Aim YiQiFuMai Powder Injection is a well-known traditional Chinese medicine formula that has been used extensively in clinical treatment of cardio-cerebral ischemic diseases in China. However, the mechanisms under-lyi...Aim YiQiFuMai Powder Injection is a well-known traditional Chinese medicine formula that has been used extensively in clinical treatment of cardio-cerebral ischemic diseases in China. However, the mechanisms under-lying its clinical efficacy remain unknown. In this study, a network pharmacology approach was employed to identify the YiQiFuMai Powder Injection＇s potential pathways and targets against cardio-cerebral ischemia. The target-path- way interaction network clustered the signaling pathways based on high degree nodes of the drug-target network. The potential protein targets presented in the highly scored clustered pathways were the key network hubs and concentrated on one or limited functional signaling pathways amenable to experimental verification. Twelve main functional annota- tion clusters and main signaling pathways for YiQiFuMai Powder Injection were established by Biocarta analysis, in- eluding the NF-KB signaling pathway, the MAPKinase signaling pathway and the mTOR-signaling pathway and so on. YiQiFuMai Powder Injection is hypothesized to target multiple proteins with a high degree and betweenness of net- work. In addition, the most related pathways were also confirmed in tumor necrosis factor-alpha （TNF-oL） induced human vascular endothelial cell line EA. hy926 by Western blot. This study elucidates the systematic network and pathway analysis of multi-targets in YiQiFuMai Powder Injection. The results provide the possible mechanisms for its mode of action against cardio-cerebral ischemic diseases and may also reveal new clues for its potential application in the inflammatory diseases or tumors.展开更多
Perlecan,a heparan sulfate proteoglycan,acts as a mechanical sensor for bone to detect external loading.Deficiency of perlecan increases the risk of osteoporosis in patients with Schwartz-Jampel Syndrome(SJS)and atten...Perlecan,a heparan sulfate proteoglycan,acts as a mechanical sensor for bone to detect external loading.Deficiency of perlecan increases the risk of osteoporosis in patients with Schwartz-Jampel Syndrome(SJS)and attenuates loading4nduced bone formation in perlecan deficient mice(Hypo).Considering that intracellular calcium[Ca2+]i is an ubiquitous messenger controlling numerous cellular processes including mechanotransduction,we hypothesized that perlecan deficiency impairs bone’s calcium signaling in response to loading.To test this,we performed real-time[Ca2+]i imaging on in situ osteocytes of adult murine tibiae under cyclic loading(8 N,Figure 1).Relative to wild type(WT),Hypo osteocytes showed decreases in the overall[Ca2+]i response rate(-58%),calcium peaks(-33%),cells with multiple peaks(-53%),peak magnitude(-6.8%),and recovery speed to baseline(-23%).RNA sequencing and pathway analysis of tibiae from mice subjected to one or seven days of unilateral loading demonstrated that perlecan deficiency significantly suppressed the calcium signaling,ECM-receptor interaction,and focal adhesion pathways following repetitive loading.Defects in the endoplasmic reticulum(ER)calcium cycling regulators such as Ryr1/ryanodine receptors and Atp2a1/Sercal calcium pumps were identified in Hypo bones.Taken together,impaired calcium signaling may contribute to bone’s reduced anabolic response to loading,underlying the osteoporosis risk for the SJS patients.展开更多
文摘Aim YiQiFuMai Powder Injection is a well-known traditional Chinese medicine formula that has been used extensively in clinical treatment of cardio-cerebral ischemic diseases in China. However, the mechanisms under-lying its clinical efficacy remain unknown. In this study, a network pharmacology approach was employed to identify the YiQiFuMai Powder Injection＇s potential pathways and targets against cardio-cerebral ischemia. The target-path- way interaction network clustered the signaling pathways based on high degree nodes of the drug-target network. The potential protein targets presented in the highly scored clustered pathways were the key network hubs and concentrated on one or limited functional signaling pathways amenable to experimental verification. Twelve main functional annota- tion clusters and main signaling pathways for YiQiFuMai Powder Injection were established by Biocarta analysis, in- eluding the NF-KB signaling pathway, the MAPKinase signaling pathway and the mTOR-signaling pathway and so on. YiQiFuMai Powder Injection is hypothesized to target multiple proteins with a high degree and betweenness of net- work. In addition, the most related pathways were also confirmed in tumor necrosis factor-alpha （TNF-oL） induced human vascular endothelial cell line EA. hy926 by Western blot. This study elucidates the systematic network and pathway analysis of multi-targets in YiQiFuMai Powder Injection. The results provide the possible mechanisms for its mode of action against cardio-cerebral ischemic diseases and may also reveal new clues for its potential application in the inflammatory diseases or tumors.
基金supported by NIH grants ( P30GM103333,R01AR054385)supported partially by a core access award through NIH NIGMS IDeA Program grant ( P20GM103446)
文摘Perlecan,a heparan sulfate proteoglycan,acts as a mechanical sensor for bone to detect external loading.Deficiency of perlecan increases the risk of osteoporosis in patients with Schwartz-Jampel Syndrome(SJS)and attenuates loading4nduced bone formation in perlecan deficient mice(Hypo).Considering that intracellular calcium[Ca2+]i is an ubiquitous messenger controlling numerous cellular processes including mechanotransduction,we hypothesized that perlecan deficiency impairs bone’s calcium signaling in response to loading.To test this,we performed real-time[Ca2+]i imaging on in situ osteocytes of adult murine tibiae under cyclic loading(8 N,Figure 1).Relative to wild type(WT),Hypo osteocytes showed decreases in the overall[Ca2+]i response rate(-58%),calcium peaks(-33%),cells with multiple peaks(-53%),peak magnitude(-6.8%),and recovery speed to baseline(-23%).RNA sequencing and pathway analysis of tibiae from mice subjected to one or seven days of unilateral loading demonstrated that perlecan deficiency significantly suppressed the calcium signaling,ECM-receptor interaction,and focal adhesion pathways following repetitive loading.Defects in the endoplasmic reticulum(ER)calcium cycling regulators such as Ryr1/ryanodine receptors and Atp2a1/Sercal calcium pumps were identified in Hypo bones.Taken together,impaired calcium signaling may contribute to bone’s reduced anabolic response to loading,underlying the osteoporosis risk for the SJS patients.
