CNS Neuroscience & Therapeutics
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2017
·Vol. 23
·期 6
·498-509
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IF 3.919
Cui Huang,Dong Dong,Qian Jiao,Hui Pan,Lei Ma,Rui Wang
Summary Aims Sarsasapogenin has been reported to improve dementia symptoms somehow, probably through modulating the function of cholinergic system, suppressing neurofibrillary tangles, and inhibiting inflammation. However, the role of sarsasapogenin in response to beta-amyloid (A β ) remains to be delineated. This study aimed to determine the therapeutic effect of sarsasapogenin-13 (AA13, a sarsasapogenin derivative) on learning and memory impairments in A β -injected mice, as well as the role of AA13 in neuroglia-mediated antiinflammation and A β clearance. Methods Focusing on the role of AA13 in regulating glial responses to A β , we conducted behavioral, morphological, and protein expression studies to explore the effects of AA13 on A β clearance and inflammatory regulation. Results The results indicated that oral administration of AA13 attenuated the memory deficits of intracerebroventricular (i.c.v.) A β -injected mice; also, AA13 protected neuroglial cells against A β -induced cytotoxicity. The further mechanical studies demonstrated that AA13 reversed the upregulation of proinflammatory M1 markers and increased the expression of antiinflammatory M2 markers in A β -treated cells. Furthermore, AA13 facilitated A β clearance through promoting A β phagocytosis and degradation. AA13 modulated the expression of fatty acid translocase (CD36), insulin-degrading enzyme (IDE), neprilysin (NEP), and endothelin-converting enzyme (ECE) in neuroglia. Conclusion The present study indicated that the neuroprotective effect of AA13 might relate to its modulatory effects on microglia activation state, phagocytic ability, and expression of A β -degrading enzymes, which makes it a promising therapeutic agent in the early stage of Alzheimer's disease (AD).
研究领域:
神经科学
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药理学
·
神经退行性疾病
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Fang Wang,Fanxuan Zhang,Bingfeng Lin,Wenlong Xiao,Xuchen Wang,Nani Wang
Background Promoting 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. Methods Bone 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. Results SAR 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. Conclusions These 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.
研究领域:
医学
·
分子生物学
·
药理学
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DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Qiang Yuan,Yaoke Li,Kaiwen Shen,Ruibo Zhang,Qiang Wang,Shasha Xia,Jun Shen
Background Renal ischemia-reperfusion injury (RIRI) contributes significantly to acute kidney injury (AKI), which is associated with high morbidity and mortality rates. Currently, therapeutic options for RIRI remain limited. Sarsasapogenin (Sar), a steroidal saponin from Anemarrhena asphodeloides, exhibits strong anti-inflammatory properties. However, its renoprotective effects, dose-response characteristics, and tissue-specific benefits in acute RIRI have not been thoroughly explored. This study aimed to determine whether Sar provides protection against RIRI-induced AKI and to investigate the potential signaling pathways involved. Methods Rats underwent 45 min of renal ischemia followed by reperfusion. Sar (20 or 60 mg/kg) was administered daily via gavage for one week prior to surgery. As a positive control, INF39 (7.5 mg/kg), an NLRP3 inhibitor, was injected intraperitoneally 2 h before surgery. Renal function was assessed through serum creatinine and BUN levels, while histopathology was evaluated using H&E and TEM. Tubular injury markers, such as KIM-1, were also assessed. Total cell death was determined using the TUNEL assay, which detects DNA fragmentation but does not specifically identify pyroptosis. The expression of inflammatory factors (IL-1β, IL-6, TNF-α) and key proteins of the NF-κB pathway (p-p65/p65) and NLRP3 inflammasome (NLRP3, Caspase-1, GSDMD) were measured using ELISA, immunohistochemistry, immunofluorescence, and Western blotting. Results RIRI led to severe renal dysfunction, structural damage, and increased KIM-1 expression. These pathological changes were linked to significant activation of the NF-κB pathway, upregulation of NLRP3 inflammasome components, and increased pyroptosis, indicated by elevated levels of cleaved Caspase-1, GSDMD-N, and mature IL-1β. Pretreatment with Sar dose-dependently improved renal function and reduced histopathological injury. Sar provided tissue-specific protection by maintaining mitochondrial integrity in renal tubular epithelial cells. These beneficial effects were accompanied by decreased phosphorylation of p65, reduced expression of NLRP3, cleaved Caspase-1, and GSDMD-N, as well as lower IL-1β production. High-dose Sar exhibited renoprotective effects comparable to INF39, acting as a multi-stage regulator that inhibits both NF-κB priming and NLRP3 inflammasome activation, suggesting advantages over single-target inhibitors. Conclusion Sar effectively attenuated RIRI-induced AKI, demonstrating favorable dose-dependent and tissue-specific renoprotective effects. This protective effect was associated with suppression of the NF-κB/NLRP3 inflammasome axis and reduced pyroptosis, highlighting its potential as a safe, multi-stage, natural candidate for treating ischemia-related renal injury.
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PubMed
高影响因子
Cardiovascular Diagnosis and Therapy
·
2023
·
IF 2.4
Haiying Zhai,Hongqin Liu,Baoling Shang,Xu Zou
Background Atherosclerosis (AS) is a pathological vascular disorder responsible for the majority of cardiovascular deaths. Sarsasapogenin (Sar) is a natural steroidal compound which has been extensively applied to multiple human diseases due to its pharmacological properties. In the present paper, the impacts of Sar on oxidized low-density lipoprotein (ox-LDL)-treated vascular smooth muscle cells (VSMCs) and its possible action mechanism were investigated. Methods Firstly, Cell Counting Kit-8 (CCK-8) estimated the viability of VSMCs following treatment with ascending doses of Sar. Then, VSMCs were treated by ox-LDL to stimulate an in vitro cell model of AS. CCK-8 and 5-Ethynyl-2’-deoxyuridine (EDU) assays were used to assess cell proliferation. Wound healing and transwell assays were applied to measure the migratory and invasive capacities, respectively. The expression of proliferation-, metastasis-, and stromal interaction molecule 1 (STIM1)/Orai signaling-associated proteins was measured by western blot. Results The experimental data illuminated that Sar treatment noticeably protected against ox-LDL-elicited VSMCs proliferation, migration, and invasion. Besides, Sar lowered the elevated STIM1 and Orai expression in ox-LDL-treated VSMCs. Further, STIM1 elevation partially abrogated the impacts of Sar on the proliferation, migration, and invasion of VSMCs challenged with ox-LDL. Conclusions In conclusion, Sar might reduce STIM1 expression to impede the aggressive phenotypes of ox-LDL-treated VSMCs.
研究领域:
心血管疾病
·
药理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
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