Bioconjugation of gold nanoclusters (AuNC) onto protein scaffolds is a popular technique in the bioengineering field due to its broad applications in modulating protein structure and function. Recent work showed that AuNC bioconjugation could alter the structure of hen egg white lysozyme (Lys), converting the normally α-helical protein into a predominantly β-sheet structure with reduced antibody binding. Unfunctionalized Lys is often used as a model for amyloid fibril formation. Here, Lys undergoes a similar α-helix to β-sheet transition, the end product of which aggregates to form insoluble amyloid fibrils. Despite these similarities, our work shows that the β-sheet AuNC-Lys bioconjugate is highly resistant to fibril formation under a range of amylogenic conditions and could even inhibit amyloid formation in native, unfunctionalized Lys. These results illustrate the potential of AuNC bioconjugation to “trap” amylogenic proteins in their partially unfolded intermediate state without triggering further fibril formation. This could have implications for the future design and use of AuNC-based biomolecules while opening up new avenues for therapeutic design.
The rising global incidence of chronic kidney disease has positioned peritoneal dialysis (PD) as a critical renal replacement therapy. However, its long-term efficacy is often compromised by peritoneal fibrosis and encapsulating peritoneal sclerosis, leading to treatment failure in kidney failure patients. Furthermore, this population faces compounded health challenges, including heightened cardiovascular risk and metabolic syndrome. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, initially developed as anti-diabetic agents, have garnered significant attention for their demonstrated clinical benefits in renal and cardiovascular protection, as well as metabolic improvement. This review aims to comprehensively analyze the mechanisms of action and clinical application prospects of SGLT-2 inhibitors in PD patients, synthesizing evidence from preclinical studies, observational data, and extrapolated findings from trials in chronic kidney disease (CKD) populations. By synthesizing existing literature, we seek to provide insights for clinical practice and illuminate future research directions.
Background and objectives Hypertension is a significant global health issue that raises the risk of cardiovascular diseases (CVDs). Qingda Granule (QDG) is a traditional Chinese medicine formula used to treat hypertension, but its active compounds and mechanisms of action remain poorly understood. Methods Network pharmacology identified potential active compounds and KEGG pathways. Four compounds-gastrodin, rhynchophylline, baicalin, and liensinine were selected. Hypertension was induced in mice via Angiotensin II (Ang II) infusion. QDG (1145 mg/kg/day) or each compound (10 mg/kg/day) was administered orally once daily. Outcomes measured included systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse wave velocity (PWV), and abdominal aortic wall thickness. Histological examination and immunohistochemistry for expression of total myosin light chain (MLC) and phosphorylation of myosin light chain (p-MLC) were performed in exploratory subgroups of three mice per group. Results Network pharmacology analysis identified 482 predicted targets overlapping with hypertension-related targets. The compound-target network was constructed and analyzed, and hub nodes were identified using multiple parameters, such as betweenness centrality and degree. These four selected compounds-gastrodin, rhynchophylline, baicalin, and liensinine-ranked among the top 50 nodes in the compound-target network. Consequently, these four compounds were selected for further validation. KEGG enrichment analysis identified vascular smooth muscle contraction as an enriched candidate pathway (18 targets). In vivo, QDG and all four compounds treatment significantly lowered blood pressure, lowered PWV, and reduced abdominal aortic wall thickness. Exploratory subgroup analyses showed attenuated aortic histopathological changes and reduced p-MLC immunoreactivity, with no significant difference in total MLC immunoreactivity in abdominal aortic tissues of Ang II-infused mice. Conclusion QDG and its four individually administered compounds attenuated blood pressure elevation and were associated with lower PWV and reduced abdominal aortic wall thickening in Ang II-infused mice, as well as reduced p-MLC immunoreactivity. These findings suggest that the QDG and its four compounds contribute to antihypertensive effects.
The ubiquitin-proteasome system (UPS) plays a central role in cellular protein homeostasis by regulating the degradation, trafficking, and activity of target proteins. Deubiquitinases (DUBs) are a crucial component of this regulatory network, catalyzing the removal of ubiquitin moieties from modified substrates to modulate signaling pathways that govern cell cycle control, apoptosis, DNA repair, immune responses, and stress adaptation. Aberrant DUB expression or activity is increasingly recognized as a driver of oncogenesis, tumor progression, drug resistance, and metastasis. As a result, DUBs have emerged as novel therapeutic targets in cancer, complementing existing proteasome inhibitors. This review provides an overview of DUB classification, their mechanistic roles in cancer biology, current progress in small-molecule DUB inhibitors and DUB-directed PROTACs, and discusses translational challenges and future opportunities for therapeutic development.
Atherosclerosis is a chronic inflammatory disease closely related to senescence, in which the imbalance of macrophage migration plays a key but not yet fully understood role. A clear conceptual distinction must be drawn between two directionally opposite migratory events: the ingress of circulating monocytes into the arterial intima, which is generally pro-atherogenic, and the egress of lipid-laden macrophages out of plaques, which is atheroprotective. Macrophages constitute a heterogeneous population of subpopulations—including M1, M2a–M2d, Mox, M4, Mhem and M(Hb) phenotypes—, each exhibiting distinct migratory capacities and occasionally opposing functions. Consequently, we hypothesize that the migration of macrophages plays a dual, context-dependent role in the pathogenesis of atherosclerosis. Some subsets of macrophages have been observed to promote inflammation and foam cell formation, while others exhibit anti-inflammatory properties and enhance plaque stability. It is crucial to acknowledge that the process of cellular senescence disrupts this balance through multiple pathways. Impaired chemokine receptor expression and intracellular localization, cytoskeletal dysfunction, metabolic reprogramming and defective efferocytosis all weaken directed migration. Concurrently, the senescence-associated secretory phenotype releases proinflammatory factors and induces senescence-associated extracellular vesicles, which continuously maintain a pro-atherosclerotic microenvironment. The regulatory pathways of macrophage migration, including the classic G protein-coupled receptor signaling pathway, guidance cues such as netrin-1, acute-phase proteins, lipoproteins and non-classical mediators, interact with senescence in a polarization-dependent manner. This review integrates recent evidence on the relationship between macrophage migration, senescence and atherosclerosis. We believe that senescence disrupts the balance of macrophage migration, thereby exacerbating atherosclerosis, and that stage- and subset-specific intervention at key targets of macrophage migration may be the key to the precise prevention and control of atherosclerosis.
