Browsing by Author "Zhang, Xin"

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    Differential microRNA profiles of intramuscular and secreted extracellular vesicles in human tissue-engineered muscle.
    (Frontiers in physiology, 2022-01) Vann, Christopher G; Zhang, Xin; Khodabukus, Alastair; Orenduff, Melissa C; Chen, Yu-Hsiu; Corcoran, David L; Truskey, George A; Bursac, Nenad; Kraus, Virginia B
    Exercise affects the expression of microRNAs (miR/s) and muscle-derived extracellular vesicles (EVs). To evaluate sarcoplasmic and secreted miR expression in human skeletal muscle in response to exercise-mimetic contractile activity, we utilized a three-dimensional tissue-engineered model of human skeletal muscle ("myobundles"). Myobundles were subjected to three culture conditions: no electrical stimulation (CTL), chronic low frequency stimulation (CLFS), or intermittent high frequency stimulation (IHFS) for 7 days. RNA was isolated from myobundles and from extracellular vesicles (EVs) secreted by myobundles into culture media; miR abundance was analyzed by miRNA-sequencing. We used edgeR and a within-sample design to evaluate differential miR expression and Pearson correlation to evaluate correlations between myobundle and EV populations within treatments with statistical significance set at p < 0.05. Numerous miRs were differentially expressed between myobundles and EVs; 116 miRs were differentially expressed within CTL, 3 within CLFS, and 2 within IHFS. Additionally, 25 miRs were significantly correlated (18 in CTL, 5 in CLFS, 2 in IHFS) between myobundles and EVs. Electrical stimulation resulted in differential expression of 8 miRs in myobundles and only 1 miR in EVs. Several KEGG pathways, known to play a role in regulation of skeletal muscle, were enriched, with differentially overrepresented miRs between myobundle and EV populations identified using miEAA. Together, these results demonstrate that in vitro exercise-mimetic contractile activity of human engineered muscle affects both their expression of miRs and number of secreted EVs. These results also identify novel miRs of interest for future studies of the role of exercise in organ-organ interactions in vivo.
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    Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.
    (Pain, 2021-10-12) Wang, Yaomin; Scarneo, Scott A; Kim, Shin Hyung; Zhang, Xin; Chen, Jiegen; Yang, Kelly W; Hughes, Philip; Haystead, Timothy; Nackley, Andrea G
    Heat shock protein 90 (Hsp90) is a ubiquitously expressed integral cellular protein essential for regulating proteomic stress. Previous research has shown that Hsp90 regulates critical signaling pathways underlying chronic pain and inflammation. Recent discovery of membrane bound ectopic Hsp90 (eHsp90) on tumor cells has shown that Hsp90 induction to the plasma membrane can stabilize disease-relevant proteins. Here, we characterize eHsp90 expression in a mouse model of inflammation and demonstrate its role in nociception and pain. We found that intraplantar complete Freund adjuvant (CFA) induced robust expression of eHsp90 on the cell membranes of primary afferent nociceptors located in the L3-L5 dorsal root ganglia (DRG), bilaterally, with minimal to no expression in other tissues. Complete Freund adjuvant-induced increases in eHsp90 expression on lumbar DRG were significantly greater in females compared with males. Furthermore, exogenous Hsp90 applied to primary Pirt-GCaMP3 nociceptors induced increases in calcium responses. Responses were estrogen-dependent such that greater activity was observed in female or estrogen-primed male nociceptors compared with unprimed male nociceptors. Treatment of mice with the selective eHsp90 inhibitor HS-131 (10 nmol) significantly reversed CFA-induced mechanical pain, thermal heat pain, and hind paw edema. Notably, a higher dose (20 nmol) of HS-131 was required to achieve analgesic and anti-inflammatory effects in females. Here, we provide the first demonstration that inflammation leads to an upregulation of eHsp90 on DRG nociceptors in a sex-dependent manner and that inhibition of eHsp90 reduces nociceptor activity, pain, and inflammation. Thus, eHsp90 represents a novel therapeutic axis for the development of gender-tailored treatments for inflammatory pain.
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    Moving Duke to A Clean Future – An Approach through Electric Vehicles
    (2020-04-20) Zhang, Xin; Zhu, Yuchen
    Duke’s 2009 Climate Action Plan (CAP) has committed Duke to a carbon-neutral institution by 2024. In a recent update version published in 2019, Duke’s CAP focused on internal emission reduction strategies, especially on energy usage and transportation, to make sure Duke University strives to reduce emissions by 78% by 2024 compared to the 2007 baseline. Additionally, the updated plan showed that only transportation emission went up by 24% in 2019 compared to the 2007 baseline, especially the emission from employees’ commuting. Therefore, Sustainable Duke initiated this study to explore the potential of cutting transportation-related emissions from employees’ commuting by electrifying employee-owned vehicles. The results of the study show that Duke University can cut up to 17% of emission if implemented suggested incentive programs, and it is necessary to install additional EV charging infrastructure on campus.
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    Psychological reactions to COVID-19: Survey data assessing perceived susceptibility, distress, mindfulness, and preventive health behaviors.
    (Data in brief, 2021-02) O'Brien, William H; Wang, Shan; Xu, Huanzhen; Wang, Shiwei; Yang, Zaiying; Yang, Joy Ting; Liu, Qinwanxian; Zhang, Xin; Tang, Lingli; Varga, Aniko V; Sims, Tracy; Lim, Chung Xiann; Jarukasemthawee, Somboon; Pisitsungkagarn, Kullaya
    The COVID-19 pandemic created a complex psychological environment for persons in America. A total of 450 USA MTurk workers completed measures of: (a) basic demographic characteristics; (b) health risk factors for COVID-19; (c) perceived susceptibility variables related to COVID-19; (d) COVID-19 preventive health behaviors; and (e) distress, physical symptoms, and quality of life measures. The surveys were completed between April 9, 2020 and April 18, 2020. This recruitment period corresponded to the first 2-3 weeks of lockdown in most of the USA. Follow-up surveys were completed by 151 of the USA participants between June 19, 2020 and July 11, 2020 (approximately 2 months after the first measurement). These data permit evaluation of relationships among demographic variables, COVID-19 stress and coping, COVID-19 preventive health behavior, and the role of mindfulness as a possible moderator of distress as well as a predictor of preventive health behavior. The availability of follow-up data permit longitudinal analyses that provide a stronger basis for causal inference.
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    Synergistic roles of CBX4 chromo and SIM domains in regulating senescence of primary human osteoarthritic chondrocytes.
    (Arthritis research & therapy, 2023-10) Chen, Yu-Hsiu; Zhang, Xin; Attarian, David; Kraus, Virginia Byers

    Background

    Cellular senescence is a critical factor contributing to osteoarthritis (OA). Overexpression of chromobox homolog 4 (CBX4) in a mouse system was demonstrated to alleviate post-traumatic osteoarthritis (PTOA) by reducing cellular senescence. Additionally, replicative cellular senescence of WI-38 fibroblasts can be attenuated by CBX4. However, the mechanisms underlying this senomorphic function of CBX4 are not fully understood. In this study, we aimed to investigate the role of CBX4 in cellular senescence in human primary osteoarthritic chondrocytes and to identify the functional domains of CBX4 necessary for its function in modulating senescence.

    Methods

    Chondrocytes, isolated from 6 individuals undergoing total knee replacement for OA, were transduced with wild-type CBX4, mutant CBX4, and control lentiviral constructs. Senescence-related phenotypic outcomes included the following: multiple flow cytometry-measured markers (p16INK4A, senescence-associated β-galactosidase [SA-β-gal] activity and dipeptidyl peptidase-4 [DPP4], and proliferation marker EdU), multiplex ELISA-measured markers in chondrocyte culture media (senescence-associated secretory phenotypes [SASPs], including IL-1β, IL-6, IL-8, TNF-α, MMP-1, MMP-3, and MMP-9), and PCR array-evaluated senescence-related genes.

    Results

    Compared with control, CBX4 overexpression in OA chondrocytes decreased DPP4 expression and SASP secretion and increased chondrocyte proliferation confirming CBX4 senomorphic effects on primary human chondrocytes. Point mutations of the chromodomain domain (CDM, involved in chromatin modification) alone were sufficient to partially block the senomorphic activity of CBX4 (p16INK4A and DPP4 increased, and EdU decreased) but had minimal effect on SASP secretion. Although having no effect on p16INK4A, DPP4, and EdU, deletion of two small-ubiquitin-like-modifier-interaction motifs (CBX4 ΔSIMs) led to increased SASP secretion (IL-1β, TNF-α, IL-8). The combination CBX4 CDMΔSIMs altered all these measures adversely and to a greater degree than the single domain mutants. Deletion of the C-terminal (CBX4 ΔC-box) involved with transcriptional silencing of polycomb group proteins increased IL-1β slightly but significantly but altered none of the other senescence outcome measures.

    Conclusions

    CBX4 has a senomorphic effect on human osteoarthritic chondrocytes. CDM is critical for CBX4-mediated regulation of senescence. The SIMs are supportive but not indispensable for CBX4 senomorphic function while the C-box is dispensable.
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    Systemic changes in Immune System-Related Plasma Extracellular Vesicles During Healthy Aging
    (Journal of Extracellular Vesicles, 2024-07-13) Zhang, Xin; Ma, Sisi; Syeda Iffat, Naz; Huebner, Janet; Soderblom, Erik; Alnemer, Noor; Aliferis, Constantin; Kraus, Virginia
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    Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain.
    (The journal of pain, 2023-04) Scarneo, Scott; Zhang, Xin; Wang, Yaomin; Camacho-Domenech, Jose; Ricano, Jennifer; Hughes, Philip; Haystead, Tim; Nackley, Andrea G
    The origin of chronic pain is linked to inflammation, characterized by increased levels of pro-inflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of pro-inflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small molecule inhibitor, takinib, to attenuate pain and inflammation in pre-clinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund's adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the COMT inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the dorsal root ganglia of Gcamp3 mice. In all three models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of pro-inflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid based pain treatments.
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    Tunable Meta-Liquid Crystals.
    (Adv Mater, 2016-02-24) Liu, Mingkai; Fan, Kebin; Padilla, Willie; Powell, David A; Zhang, Xin; Shadrivov, Ilya V
    Meta-liquid crystals, a novel form of tunable 3D metamaterials, are proposed and experimentally demonstrated in the terahertz frequency regime. A morphology change under a bias electric field and a strong modulation of the transmission are observed. In comparison to conventional liquid crystals, there is considerable freedom to prescribe the electromagnetic properties through the judicious design of the meta-atom geometry.