Photoactive NO hybrids with pseudo-zero-order release kinetics for antimicrobial applications.

Bacterial infection is a major threat to the health and life of humans due to the development of drug resistance, which is related to biofilm formation. Nitric oxide (NO) has emerged as an important factor in regulating biofilm formation. In order to harness the potential benefits of NO and develop effective antibacterial agents, we designed and synthesized a new class of NO hybrids in which the active scaffold benzothienoazepine was tagged with a nitroso group and further conjugated with quaternary ammoniums or phosphoniums. The temporal release of NO from these hybrids can be achieved by photoactivation. Interestingly, the NO release follows a pseudo-zero-order kinetics, which is easily determined by measuring the fluorescent benzothienoazepine or NO. Compared to the positive control ciprofloxacin, the NO hybrid with triphenyl phosphonium (TPP) exhibited more effective activity against S. aureus biofilm in darkness. Irradiation of the NO hybrid led to higher inhibition against S. aureus biofilm compared to the parental NO hybrid in darkness or the corresponding NO-released product, indicating the combined effect of NO and the NO-released product. Therefore, this new class of NO hybrids includes very promising antimicrobial agents and this work provides a new way for the design of highly effective antimicrobial agents.

Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH.

Cancer stem cells (CSCs) play a pivotal role in tumor initiation, proliferation, metastasis, drug resistance, and recurrence. Consequently, targeting CSCs has emerged as a promising avenue for cancer therapy. Recently, 3-phosphoglycerate dehydrogenase (PHGDH) has been identified as being intricately associated with the regulation of numerous cancer stem cells. Yet, reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited. In this study, the novel "molecular glue" LXH-3-71 was identified, and it robustly induced degradation of PHGDH, thereby modulating the stemness of colorectal cancer cells (CRCs) both in vitro and in vivo. Remarkably, LXH-3-71 was observed to form a dynamic chimera, between PHGDH and the DDB1-CRL E3 ligase. These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors. Additionally, compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase, facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

Increased apoptosis and cysteinyl aspartate specific protease-3 gene expression in human intracranial aneurysm.

OBJECTIVE: To investigate apoptosis in vascular smooth muscle cells (VSMCs) and caspase-3 expression in ruptured intracranial aneurysm. METHODS: Tissue samples of 15 ruptured intracranial aneurysms, 6 abdominal aortic aneurysms (AAA) and 6 normal vessels were evaluated. Apoptosis in VSMCs was determined on transmission electron microscopy. Immunohistochemistry for alpha-SMC actin and direct cell counts (medial VSMCs per high-power field (HPF)) were employed to determine medial VSMC density. Additionally, gene expression of caspase-3 was determined using real-time RT-PCR. RESULTS: We demonstrated medial VSMCs exhibiting morphological apoptotic changes in cerebral aneurysm and AAA. Medial VSMC density was significantly decreased in intracranial aneurysm (43.9+/-4.3 SMCs/HPF) and AAA (53.2+/-9.4 SMCs/HPF) compared with the normal arteries (222.8+/-12.1 SMCs/HPF; p<0.01). An 8.94-fold and 6.73-fold increase in expression of caspase-3mRNA in intracranial aneurysm and AAA, respectively, were obtained relative to the normal vessels. CONCLUSIONS: These results suggest that real time RT-PCR provides a useful tool to test gene expression in small samples, and may contribute to a better understanding of the role of apoptosis in ruptured intracranial aneurysm.