Sarsasapogenin stimulates angiogenesis and osteogenesis coupling to treat estrogen deficiency-induced osteoporosis by activating the GPX4/SLIT3/ROBO1 axis

Article

Author: Lin, Bingfeng ; Wang, Xuchen ; Xiao, Wenlong ; Wang, Nani ; Zhang, Fanxuan ; Wang, Fang

BACKGROUNDPromoting the coupling of osteogenesis and angiogenesis is a crucial strategy for the treatment of postmenopausal osteoporosis (PMOP). Estrogen deficiency induces ferroptosis, which is closely associated with the pathophysiology of PMOP. Sarsasapogenin (SAR) is a natural sapogenin with anti-oxidative effects. However, it is unclear whether SAR has a protective role against the impaired osteogenesis and angiogenesis coupling in PMOP. In this study, we evaluated the efficacy of SAR in estrogen deficiency-induced osteoporosis and explored the underlying mechanisms.METHODSBone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) were utilized to assess the in vitro effects of SAR on the coupling of osteogenesis and angiogenesis. In vivo experiments involved bilateral ovariectomy (OVX)-induced osteoporosis in mice and glutathione peroxidase 4 (GPX4)-knockout (KO) mice. Mice were orally administered SAR (5 or 10 mg/kg/d) for a duration of 12 weeks. The direct target of SAR was investigated through molecular docking, a cellular thermal shift assay, and surface plasmon resonance. Additionally, RNA sequencing was employed to elucidate the underlying mechanisms.RESULTSSAR treatment improved cell viability and osteogenic differentiation while inhibiting ferroptosis in iron dextran-induced BMSCs. Furthermore, SAR enhanced the production of slit guidance ligand 3 (SLIT3) in these cells, which stimulated angiogenesis by activating its receptor, roundabout human homolog 1 (ROBO1), in HUVECs. An in vitro model of ferroptosis induced by erastin demonstrated that SAR promoted the coupling of osteogenesis and angiogenesis by upregulating the BMSCs-SLIT3/HUVECs-ROBO1 axis. Activation of GPX4 was identified as a contributing factor to the effects of SAR on this coupling. Transfection of GPX4 small interfering RNA (siRNA) in BMSCs negated the impact of SAR on the BMSCs-SLIT3/HUVECs-ROBO1 axis. Additionally, SAR was found to directly interact with GPX4, enhancing protein stability, with an equilibrium dissociation constant of 44.6 μM. Notably, SAR did not increase SLIT3, ROBO1, or indicators of osteogenesis or angiogenesis in GPX4-KO mice.CONCLUSIONSThese findings underscore the significance of restoring the GPX4/SLIT3/ROBO1 axis in promoting the coupling of angiogenesis and osteogenesis. SAR mitigates PMOP, in part, by activating the BMSCs-SLIT3/HUVECs-ROBO1 axis, with GPX4 serving as an upstream signaling modulator responsible for SLIT3 production. Our observations provide experimental evidence supporting the clinical application of SAR in the treatment of PMOP.

25 Dec 2024·Modern Rheumatology

The effects of sarilumab as monotherapy and in combination with non-methotrexate disease-modifying anti-rheumatic drugs on unacceptable pain in patients with rheumatoid arthritis: A post-hoc analysis of the HARUKA phase 3 study

Article

Author: van Hoogstraten, Hubert ; Tanaka, Yoshiya ; Kato, Naoto ; Takahashi, Toshiya ; Kameda, Hideto

ABSTRACTObjectivesTo investigate unacceptable pain [UP; visual analogue scale (VAS) >40 mm] and uncontrolled inflammation [C-reactive protein (CRP) ≥1.0 mg/dL] in patients with active rheumatoid arthritis (RA) receiving sarilumab (SAR) as monotherapy or in combination with non-methotrexate conventional synthetic disease-modifying antirheumatic drugs (SAR + csDMARDs).MethodsIn the HARUKA Phase 3 study (NCT02373202), Japanese patients received either SAR monotherapy (n = 61) or SAR + csDMARDs (n = 30). In this post-hoc analysis, changes in the proportions of patients with/without UP and controlled/uncontrolled inflammation were assessed over 52 weeks.ResultsAt baseline, 80.3% (49/61) of patients receiving SAR monotherapy had UP and this proportion decreased with treatment to 55.9% (33/59) at Week 4 and 15.5% (9/58) at Week 52. The SAR + csDMARDs group achieved a reduction in UP from 73.3% (22/30) at baseline to 34.5% (10/29) at Week 4 and 0% (0/24) by Week 52. At baseline, 34.4% (21/61) and 50% (15/30) of patients had both UP and uncontrolled inflammation in the SAR monotherapy and SAR + csDMARDs groups; by Week 2, the proportions decreased to 6.6% (4/61) and 3.3% (1/30), respectively; and 0% in both groups by Week 52.ConclusionUP and inflammation were reduced in patients with active RA in Japan in both SAR monotherapy and SAR + csDMARDs treatment groups.

30 Oct 2024·Rapid Communications in Mass Spectrometry

Integrated network pharmacology and GC–MS‐based metabolomics to investigate the chemical profile and efficacy of Anemarrhenae Rhizoma and its processed products

Article

Author: Wang, Nan ; Tian, Xi ; Wei, Jinhuan ; Li, Wenyu ; Jin, Yiran ; Niu, Yukun ; Du, Yingfeng ; Yang, Mengxin ; Zhang, Qian ; Zhang, Huiyi

RationaleAnemarrhenae Rhizoma (AR) has been a frequently utilized traditional Chinese medicine (TCM) for an extended period, with its salt‐processed variant being a prevalent application form. Contemporary pharmacological investigations have demonstrated that the salt‐processed iteration exhibits a multitude of markedly augmented pharmacological properties. However, whether the pharmacodynamic material basis of this change is related to volatile substances remains unclear. The aim of this study was to develop a strategy to screen volatile pharmacodynamic substances in AR and salt‐processed AR (SAR).MethodsA comprehensive approach was developed to identify volatile pharmacodynamic compounds by integrating plant metabolomics, target network pharmacology, and molecular docking technology. Plant metabolomics using GC–MS analysis was conducted to identify volatile chemical markers distinguishing between AR and SAR. Subsequently, network pharmacology was utilized to investigate the correlation between chemical markers and associated diseases. Following this, molecular docking technology was utilized to explore the correlation between chemical markers and disease targets, resulting in the discovery of potential quality control markers.ResultsFifty volatile compounds were isolated and identified in the salt of AR and SAR. The findings from plant metabolomics analysis demonstrated a distinct differentiation, revealing 13 volatile chemical markers that distinguish between AR and SAR. A target (PPARG) associated with diabetes was identified through target network pharmacology analysis. Thirteen volatile components were subsequently chosen as potential quality markers, taking into account their hypoglycemic activity.ConclusionsThe method developed provides a novel strategy for the identification of pharmacophores in AR and SAR, as well as establishing a foundation for the exploration of the volatile differential components and pharmacodynamics in various processed products of TCMs. Additionally, the findings of this study can serve as a theoretical framework for the development and utilization of volatile components in AR and its processed derivatives.

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