The 3-azabicyclo[3.1.0]hexan-2-one motif has emerged as a promising scaffold in medicinal and agrochemical research, where it is increasingly incorporated into bioactive compounds. Synthetic approaches to this scaffold rely on oxidation of preformed bicyclic amines or cyclopropanation reactions using diazo-derived carbene precursors. Consequently, the development of diazo-free, redox-neutral strategies for its synthesis remains highly desirable. Among these, strain-release activation of bicyclo[1.1.0]butanes provides an atom-economical platform for generating metal carbenes, enabling diverse bond-forming transformations without the need for diazo compounds.Herein, we report a phosphine ligand-enabled rhodium(I)-catalyzed rearrangement of bicyclo[1.1.0]butane carboxamides that provides a complementary approach to the synthesis of 3-azabicyclo[3.1.0]hexan-2-one derivatives. A series of N-aryl-, N-benzyl-, and N-alkyl-substituted products was synthesized. A plausible mechanistic pathway involving a rhodium carbenoid intermediate is proposed. In addition, the synthesized bicyclic lactams were evaluated for their effects on the viability of MOLT-4T-lymphoblast cells, providing a preliminary assessment of the biological potential of this scaffold.
Background While carotid revascularization reduces stroke risk in both asymptomatic (AD) and symptomatic (SD) carotid diseases, its role continues to evolve with advances in medical therapy, surgical techniques, and cost considerations. Methods This retrospective study reviews outcomes of patients undergoing revascularization at a level 1 stroke center between 2019 and 2024. Primary endpoints were ipsilateral stroke, myocardial infarction (MI), and death at 30 days, 90 days, and 1 year. Secondary endpoints include restenosis rates. Results A total of 113 patients underwent 127 carotid endarterectomies. Sixty-four percent presented with SD, with a median time to intervention of 9 days (interquartile range 6–11). Patients with SD had a longer median length of stay (2 vs. 1 day, P = 0.076. Follow-up rates were higher in AD at 1 year (65% vs. 36%, P = 0.003). MI rates were 0% at 30 days and 90 days and 0.9% at 1 year. Stroke rates were 0.9%, 0.9%, and 1.8% at 30 days, 90 days, and 1 year, with no difference between AD versus SD. One-year mortality rates were 0.9% and 5.3% at 90 days and 1 year, without a difference by AD versus SD. Restenosis occurred in 4% of patients, with no difference between groups. Conclusion Carotid endarterectomy was associated with low perioperative rates of ipsilateral stroke, MI, and death. Despite a longer length of stay, patients with SD did not have significantly different outcomes or restenosis rates. While males had improved follow-up rates, there was no significant difference in outcomes by gender or race. These findings support favorable outcomes following CEA in both AD and SD.
The deregulation of microRNAs (miRNAs) plays an important role in human hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in hepatocellular carcinoma (HCC) cells. First, we examined the different miRNA expression profiles in HCC cells and HCC cell–derived exosomes. Next, coculture experiments indicated that HCC cell–derived exosomes promoted the cell growth, migration, and invasion of HCC cells and had the ability to shuttle miRNAs to recipient cells. Further, our data showed that Vps4A, a key regulator of exosome biogenesis, was frequently down‐regulated in HCC tissues. The reduction of Vps4A in HCC tissues was associated with tumor progression and metastasis. In vitro studies revealed that Vps4A repressed the growth, colony formation, migration, and invasion of HCC cells. We further investigated the role and involvement of Vps4A in suppressing the bioactivity of exosomes and characterized its ability to weaken the cell response to exosomes. By small RNA sequencing, we demonstrated that Vps4A facilitated the secretion of oncogenic miRNAs in exosomes as well as accumulation and uptake of tumor suppressor miRNAs in cells. A subset of Vps4A‐associated miRNAs was identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the phosphatidylinositol‐3‐kinase/Akt signaling pathway was the most likely candidate pathway for modulation by these miRNAs. Indeed, we proved that the phosphatidylinositol‐3‐kinase/Akt pathway was inactivated by Vps4A overexpression. Conclusion: Exosome‐mediated miRNA transfer is an important mechanism of self‐modulation of the miRNA expression profiles in HCC cells, and Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells; these observations provide new insights into the development of HCC. (Hepatology 2015;61:1284–1294)
Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disease characterized by structural weakening and pathological dilatation of the abdominal aortic wall. Currently, no effective pharmacological therapies are available, and treatment remains largely limited to surgical intervention. This underscores the urgent need to better understand the mechanisms driving disease development and progression. Among the cellular mediators implicated in AAA, neutrophils have emerged as key contributors to vascular inflammation and tissue destruction. We performed a comprehensive literature review of original research articles and relevant reviews addressing the role of neutrophils in AAA pathogenesis. Studies were identified through systematic searches of major databases, including PubMed and Google Scholar, using the keywords “abdominal aortic aneurysm”, “neutrophils”, “vascular inflammation”, “oxidative stress”, “proteases”, and “extracellular matrix degradation”. Both experimental and clinical studies were included to provide an integrated overview of current knowledge in the field. Accumulating evidence indicates that neutrophils actively infiltrate the aortic wall during AAA development, where they release a diverse array of effector molecules, including reactive oxygen species, proteolytic enzymes, pro-inflammatory cytokines, chemotactic mediators, and granule proteins. Collectively, these mediators sustain chronic vascular inflammation, promote extracellular matrix degradation, and contribute to progressive structural weakening of the arterial wall. This review summarizes both established and emerging roles of neutrophils in AAA pathogenesis, with a particular focus on their contribution to vascular inflammation, thereby providing a conceptual framework for future diagnostic and therapeutic development. Neutrophils are central regulators of AAA pathogenesis through their multifaceted roles in vascular inflammation and extracellular matrix remodeling. Targeting neutrophil activation and downstream inflammatory pathways may represent a promising therapeutic strategy. A deeper mechanistic understanding of neutrophil-driven processes may facilitate the development of novel biomarkers and pharmacological approaches aimed at limiting AAA progression and preventing rupture.
Traumatic brain injury (TBI) is increasingly recognized as a systemic disorder with significant effects on skeletal biology. This review summarizes current evidence describing how TBI impacts fracture healing, heterotopic ossification, and long-term bone remodeling. Clinical observations and experimental models demonstrate that TBI can accelerate early fracture callus formation and increase the risk of heterotopic ossification, suggesting a transient pro-osteogenic state following injury. Proposed mechanisms include neuroinflammatory cytokine release, sympathetic nervous system activation, neuroendocrine dysregulation, and mobilization of osteoprogenitor cells. Conversely, persistent neuroinflammation, hypothalamic–pituitary axis dysfunction, oxidative stress, and altered autonomic signaling are associated with impaired fracture remodeling, increased bone resorption, and progressive bone loss. Emerging data implicate extracellular vesicle-mediated signaling as a key pathway linking brain injury to skeletal outcomes. TBI induces a contextual, biphasic skeletal response with both osteogenic and degenerative consequences. Understanding this duality is essential for optimizing fracture care and preserving bone health after neurotrauma.
