Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment.However,it is unclear whether the signals of bone cells in response to mechanical stress are processed...Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment.However,it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain.In this study,we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2(PGE2)concentration in response to mechanical loading.Bone PGE2 levels are in proportion to their weight bearing.When weight bearing changes in the tail-suspension mice,the PGE2 concentrations in bones change in line with their weight bearing changes.Deletion of cyclooxygenase-2(COX2)in the osteoblast lineage cells or knockout of receptor 4(EP4)in sensory nerve blunts bone formation in response to mechanical loading.Moreover,knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation.Moreover,mechanical loading induces cAMP-response element binding protein(CREB)phosphorylation in the hypothalamic arcuate nucleus(ARC)to inhibit sympathetic tyrosine hydroxylase(TH)expression in the paraventricular nucleus(PVN)for osteogenesis.Finally,we show that elevated PGE2 is associated with ankle osteoarthritis(AOA)and pain.Together,our data demonstrate that in response to mechanical loading,skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis,while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.展开更多
Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chem...Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.展开更多
Background:Radix Aconiti Lateralis Preparata(Fu-zi)is a traditional Chinese medicinal herb,which has been widely used in the clinic and has potent anti-inflammatory activities.we aimed to explore the mechanisms of ext...Background:Radix Aconiti Lateralis Preparata(Fu-zi)is a traditional Chinese medicinal herb,which has been widely used in the clinic and has potent anti-inflammatory activities.we aimed to explore the mechanisms of extract containing alkaloids from different Fu-zi Processed Products(FPP)in treating inflammation,especially rheumatoid arthritis(RA).Methods:Firstly,using network pharmacology technology,the ingredients,and targets of Fu-zi were obtained by searching and screening,the targets involving RA were acquired,the intersection targets were constructed a"component-target-pathway"network.A comprehensive investigation was conducted on the anti-rheumatoid arthritis mechanisms of 5 FPPs in lipopolysaccharide(LPS)induced RAW264.7 cells,which serve as a model for RA.The production of NO and inflammatory cytokines were measured by ELISA kit.Quantitative Real-time PCR(qRT-PCR)was utilized to measure the mRNA levels.COX-2/PGE2 signaling pathway-associated proteins were determined by western blot.Results:According to a network pharmacological study,16 chemical components and 43 common targets were found in Fu-zi and 6 key targets including PTGS2 were closely related to the mechanism of Fu-zi in treating RA.The in vitro study revealed that the levels of NO,TNF-α,and IL-1βwere substantially decreased by the 5 FPPs.The 5 FPPs significantly suppressed the expression of proteins COX-2,iNOS,and NF-κB,with particularly notable effects observed for PFZ and XFZ.Conclusion:Altogether,these results demonstrated that the 5 PPS containing alkaloids have a good anti-RA-related inflammatory effect,and the mechanism may be related to COX-2/PGE2 signaling pathway,particularly,Fu-zi prepared utilizing a traditional Chinese technique.展开更多
目的探究通经补肾益髓汤联合调督理筋针法对腰椎间盘突出症患者的疗效及对血清前列腺素E2(Prostaglandin E2,PGE2)、血清磷酸化p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p-p38MAPK)水平的影响。方法选取医院收治的...目的探究通经补肾益髓汤联合调督理筋针法对腰椎间盘突出症患者的疗效及对血清前列腺素E2(Prostaglandin E2,PGE2)、血清磷酸化p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p-p38MAPK)水平的影响。方法选取医院收治的腰椎间盘突出症患者150例,将其随机分为对照组和观察组,两组各75例。对照组给予常规西药治疗,观察组给予通经补肾益髓汤联合调督理筋针法治疗,两组疗程均为4周,对比治疗后的临床治疗效果、视觉模拟评分法(visual analogue scale,VAS)、Oswestry功能障碍指数(Oswestry disability index,ODI)、腰椎间隙和腰椎活动度、血清PGE2、p-P38MAPK水平、健康调查简表(the MOS item short from health survey,SF-36)评分。结果两组患者经4周治疗,观察组总有效率为96.00%(72/75),较对照组(84.00%,63/75)有显著提高(P<0.05);治疗后,VAS评分、ODI指数均较治疗前显著降低(P<0.05),且观察组降低程度显著优于对照组(P<0.05);治疗后两组腰椎间隙高度较治疗前升高(P<0.05),腰椎活动度均较治疗前降低,且观察组显著优于对照组(P<0.05);治疗后,血清PGE2水平较治疗前显著降低,血清p-P38MAPK水平较治疗前显著升高(P<0.05),同时观察组较对照组改善显著(P<0.05);两组患者治疗后SF-36量表各条目评分较治疗前均显著提高(P<0.05),观察组提高程度更明显(P<0.05)。结论通经补肾益髓汤联合调督理筋针法能显著提高腰椎间盘突出症患者的临床治疗效果,改善患者疼痛及活动功能,显著降低血清PGE2水平,提高p-P38MAPK水平,提高患者生活质量。展开更多
基金This research was supported by NIH National Institute on Aging under Award Number R01 AG076783,R01 AG068997 and P01 AG066603(to X.C.).
文摘Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment.However,it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain.In this study,we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2(PGE2)concentration in response to mechanical loading.Bone PGE2 levels are in proportion to their weight bearing.When weight bearing changes in the tail-suspension mice,the PGE2 concentrations in bones change in line with their weight bearing changes.Deletion of cyclooxygenase-2(COX2)in the osteoblast lineage cells or knockout of receptor 4(EP4)in sensory nerve blunts bone formation in response to mechanical loading.Moreover,knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation.Moreover,mechanical loading induces cAMP-response element binding protein(CREB)phosphorylation in the hypothalamic arcuate nucleus(ARC)to inhibit sympathetic tyrosine hydroxylase(TH)expression in the paraventricular nucleus(PVN)for osteogenesis.Finally,we show that elevated PGE2 is associated with ankle osteoarthritis(AOA)and pain.Together,our data demonstrate that in response to mechanical loading,skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis,while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.
基金National Yang Ming Chiao Tung University Far Eastern Memorial Hospital Joint Research Programs(NYCU-FEMH 109DN03,110DN06,111DN04,112DN05).
文摘Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.
基金supported by Sichuan Province Science and Technology Support Program(NO.2020JDJQ0063,NO.2020YFS0566 and NO.2021JDKY0037,A-2021N-Z-5).
文摘Background:Radix Aconiti Lateralis Preparata(Fu-zi)is a traditional Chinese medicinal herb,which has been widely used in the clinic and has potent anti-inflammatory activities.we aimed to explore the mechanisms of extract containing alkaloids from different Fu-zi Processed Products(FPP)in treating inflammation,especially rheumatoid arthritis(RA).Methods:Firstly,using network pharmacology technology,the ingredients,and targets of Fu-zi were obtained by searching and screening,the targets involving RA were acquired,the intersection targets were constructed a"component-target-pathway"network.A comprehensive investigation was conducted on the anti-rheumatoid arthritis mechanisms of 5 FPPs in lipopolysaccharide(LPS)induced RAW264.7 cells,which serve as a model for RA.The production of NO and inflammatory cytokines were measured by ELISA kit.Quantitative Real-time PCR(qRT-PCR)was utilized to measure the mRNA levels.COX-2/PGE2 signaling pathway-associated proteins were determined by western blot.Results:According to a network pharmacological study,16 chemical components and 43 common targets were found in Fu-zi and 6 key targets including PTGS2 were closely related to the mechanism of Fu-zi in treating RA.The in vitro study revealed that the levels of NO,TNF-α,and IL-1βwere substantially decreased by the 5 FPPs.The 5 FPPs significantly suppressed the expression of proteins COX-2,iNOS,and NF-κB,with particularly notable effects observed for PFZ and XFZ.Conclusion:Altogether,these results demonstrated that the 5 PPS containing alkaloids have a good anti-RA-related inflammatory effect,and the mechanism may be related to COX-2/PGE2 signaling pathway,particularly,Fu-zi prepared utilizing a traditional Chinese technique.
文摘目的探究通经补肾益髓汤联合调督理筋针法对腰椎间盘突出症患者的疗效及对血清前列腺素E2(Prostaglandin E2,PGE2)、血清磷酸化p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p-p38MAPK)水平的影响。方法选取医院收治的腰椎间盘突出症患者150例,将其随机分为对照组和观察组,两组各75例。对照组给予常规西药治疗,观察组给予通经补肾益髓汤联合调督理筋针法治疗,两组疗程均为4周,对比治疗后的临床治疗效果、视觉模拟评分法(visual analogue scale,VAS)、Oswestry功能障碍指数(Oswestry disability index,ODI)、腰椎间隙和腰椎活动度、血清PGE2、p-P38MAPK水平、健康调查简表(the MOS item short from health survey,SF-36)评分。结果两组患者经4周治疗,观察组总有效率为96.00%(72/75),较对照组(84.00%,63/75)有显著提高(P<0.05);治疗后,VAS评分、ODI指数均较治疗前显著降低(P<0.05),且观察组降低程度显著优于对照组(P<0.05);治疗后两组腰椎间隙高度较治疗前升高(P<0.05),腰椎活动度均较治疗前降低,且观察组显著优于对照组(P<0.05);治疗后,血清PGE2水平较治疗前显著降低,血清p-P38MAPK水平较治疗前显著升高(P<0.05),同时观察组较对照组改善显著(P<0.05);两组患者治疗后SF-36量表各条目评分较治疗前均显著提高(P<0.05),观察组提高程度更明显(P<0.05)。结论通经补肾益髓汤联合调督理筋针法能显著提高腰椎间盘突出症患者的临床治疗效果,改善患者疼痛及活动功能,显著降低血清PGE2水平,提高p-P38MAPK水平,提高患者生活质量。
