Selisistat

Postmenopausal osteoporosis (PMOP) is a prevalent condition among postmenopausal women, closely linked to estrogen deficiency, aging, and oxidative stress. Cellular senescence, through mechanisms such as the senescence-associated secretory phenotype (SASP) and bone marrow stromal cells (BMSCs) differentiation imbalance, disrupts bone homeostasis in PMOP. Macrophages play a critical role in maintaining bone homeostasis. However, the extent of macrophage senescence in PMOP and the mechanisms by which it disrupts bone homeostasis have not yet been elucidated. Eldecalcitol (ED-71), a novel drug, has shown potential in osteoporosis treatment, though its effects on macrophage are not fully elucidated. In this study, using hydrogen peroxide (H₂O₂), we induced senescence in macrophages and assessed senescence-associated markers by SA-β-gal staining, Western blotting, and RT-qPCR. We then employed an indirect co-culture system to investigate the paracrine impact of these senescent macrophages on the osteogenic differentiation of BMSCs. The PMOP model was established using ovariectomy (OVX) in mice, followed by histological evaluation. Both 17β-Estradiol (E2) and ED-71 effectively reduced cellular senescence-related indicators such as p16, p53 and β-galactosidase in macrophages, suggesting E2 can alleviate macrophage senescence, and ED-71 may serve as an alternative. Co-culture systems revealed that senescent macrophages impaired BMSCs osteogenic differentiation, an effect reversed by ED-71. SIRT1 inhibition with EX-527 disrupted ED-71's anti-senescence action. Additionally, ED-71 improved bone mass and aging in OVX mice. In conclusion, ED-71 alleviates macrophage senescence via the SIRT1/PGC-1α signaling axis, thereby enhancing BMSC osteogenic potential and mitigating bone loss in OVX-induced osteoporosis.

Patchoulol (PAT) is the key bioactive component from Pogostemon cablin (Blanco) Benth., a well-known botanical medicine for gastrointestinal diseases. However, the action of PAT on adipose tissue remodeling in obesity remains unknown.

In this study, cellular contribution to adipose tissue remodeling at single-cell and the action of PAT were explored.

Single-cell transcriptional analysis was performed on visceral adipose tissue from lean and obese mice. Obese mouse model was conducted, TNF-α induced mature adipocytes was utilized, and the co-culture system of adipocytes and macrophages was used to assess the action of PAT. RNA-sequencing, cellular thermal shift assay and specific inhibitor EX527 was utilized to estimate the mechanism of PAT.

Single-cell analysis revealed the adipocytes served as the initiator that aggravated inflammatory response and associated fibrosis, and RNA-sequencing found PAT recovered aberrant changes of genes in mature adipocytes, especially those related to inflammatory response and NAD⁺ dependent protein deacetylase activity. In obese mice, PAT mitigated insulin resistance and adipose tissue remodeling by promoting deacetylase SIRT1 with inhibition of MAPK and NF-κB signals, manifested as reduction of macrophage infiltration, decline of pro-inflammatory macrophage polarization and abnormal deposition of extracellular matrix. Moreover, PAT alleviates inflammatory responses in mature adipocytes and suppressed macrophage migration towards inflammatory adipocytes by activating SIRT1, which were abolished by the specific inhibitor EX527.

Current findings provide a novel understanding of adipose tissue remodeling at single-cell level, and SIRT1 might be a critical pharmacological target of PAT that contributes to treat obesity and metabolic diseases.