Bone frequently serves as a metastatic site for breast and prostate cancers. Given the potential of low-intensity vibration(LIV) to increase bone health and reduce cancer risk, this study investigated the impact of LI...Bone frequently serves as a metastatic site for breast and prostate cancers. Given the potential of low-intensity vibration(LIV) to increase bone health and reduce cancer risk, this study investigated the impact of LIV on cancer cells, as well as noncancer cells such as lymphocytes and peripheral blood mononuclear cells(PBMCs). The results revealed that LIV exposure not only suppressed cancer cell migration but also triggered the generation of induced tumor-suppressing(iTS) cells. Conditioned medium(CM) derived from LIV-treated PBMCs shrank freshly isolated breast and prostate cancer tissues, and when CM was combined with a chemotherapeutic agent, additional antitumor effects were observed.Notably, iTS cell-derived CM hindered the maturation of the receptor activator of nuclear factor-kappa B ligand(RANKL)-stimulated bone-resorbing osteoclasts while promoting the differentiation of bone-forming osteoblasts. Intriguingly, the anticancer effects induced by LIV were replicated by simply shaking a cell-containing tube with a regular tube shaker. Using mass spectrometry-based proteomics, this study revealed enrichment of tumor-suppressing proteins, including enolase 1, moesin(MSN), and aldolase A(ALDOA), which are commonly found in oncogene-activated iTS cells, in LIV-induced CM. Sad1 and UNC-84 domain containing 1(SUN1), a core component of the linker of the nucleoskeleton and cytoskeleton(LINC) complex, exhibited heightened expression, notably enhancing the response of lymphocytes to LIV. An ex vivo bone cancer model further demonstrated the potent anticancer effects of lymphocyte-derived CM. In conclusion, this study underscores the pivotal role of LIV in preventing bone loss in the tumor microenvironment.展开更多
Direct evidence regarding ion channel-mediated initiation of baroreflex/visceral neurotransmission remains limited.Here,aortic-arch,vagus-nodose slice,and isolated neurons were employed with single-fiber/whole-cell pa...Direct evidence regarding ion channel-mediated initiation of baroreflex/visceral neurotransmission remains limited.Here,aortic-arch,vagus-nodose slice,and isolated neurons were employed with single-fiber/whole-cell patch-clamp recordings to record instantaneous discharge of the aortic depressor nerve,spontaneous/evoked membrane depolarizations under different pharmacological interventions.Strikingly,profiles of A-fiber’s instantaneous firing frequency(IFF),including pressure threshold,rate,and sensitivity,were significantly reduced by 10µmol/L flufenamic acid(FAA)and further suppressed by 3µmol/L GsMTx4.Conversely,3µmol/L Yoda1-enhanced IFF was reversed by GsMTx4 and partially inhibited by FAA,consistent with step depolarization-evoked action potentials(APs).In<10%of A-type neurons,spontaneous APs accompanied by major(Ma-STPs)and minor sub-threshold depolarizations(Mi-STPs)were abolished by nanomolar tetrodotoxin.FAA only blocked spontaneous APs,while GsMTx4 suppressed both APs and Ma-STPs.The equal number of APs and Ma-STPs before and after FAA suggests that spontaneous APs initiate from Ma-STPs.Further,single-cell transcriptomic analysis revealed significant Piezo1 and TRPM4 co-expression in neurons.Gene co-expression and clustering analysis support their cooperative role in the baroreflex and visceral afferent pathways,validated by gene expression data.These findings demonstrate that TTX-sensitive Na+(TTX-S),Piezo1,and TRPM4 channels each possess important intrinsic functions and play unique roles in the initiation of baroreflex/visceral neurotransmission.展开更多
基金funded by the Indiana Clinical and Translational Science Institute and Showalter Trust (to Uma K. Aryal)the Human Resources Program in Energy Technology of the Korea Institute of Energy Technology Evaluation and Planning (20214000000140 (to HeeChang Lim))+2 种基金the National Institutes of Health R35GM147412 (to Jing Liu) and R01AR074473 (to William R. Thompson)the National Natural Science Foundation of China, 81971326 (to Bai-Yan Li)the 100 Voices of Hope (to Hiroki Yokota)。
文摘Bone frequently serves as a metastatic site for breast and prostate cancers. Given the potential of low-intensity vibration(LIV) to increase bone health and reduce cancer risk, this study investigated the impact of LIV on cancer cells, as well as noncancer cells such as lymphocytes and peripheral blood mononuclear cells(PBMCs). The results revealed that LIV exposure not only suppressed cancer cell migration but also triggered the generation of induced tumor-suppressing(iTS) cells. Conditioned medium(CM) derived from LIV-treated PBMCs shrank freshly isolated breast and prostate cancer tissues, and when CM was combined with a chemotherapeutic agent, additional antitumor effects were observed.Notably, iTS cell-derived CM hindered the maturation of the receptor activator of nuclear factor-kappa B ligand(RANKL)-stimulated bone-resorbing osteoclasts while promoting the differentiation of bone-forming osteoblasts. Intriguingly, the anticancer effects induced by LIV were replicated by simply shaking a cell-containing tube with a regular tube shaker. Using mass spectrometry-based proteomics, this study revealed enrichment of tumor-suppressing proteins, including enolase 1, moesin(MSN), and aldolase A(ALDOA), which are commonly found in oncogene-activated iTS cells, in LIV-induced CM. Sad1 and UNC-84 domain containing 1(SUN1), a core component of the linker of the nucleoskeleton and cytoskeleton(LINC) complex, exhibited heightened expression, notably enhancing the response of lymphocytes to LIV. An ex vivo bone cancer model further demonstrated the potent anticancer effects of lymphocyte-derived CM. In conclusion, this study underscores the pivotal role of LIV in preventing bone loss in the tumor microenvironment.
基金financially supported by the National Natural Science Foundation of China(Nos.81971326 and 81573431)partially supported by the Heilongjiang Provincial Research Institute Project(No.CZKYF2024-1-A003).
文摘Direct evidence regarding ion channel-mediated initiation of baroreflex/visceral neurotransmission remains limited.Here,aortic-arch,vagus-nodose slice,and isolated neurons were employed with single-fiber/whole-cell patch-clamp recordings to record instantaneous discharge of the aortic depressor nerve,spontaneous/evoked membrane depolarizations under different pharmacological interventions.Strikingly,profiles of A-fiber’s instantaneous firing frequency(IFF),including pressure threshold,rate,and sensitivity,were significantly reduced by 10µmol/L flufenamic acid(FAA)and further suppressed by 3µmol/L GsMTx4.Conversely,3µmol/L Yoda1-enhanced IFF was reversed by GsMTx4 and partially inhibited by FAA,consistent with step depolarization-evoked action potentials(APs).In<10%of A-type neurons,spontaneous APs accompanied by major(Ma-STPs)and minor sub-threshold depolarizations(Mi-STPs)were abolished by nanomolar tetrodotoxin.FAA only blocked spontaneous APs,while GsMTx4 suppressed both APs and Ma-STPs.The equal number of APs and Ma-STPs before and after FAA suggests that spontaneous APs initiate from Ma-STPs.Further,single-cell transcriptomic analysis revealed significant Piezo1 and TRPM4 co-expression in neurons.Gene co-expression and clustering analysis support their cooperative role in the baroreflex and visceral afferent pathways,validated by gene expression data.These findings demonstrate that TTX-sensitive Na+(TTX-S),Piezo1,and TRPM4 channels each possess important intrinsic functions and play unique roles in the initiation of baroreflex/visceral neurotransmission.
