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Browsing by Author "Li, Ke-Xin"
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Item Anticancer peptides from induced tumor-suppressing cells for inhibiting osteosarcoma cells(e-Century, 2023-09-15) Cui, Chang-Peng; Huo, Qing-Ji; Xiong, Xue; Li, Ke-Xin; Ma, Peng; Qiang, Gui-Fen; Pandya, Pankita H.; Saadatzadeh, Mohammad R.; Vishehsaraei, Khadijeh Bijangi; Kacena, Melissa A.; Aryal, Uma K.; Pollok, Karen E.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyOsteosarcoma (OS) is the most frequent primary bone cancer, which is mainly suffered by children and young adults. While the current surgical treatment combined with chemotherapy is effective for the early stage of OS, advanced OS preferentially metastasizes to the lung and is difficult to treat. Here, we examined the efficacy of ten anti-OS peptide candidates from a trypsin-digested conditioned medium that was derived from the secretome of induced tumor-suppressing cells (iTSCs). Using OS cell lines, the antitumor capabilities of the peptide candidates were evaluated by assaying the alterations in metabolic activities, proliferation, motility, and invasion of OS cells. Among ten candidates, peptide P05 (ADDGRPFPQVIK), a fragment of aldolase A (ALDOA), presented the most potent OS-suppressing capabilities. Its efficacy was additive with standard-of-care chemotherapeutic agents such as cisplatin and doxorubicin, and it downregulated oncoproteins such as epidermal growth factor receptor (EGFR), Snail, and Src in OS cells. Interestingly, P05 did not present inhibitory effects on non-OS skeletal cells such as mesenchymal stem cells and osteoblast cells. Collectively, this study demonstrated that iTSC-derived secretomes may provide a source for identifying anticancer peptides, and P05 may warrant further evaluations for the treatment of OS.Item Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells(MDPI, 2021-11-09) Li, Ke-Xin; Sun, Xun; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyOsteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.Item Correction: Sun et al. Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling. Cancers 2022, 14, 3039(MDPI, 2022-09-09) Sun, Xun; Li, Ke-Xin; Figueiredo, Marxa L.; Lin, Chien-Chi; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyErratum for: Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling. Sun X, Li KX, Figueiredo ML, Lin CC, Li BY, Yokota H. Cancers (Basel). 2022 Jun 21;14(13):3039. doi: 10.3390/cancers14133039. PMID: 35804814Item Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling(MDPI, 2022-06-21) Sun, Xun; Li, Ke-Xin; Figueiredo, Marxa L.; Lin, Chien-Chi; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyPurpose: To develop a novel treatment option for Chondrosarcoma (CS) and inflammatory arthritis, we evaluated a counterintuitive approach of activating tumorigenic and inflammatory signaling for generating joint-protective proteomes. Methods: We employed mesenchymal stem cells and chondrocytes to generate chondroprotective proteomes by activating PI3K signaling and the administration of TNFα. The efficacy of the proteomes was examined using human and mouse cell lines as well as a mouse model of CS. The regulatory mechanism was analyzed using mass spectrometry-based whole-genome proteomics. Results: While tumor progression and inflammatory responses were promoted by activating PI3K signaling and the administration of TNFα to CS cells and chondrocytes, those cells paradoxically generated a chondroprotective conditioned medium (CM). The application of CM downregulated tumorigenic genes in CS cells and TNFα and MMP13 in chondrocytes. Mechanistically, Hsp90ab1 was enriched in the chondroprotective CM, and it immunoprecipitated GAPDH. Extracellular GAPDH interacted with L1CAM and inhibited tumorigenic behaviors, whereas intracellular GAPDH downregulated p38 and exerted anti-inflammatory effects. Conclusions: We demonstrated that the unconventional approach of activating oncogenic and inflammatory signaling can generate chondroprotective proteomes. The role of Hsp90ab1 and GAPDH differed in their locations and they acted as the uncommon protectors of the joint tissue from tumor and inflammatory responses.Item Parkinson‐like early autonomic dysfunction induced by vagal application of DOPAL in rats(Wiley, 2021) Sun, Jie; He, Chao; Yan, Qiu-Xin; Wang, Hong-Dan; Li, Ke-Xin; Sun, Xun; Feng, Yan; Zha, Rong-Rong; Cui, Chang-Peng; Xiong, Xue; Gao, Shan; Wang, Xue; Yin, Rui-Xue; Qiao, Guo-Fen; Li, Bai-Yan; Biomedical Engineering, School of Engineering and TechnologyAim: To understand why autonomic failures, a common non-motor symptom of Parkinson's disease (PD), occur earlier than typical motor disorders. Methods: Vagal application of DOPAL (3,4-dihydroxyphenylacetaldehyde) to simulate PD-like autonomic dysfunction and understand the connection between PD and cardiovascular dysfunction. Molecular and morphological approaches were employed to test the time-dependent alternation of α-synuclein aggregation and the ultrastructure changes in the heart and nodose (NG)/nucleus tractus solitarius (NTS). Results: Blood pressure (BP) and baroreflex sensitivity of DOPAL-treated rats were significantly reduced accompanied with a time-dependent change in orthostatic BP, consistent with altered echocardiography and cardiomyocyte mitochondrial ultrastructure. Notably, time-dependent and collaborated changes in Mon-/Tri-α-synuclein were paralleled with morphological alternation in the NG and NTS. Conclusion: These all demonstrate that early autonomic dysfunction mediated by vagal application of DOPAL highly suggests the plausible etiology of PD initiated from peripheral, rather than central site. It will provide a scientific basis for the prevention and early diagnosis of PD.Item Spontaneous activities in baroreflex afferent pathway contribute dominant role in parasympathetic neurocontrol of blood pressure regulation(Wiley, 2018-12) Xu, Wen-Xiao; Yu, Jin-Ling; Feng, Yan; Yan, Qiu-Xin; Li, Xin-yu; Li, Ying; Liu, Zhuo; Wang, Di; Sun, Xun; Li, Ke-Xin; Wang, Lu-Qi; Qiao, Guo-Fen; Li, Bai-Yan; Biomedical Engineering, School of Engineering and TechnologyAim To study the dominant role of parasympathetic inputs at cellular level of baroreflex afferent pathway and underlying mechanism in neurocontrol of blood pressure regulation. Methods Whole‐cell patch‐clamp and animal study were conducted. Results For the first time, we demonstrated the spontaneous activities from resting membrane potential in myelinated A‐ and Ah‐type baroreceptor neurons (BRNs, the 1st‐order), but not in unmyelinated C‐types, using vagus‐nodose slice of adult female rats. These data were further supported by the notion that the spontaneous synaptic currents could only be seen in the pharmacologically and electrophysiologically defined myelinated A‐ and Ah‐type baroreceptive neurons (the 2nd‐order) of NTS using brainstem slice of adult female rats. The greater frequency and the larger amplitude of the spontaneous excitatory postsynaptic currents (EPSCs) compared with the inhibitory postsynaptic currents (IPSCs) were only observed in Ah‐types. The ratio of EPSCs:IPSCs was estimated at 3:1 and higher. These results confirmed that the afferent‐specific spontaneous activities were generated from baroreflex afferent pathway in female‐specific subpopulation of myelinated Ah‐type BRNs in nodose and baroreceptive neurons in NTS, which provided a novel insight into the dominant role of sex‐specific baroreflex‐evoked parasympathetic drives in retaining a stable and lower blood pressure status in healthy subjects, particularly in females. Conclusion The data from current investigations establish a new concept for the role of Ah‐type baroreceptor/baroreceptive neurons in controlling blood pressure stability and provide a new pathway for pharmacological intervention for hypertension and cardiovascular diseases.Item Tumor Cell Secretomes in Response to Anti- and Pro-Tumorigenic Agents(MDPI, 2021) Liu, Sheng-Zhi; Sun, Xun; Li, Ke-Xin; Lin, Chien-Chi; Na, Sungsoo; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyTumor cells regulate their progression not only by the factors within their cell bodies but also by the secretome they produce and secrete. While their secretome significantly alters the fate of tumor cells themselves, they also regulate the growth of surrounding cells including both companion cancer and non-cancer cells. Tumor cell secretome consists of varying molecules that have been reported mostly tumor-promotive. Furthermore, their pro-tumor capability is enhanced by the application of chemotherapeutic agents. However, multiple lines of emerging evidence suggest that the tumor cell secretome can be tumor-suppressive in response to paracrine and endocrine signaling. This review introduces both tumor-promotive and tumor-suppressive secretomes, focusing on multi-tasking proteins in the intracellular and extracellular domains. We describe tumorigenic signaling that governs the nature of the tumor cell secretome and discuss the possibility of inducing tumor-suppressive proteomes as a novel option for cancer treatment. We evaluated the counterintuitive procedure to generate tumor-suppressive proteomes from a unique type of tumor-modifying cells, which are named “induced tumor-suppressing cells” (iTSCs).