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Papers by Liya Shen

Journal of Diabetes Investigation, 2020

Aims/Introduction: This secondary analysis of the 24-week SMART study examined the efficacy of ad... more Aims/Introduction: This secondary analysis of the 24-week SMART study examined the efficacy of add-on saxagliptin or acarbose to metformin across different patient subgroups with type 2 diabetes mellitus, based on baseline characteristics. Materials and Methods: Randomized patients (n = 481) were classified into subgroups based on their baseline age (<65, ≥65 years), body mass index (BMI; <24, 24-<28, ≥28 kg/m 2), glycated hemoglobin (HbA1c; <8%, 8-<9%, 9-<10%, ≥10%) and renal function (creatinine clearance 50-<80, ≥80 mL/min). Treatment effects on primary outcome (HbA1c) and key secondary outcomes of fasting plasma glucose (FPG), 2-h postprandial glucose and homeostatic model assessment of b-cell function were assessed across patient subgroups. Results: For saxagliptin, reductions in HbA1c from baseline to week 24 were consistent across different subgroups regardless of baseline age, body mass index, HbA1c and renal function (range-0.66 to-1.16%). Saxagliptin was associated with consistent reductions in FPG (-0.60 to-1.33 mmol/L) and 2-h postprandial glucose (-0.48 to-1.95 mmol/L) across the majority of subgroups studied. The efficacy of acarbose on FPG attenuated progressively with increasing baseline HbA1c (+0.86 to-1.43 mmol/L); an increase from baseline FPG was observed in patients with HbA1c >9%. The effect of acarbose on postprandial glucose was also variable (+0.23 to-3.38 mmol/L). Conclusions: As add-on to metformin, both saxagliptin and acarbose reduced HbA1c regardless of baseline HbA1c, age, body mass index and renal function; however, only saxagliptin was effective at a stable glycemic control (FPG and PPG). The efficacy of acarbose on FPG and PPG was significantly attenuated in patients with higher baseline HbA1c (≥8%). diabetes worldwide, with a prevalence of 10.9% (114 million) among adults aged 20-79 years; approximately 90% of these patients have type 2 diabetes 1. The high prevalence of type 2 diabetes and the corresponding costs of its associated complications place a considerable strain on China's public health services 1-3 .

Cold Spring Harbor Symposia on Quantitative Biology

Cellular and molecular biology (Noisy-le-Grand, France), 2002

The standardized extract of Ginkgo biloba leaves (EGb 761) has been shown to inhibit aggressive h... more The standardized extract of Ginkgo biloba leaves (EGb 761) has been shown to inhibit aggressive human breast cancer cell proliferation both in vitro and in vivo. These results were extended to human glioma and hepatoma cells in vitro suggesting that EGb 761 may have a more widespread application for tumor growth control. To understand the mechanism by which EGb 761 acts to inhibit cell proliferation, we investigated the effects of EGb 761 on human breast cancer, glioma and hepatoma cell transcriptomes by means of various large-scale DNA array techniques. The data presented focus on genes regulated by EGb 761 that are common to the three tumor cell types and for which the data were verified by two different types of DNA microarray and/or RNA (Northern) blot analysis and real-time quantitative PCR. These results could therefore help elucidate the mechanism of cytostatic action of EGb 761 and identify genes important for tumor growth.

Proceedings of the National Academy of Sciences, 1998

We report the identification of an additional member of the glial cell line-derived neurotrophic ... more We report the identification of an additional member of the glial cell line-derived neurotrophic factor (GDNF) family receptor, termed GFRα3, that is homologous to the previously identified GDNF and neurturin ligand binding receptors GFRα1 and GFRα2. GFRα3 is 32% and 37% identical to GFRα1 and GFRα2, respectively. RNase protection assays show that whereas gfrα1 and gfrα2 are abundant in both developing and adult brain, gfrα3 is exclusively expressed during development. All receptors are widely present in both the developing and adult peripheral nervous system and in peripheral organs. For instance, in situ hybridization shows that the developing liver, stomach, intestine, kidney, and sympathetic chain, which all contain ret-expressing cells, transcribe unique complementary and overlapping patterns of most or all of the GDNF family receptors and ligands. In sensory neurons of the trigeminal ganglion gfrα2 and gfrα3 are expressed in different subpopulations of neurons, whereas gfrα1 i...

Proceedings of the National Academy of Sciences, 2009

Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple tra... more Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from...

Proceedings of the National Academy of Sciences, 2013

Significance The brain-derived neurotrophic factor ( Bdnf ) gene is expressed either constitutive... more Significance The brain-derived neurotrophic factor ( Bdnf ) gene is expressed either constitutively or in an activity-dependent manner. Selective disruption of activity-dependent brain-derived neurotrophic factor protein expression (BDNF-KIV mice) results in specific deficits in GABAergic transmission in the prefrontal cortex (PFC) and a form of long-term synaptic plasticity in the hippocampus. Surprisingly, PFC-dependent working memory and hippocampus-dependent spatial and fear memory are normal. In contrast, BDNF-KIV mice exhibit pronounced behavioral perseverance, as reflected by impairments in spatial memory reversal and fear memory extinction. Thus, activity-dependent BDNF expression in hippocampal–PFC circuits may play an important role in cognitive behavior in vivo. Our study also may shed light on the pathogenesis of several cognitive disorders in which perseverance is prominent, including schizophrenia and posttraumatic stress disorder.

NeuroReport, 2005

Activation of microglia/macrophages after injury occurs limitedly in the CNS, which finding may e... more Activation of microglia/macrophages after injury occurs limitedly in the CNS, which finding may explain unsuccessful axonal regeneration. Therefore, the relationship between lipopolysaccharide (LPS)-induced inflammation and recovery of locomotor function of rats after spinal cord injury was examined. High-dose LPS improved locomotor function greater than low-dose LPS, being consistent with the expression of neurotrophic factor (GDNF) in microglia/macrophages. Experiments using GDNF gene mutant mice confirmed that the increase in the GDNF mRNA level, rather than the reduction in the mRNA level of inducible NO synthase, could be correlated with the restoration activity of locomotor function. These results suggest that a higher degree of inflammation leads to a higher degree of repair of CNS injuries through GDNF produced by activated microglia/macrophages.

Nature, 1996

Glial-lial-cell-line-derived neurotrophic factor (GDNF) has been isolated as neurotrophic factor ... more Glial-lial-cell-line-derived neurotrophic factor (GDNF) has been isolated as neurotrophic factor for midbrain dopaminergic neurons. Because of its neurotrophic activity on a wide range of neuronal populations in vitro and in vivo, GDNF is being considered as a potential therapeutic agent for neuronal disorders. During mammalian development, it is expressed not only in the nervous system, but also very prominently in the metanephric kidney and the gastrointestinal tract, suggesting possible functions during organogenesis. We have investigated the role of GDNF during development by generating a null mutation in the murine GDNF locus, and found that mutant mice show kidney agenesis or dysgenesis and defective enteric innervation. We demonstrate that GDNF induces ureter bud formation and branching during metanephros development, and is essential for proper innervation of the gastrointestinal tract.

Journal of Molecular Medicine, 1997

Neurotrophic factors are endogenous soluble proteins that regulate long-term survival and differe... more Neurotrophic factors are endogenous soluble proteins that regulate long-term survival and differentiation of neurons of the peripheral and central nervous systems. These factors play an important role in the structural integrity of the nervous system, and therefore are good candidates as therapeutic agents for neurodegenera-tive diseases. However, recent studies have revealed some unexpected, novel roles of neurotrophic factors. Of particular significance is the discovery of the new functions of brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF). Physiological experiments indicate that BDNF may serve as regulatory factors for synaptic transmission as well as for learning and memory. Gene targeting studies demonstrate that GDNF may be essential for development of the enteric nervous system (ENS) and kidney organogenesis. These results not only provide new insights into our understanding of the function of neurotrophic factors but may also have significant implications in the therapeutic usages of neurotrophic factors. & k w d : Key words Brain-derived neurotrophic factor • trk receptor • Long-term potentiation • Glia-derived neurotrophic factor • c-ret tyrosine kinase • Dopaminergic neurons • Kidney organogenesis • Enteric nervous system • Gene knockout • Hirschsprung's disease Abbreviations ALS Amyotrophic lateral sclerosis • BDNF Brain-derived neurotrophic factor • CNTF Ciliary neurotrophic factor • ENS Enteric nervous system • GDNF Glia-derived neurotrophic factor • LIF Leukemia inhibitory factor • LTP Long-term potentiation • NGF Nerve growth factor • NT Neurotrophin& b d y :

Cell and Tissue Research, 2000

Glial cell line-derived neurotrophic factor (GDNF), a member of the GDNF family of neurotrophic f... more Glial cell line-derived neurotrophic factor (GDNF), a member of the GDNF family of neurotrophic factors, promotes the survival and function of several neuronal populations in the peripheral and central nervous system. In the present study, expression of GDNF mRNA in the shaft of adult rat penis is demonstrated. In situ hybridization revealed GDNF mRNA expression in cells lying in the narrow zone between the tunica albuginea and the cavernous tissue. Most subtunical cells exhibited immunoreactivity for vimentin and S100beta, but they did not stain for smooth muscle alpha actin or PGP9.5. This suggests that the GDNF mRNA-expressing cells may have a mesenchymal origin. Also retrograde axonal transport of intracavernously injected 125 I-labeled GDNF in penile parasympathetic and sensory neurons is shown. The transport was inhibited by excess unlabeled GDNF, whereas excess cytochrome c had no effect. This is in agreement with the view that the transport was mediated by binding to specific receptors located on axon terminals. In addition, this study demonstrates expression of GDNF family receptor-α3 (GFRα3) mRNA in most adrenergic, but only in a minor part (5.3%) of the penis-projecting adult rat major pelvic ganglion neurons, as well as in almost half (45.6%) of the penile S1 dorsal root ganglion neurons. In conclusion, the present data suggest that GDNF may act as a neurotrophic factor for subpopulations of adult rat penile parasympathetic and sensory neurons.

Cell, 1993

We have identified three members of a mouse gene family related to the Drosophila segment polarit... more We have identified three members of a mouse gene family related to the Drosophila segment polarity gene, hedgehog (hh). Like hh, they encode putative secreted proteins and are thus implicated in cell-cell interactions. One of these, Sonic hh (Shh), is expressed in the notochord, the floor plate, and the zone of polarizing activity, signaling centers that are thought to mediate central nervous system (CNS) and limb polarity. Ectopic expression of Shh in the mouse CNS leads to the activation of floor plate-expressed genes. These results suggest that Shh may play a role in the normal inductive interactions that pattern the ventral CNS.

Biological Psychiatry, 2007

There are few efficacious medications for drug dependence. We investigated the potential of Leu-I... more There are few efficacious medications for drug dependence. We investigated the potential of Leu-Ile, which induces the expression of glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-alpha (TNF-alpha), as a novel therapeutic agent for methamphetamine (METH)-induced dependence. The levels of GDNF and TNF-alpha messenger RNA (mRNA) were determined by real-time reverse transcription polymerase chain reaction. Enzyme immunoassays and immunohistochemistry were employed to determine levels of these proteins. Effects of Leu-Ile on METH-induced rewarding effects and sensitization were investigated with conditioned place preference and locomotor activity tests. Extracellular dopamine (DA) levels and DA uptake into synaptosomes were examined with an in vivo microdialysis and trititated thymidine ([(3)H]) DA uptake assay. Leu-Ile induced the expression of not only GDNF but also TNF-alpha. Pretreatment with Leu-Ile blocked the acquisition of METH-induced place preference and sensitization. Interestingly, post-treatment with Leu-Ile attenuated them even after their development. An inhibitory effect of Leu-Ile on METH-induced place preference was observed in neither GDNF heterozygous nor TNF-alpha knockout mice. Leu-Ile inhibited DA release in the nucleus accumbens and the decrease in synaptosomal DA uptake in the midbrain induced by repeated METH treatment. These results suggest that Leu-Ile inhibits METH-induced rewarding effects and sensitization by regulating extracellular DA levels via the induction of GDNF and TNF-alpha expression.

Behavioural Brain Research, 2007

There are few efficacious medications for drug dependence at present. We have previously demonstr... more There are few efficacious medications for drug dependence at present. We have previously demonstrated that Leu-Ile, which induces the expression of not only tumor necrosis factor-␣ (TNF-␣) but also glial cell line-derived neurotrophic factor (GDNF), inhibits methamphetamine (METH) and morphine (MOR)-induced sensitization and rewarding effects by regulating extracellular dopamine levels via the induction of TNF-␣ expression, and indicated the potential of Leu-Ile as a novel therapeutic agent for METH and MOR-induced dependence. In the present study, we investigated the involvement of GDNF in inhibitory effects of Leu-Ile on MOR-induced sensitization and rewarding effects. Repeated treatment with MOR for 9 days, which results in an enhancement of the locomotor-stimulating effects (sensitization) of MOR, increased GDNF levels in the nucleus accumbens compared with those in saline-treated mice. Repeated pre-treatment with Leu-Ile for 9 days potentiated the MOR-induced increase in GDNF levels. MOR at a low dose (3 mg/kg) produced place preference in GDNF heterozygous knockout (GDNF-(+/−)) mice, but not in littermate GDNF-(+/+) mice. No inhibitory effect of Leu-Ile on MOR-induced place preference was observed in GDNF-(+/−) mice. These results suggest that GDNF is involved in the inhibitory effects of Leu-Ile on MOR-induced sensitization and rewarding effects.

The American Journal of Human Genetics, 2002

Hirschsprung disease (HSCR) is a common congenital disorder that results in intestinal obstructio... more Hirschsprung disease (HSCR) is a common congenital disorder that results in intestinal obstruction and lethality, as a result of defective innervation of the gastrointestinal (GI) tract. Despite its congenital origin, the molecular etiology of HSCR remains elusive for 170% of patients. Although mutations in the c-RET receptor gene are frequently detected in patients with HSCR, mutations in the gene encoding its ligand (glial cell line-derived neurotrophic factor [GDNF]), are rarely found. In an effort to establish a possible link between human HSCR and mutations affecting the Gdnf locus, we studied a large population of mice heterozygous for a Gdnf null mutation. This Gdnf +/5 mutant cohort recapitulates complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms. The lack of one functioning Gdnf allele causes a spectrum of defects in gastrointestinal motility and predisposes the mutant mice to HSCR-like phenotypes. As many as one in five Gdnf +/5 mutant mice die shortly after birth. Using a transgenic marking strategy, we identified hypoganglionosis of the gastrointestinal tract as a developmental defect that renders the mutant mice susceptible to clinical symptoms of HSCR. Our findings offer a plausible way to link an array of seemingly disparate features characteristic of a complex disease to a much more narrowly defined genetic cause. These findings may have general implications for the genetic analysis of cause and effect in complex human diseases.