Browsing by Author "Wang, Yun"

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    Causal effects of psychostimulants on neural connectivity: a mechanistic, randomized clinical trial
    (Wiley, 2022) Wang, Yun; Kessel, Ellen; Lee, Seonjoo; Hong, Susie; Raffanello, Elizabeth; Hulvershorn, Leslie A.; Margolis, Amy; Peterson, Bradley S.; Posner, Jonathan; Psychiatry, School of Medicine
    Background: Psychostimulants are frequently used to treat attention-deficit/hyperactivity disorder (ADHD), but side effects are common leading to many patients discontinuing treatment. Identifying neural mechanisms by which psychostimulants attenuate symptoms may guide the development of more refined and tolerable therapeutics. Methods: We conducted a 12-week, randomized, placebo-controlled trial (RCT) of a long-acting amphetamine, lisdexamfetamine (LDEX), in patients with ADHD, ages 6-25 years old. Of the 58 participants who participated in the RCT, 49 completed pre- and post-RCT magnetic resonance imaging scanning with adequate data quality. Healthy controls (HCs; n = 46) were included for comparison. Treatment effects on striatal and thalamic functional connectivity (FC) were identified using static (time-averaged) and dynamic (time-varying) measures and then correlated with symptom improvement. Analyses were repeated in independent samples from the Adolescent Brain Cognitive Development study (n = 103) and the ADHD-200 Consortium (n = 213). Results: In 49 participants (25 LDEX; 24 Placebo), LDEX increased static and decreased dynamic FC (DFC). However, only DFC was associated with the therapeutic effects of LDEX. Additionally, at baseline, DFC was elevated in unmedicated-ADHD participants relative to HCs. Independent samples yielded similar findings - ADHD was associated with increased DFC, and psychostimulants with reduced DFC. Static FC findings were inconsistent across samples. Conclusions: Changes in dynamic, but not static, FC were associated with the therapeutic effects of psychostimulants. While prior research has focused on static FC, DFC may offer a more reliable target for new ADHD interventions aimed at stabilizing network dynamics, though this needs confirmation with subsequent investigations.
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    Constructing a new nigrostriatal pathway in the Parkinsonian model with bridged neural transplantation in substantia nigra
    (Society for Neuroscience, 1996-11-01) Zhou, Feng C.; Chiang, Yung H.; Wang, Yun; Anatomy and Cell Biology, School of Medicine
    The physical repair and restoration of a completely damaged pathway in the brain has not been achieved previously. In a previous study, using excitatory amino acid bridging and fetal neural transplantation, we demonstrated that a bridged mesencephalic transplant in the substantia nigra generated an artificial nerve pathway that reinnervated the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats. In the current study, we report that a bridged mesencephalic transplant can anatomically, neurochemically, and functionally reinstate the 6-OHDA-eradicated nigro-striatal pathway. An excitatory amino acid, kainic acid, laid down in a track during the transplant generated a trophic environment that effectively guided the robust growth of transplanted neuronal fibers in a bundle to innervate the distal striatum. Growth occurred at the remarkable speed of approximately 200 microm/d. Two separate and distinct types of dopamine (DA) innervation from the transplant have been achieved for the first time: (1) DA innervation of the striatum, and (2) DA innervation of the pars reticularis of the substantia nigra. In addition, neuronal tracing revealed that reciprocal connections were achieved. The grafted DA neurons in the SNr innervated the host's striatum, whereas the host's striatal neurons, in turn, innervated the graft within 3-8 weeks. Electrochemical volt- ammetry recording revealed the restoration of DA release and clearance in a broad striatal area associated with the DA reinnervation. Furthermore, the amphetamine-induced rotation was attenuated, which indicates that the artificial pathways were motor functional. This study provides additional evidences that our bridged transplantation technique is a potential means for the repair of a completely damaged neuronal pathway.
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    EGFL6 regulates the asymmetric division, maintenance and metastasis of ALDH+ ovarian cancer cells
    (American Association for Cancer Research, 2016-11-01) Bai, Shoumei; Ingram, Patrick; Chen, Yu-Chih; Deng, Ning; Pearson, Alex; Niknafs, Yashar; O'Hayer, Patrick; Wang, Yun; Zhang, Zhong-Yin; Boscolo, Elisa; Bischoff, Joyce; Yoon, Euisik; Buckanovich, Ronald J; Biochemistry and Molecular Biology, School of Medicine
    Little is known about the factors that regulate the asymmetric division of cancer stem-like cells. Here we demonstrate that EGFL6, a stem cell regulatory factor expressed in ovarian tumor cells and vasculature, regulates ALDH+ ovarian cancer stem-like cells (CSC). EGFL6 signaled at least in part via the oncoprotein SHP2 with concomitant activation of ERK. EGFL6 signaling promoted the migration and asymmetric division of ALDH+ ovarian CSC. As such, EGFL6 increased not only tumor growth but also metastasis. Silencing of EGFL6 or SHP2 limited numbers of ALDH+ cells and reduced tumor growth, supporting a critical role for EGFL6/SHP2 in ALDH+ cell maintenance. Notably, systemic administration of an EGFL6-neutralizing antibody we generated restricted tumor growth and metastasis, specifically blocking ovarian cancer cell recruitment to the ovary. Together, our results offer a preclinical proof of concept for EGFL6 as a novel therapeutic target for the treatment of ovarian cancer.
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    Elevating brain GLP‐1 and GIP levels as a treatment strategy for neurodegenerative disorders
    (Wiley, 2025-01-09) Greig, Nigel H.; Wang, Yun; Hoffer, Barry J.; Sambamurti, Kumar; Lahiri, Debomoy K.; Tones, Michael A.; Zaleska, Margaret M.; Mattison, Julie A.; Psychiatry, School of Medicine
    Background: Epidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson’s disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP‐4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer’s disease (AD) clinical trials. DPP‐4Is are yet to be evaluated in PD or AD human studies. Methods: Incretin mimetics have been evaluated in multiple cellular/animal PD models, including in 6‐hdroxydopamine (6‐OHDA) rats, and have demonstrated efficacy. The clinically approved DPP‐4Is, sitagliptin (Januvia) and PF‐00734200 (gosogliptin/Saterex) were hence evaluated in the classic 6‐OHDA unilateral medial forebrain bundle rat PD model to evaluate their repurposing potential when administered as human equivalent oral doses. Equivalent doses then were administered to naive nonhuman primates (NHPs) to evaluate whether biomarkers of efficacy in rat could be reproduced in NHPs as a further translational step towards human studies. Pharmacokinetics, DPP‐4 inhibition, GLP‐1/GIP and dopamine levels, together with dopaminergic and neuroinflammatory markers, and GLP‐1/GIP receptor levels were quantified. Results: Sitagliptin/PF‐00734,200 pre‐ or post‐treatment mitigated 6‐OHDA‐induced dopaminergic neurodegeneration, dopamine level loss and neuroinflammation, and augmented neurogenesis in lesioned substantia nigra pars compacta and in striatum, and reduced classical methamphetamine‐induced rotation in rats. This efficacy associated with 70‐80% plasma and 20‐30% brain DPP‐4 inhibition, and with elevated plasma and brain GLP‐1/GIP levels. Alike plasma/CSF DPP‐4 inhibition and elevated GLP‐1/GIP levels were determined in NHPs administered rat equivalent (human translational) sitagliptin doses. In relation to the drug targets, brain GLP‐1/GIP receptor protein levels were age‐dependently maintained in rodents, preserved in rats challenged with 6‐OHDA, and in humans with PD. Combined GLP‐1+GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone – particularly when combined with a DPP‐4I Conclusions: These studies support further evaluation of repurposing clinically approved drugs that elevate plasma/brain/CSF GLP‐1/GIP as a treatment strategy for neurodegenerative disorders. Incretin mimetics are already in clinical evaluation in PD and AD. Similarly, the repurposing of gliptins warrants evaluation both alone and in combination with an effective incretin mimetic.
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    Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders
    (Springer, 2024) Li, Yazhou; Vaughan, Kelli L.; Wang, Yun; Yu, Seong‑Jin; Bae, Eun‑Kyung; Tamargo, Ian A.; Kopp, Katherine O.; Tweedie, David; Chiang, Cheng‑Chuan; Schmidt, Keith T.; Lahiri, Debomoy K.; Tones, Michael A.; Zaleska, Margaret M.; Hoffer, Barry J.; Mattison, Julie A.; Greig, Nigel H.; Psychiatry, School of Medicine
    The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.