an important role in CHFR mediated mitotic transitions. We demonstrated that CHFR ubiquitinates and regulates TOPK levels, which is essential for its checkpoint function. Moreover, TOPK phosphorylates and inactivates PTEN, which in turn activates Akt that leads to proper G2/M progression. Collectively, our results reveal TOPK and PTEN as new players in CHFR mediated mitotic checkpoint.

Leptospirosis is a zoonotic disease of global importance. It is caused by a Gram-negative bacterial spirochete of the genus Leptospira .

Breast cancer is the most frequently diagnosed malignancy in women. Invasive breast cancer will be diagnosed in approximately one in every eight women during their lifetime. Quinazoline-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed and synthesized using a pharmacophore hybridization technique that combined biologically active scaffolds. In vitro assays of the synthesized compounds' cancer activity against three breast cancer cell lines: MCF-7, MDA-MB-231, and MDA-MB-468, compounds 6i, 6k, and 6l exhibited significant activity. Compounds 6j and 6m exhibited equivalent efficacy relative to the standard drug against the MDA-MB-231 cell line, but compound 6i showed significant activity against the MDA-MB-468 cell line. Moreover, compound 6i (IC₅₀ = 0.37 ± 0.03 μM) demonstrated superior efficacy compared to the standard erlotinib (IC₅₀ = 0.42 ± 0.01 μM) in vitro, based on EGFR inhibitory assays and compound 6k (IC₅₀ = 0.51 ± 0.04 μM) showed good EGFR inhibitory activity. To validate the activity data and the drug-likeness of the compounds, six potent compounds were subjected to in silico molecular docking investigations using the Discovery Studio 2021 methodology.

Monophosphoryl lipid A (MPLA), a TLR4 agonist, is a clinically approved vaccine adjuvant, but its complex structure and occasional toxicity limit broader use. Synthetic small-molecule TLR4 agonists offer advantages such as ease of synthesis, lower cost, and reduced toxicity. In this study, we conducted structure-based virtual screening of the ZINC database to identify novel TLR4-targeting small molecules across human, murine, and bovine species. Three lead compounds—NSF-418, NSF-501, and NSF-951—were selected based on favorable binding interactions and subjected to in vitro and in vivo evaluation. NSF-951 emerged as a potent TLR4 agonist, inducing strong proinflammatory cytokine responses (IL-6, TNF-α), upregulating CD80 and CD86 expression, and promoting macrophage maturation. Conversely, NSF-418 and NSF-501 acted as antagonists by suppressing MPLA-induced responses. In murine immunization studies, NSF-951, alone or with Alum (AF007), significantly enhanced OVA-specific antibody and T-cell responses without observable toxicity. These findings suggest that NSF-951 is a promising, cost-effective TLR4 agonist with strong immunostimulatory and adjuvant potential. Further studies are warranted to assess its performance with other antigens and adjuvant combinations, supporting its development as a next-generation adjuvant for veterinary and human vaccines.

Introduction: The rapid emergence of methicillin-resistant and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) represents a major global health challenge, necessitating the development of new antibacterial scaffolds with improved efficacy and safety. Methods: In this study, a novel series of sulfonyl-imidazole-linked fused isoxazolo[3,4-b][1,2,3]triazolo[4,5-d]pyridine derivatives (6a–6o) was synthesized using a PEG-400-mediated, ultrasound-assisted one-pot Cu(I)-catalysed strategy under environmentally benign conditions. The synthesized compounds were evaluated for antibacterial activity against MSSA, MRSA, and VRSA strains, along with antibiofilm activity, hemolytic potential using mouse erythrocytes, and cytotoxicity in RAW 264.7, THP-1, and BoMac cells. Immunomodulatory effects were assessed through cytokine induction studies. Results: Several derivatives exhibited potent antibacterial activity, with compound 6k emerging as the most active candidate, displaying MIC values of 1.56–3.12 μg/mL and outperforming the reference drug dicloxacillin. Selected compounds also showed significant antibiofilm activity against resistant S. aureus strains. Hemolysis and cytotoxicity assays demonstrated minimal toxicity, indicating good biocompatibility. Immunomodulatory analysis revealed moderate cytokine induction, suggesting a controlled immune response. Discussion: Overall, compound 6k was identified as a promising lead with potent antibacterial, antibiofilm, and immunomodulatory properties, combined with a favourable safety profile, warranting further preclinical development against drug-resistant S. aureus infections.