Publications by authors named "GuoFang Xue"

7 Publications

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The GLP-1/GIP dual-receptor agonist DA5-CH inhibits the NF-κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP-1 single-receptor agonist NLY01.

Brain Behav 2021 Jun 14. Epub 2021 Jun 14.

Second Hospital, Neurology Department, Shanxi Medical University, Taiyuan, Shanxi Province, People's Republic of China.

The GLP-1 receptor agonist exendin-4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP-1/GIP dual receptor agonist DA5-CH and NLY01, a 40 kDa pegylated form of exendin-4, on motor impairments and reducing inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5-CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5-CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5-CH, while NLY01 showed weak effects. When analyzing levels of α-synuclein (α-Syn), DA5-CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll-like receptor 4 (TLR4), specific markers of microglia activation (Iba-1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), and transforming growth factor β1 (TGF-β1), DA5-CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell-derived neurotrophic factor (GDNF) and Brain-derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5-CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro-inflammatory cytokines (IL-6 and IL-Iβ) were much reduced by DA5-CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood-brain barrier. After injecting fluorescin-labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin-4 and the dual agonist DA5-CH did. The results show that DA5-CH shows promise as a therapeutic drug for PD.
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http://dx.doi.org/10.1002/brb3.2231DOI Listing
June 2021

The novel GLP-1/GIP dual agonist DA3-CH is more effective than liraglutide in reducing endoplasmic reticulum stress in diabetic rats with cerebral ischemia-reperfusion injury.

Nutr Metab Cardiovasc Dis 2021 01 12;31(1):333-343. Epub 2020 Sep 12.

Second Hospital, Neurology Department, Shanxi Medical University, Taiyuan 030001, Shanxi province, PR China; Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, PR China.

Background And Aims: Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury.

Methods And Results: 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly.

Conclusions: DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.
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http://dx.doi.org/10.1016/j.numecd.2020.09.002DOI Listing
January 2021

Amifostine ameliorates cerebral ischaemia-reperfusion injury via p38-mediated oxidative stress and mitochondrial dysfunction.

Folia Neuropathol 2020 ;58(4):334-346

Second Hospital of Shanxi Medical University, China.

Amifostine is a cytoprotective compound that is beneficial in ischaemic stroke cases. However, the neuroprotective effect of amifostine on ischaemia/reperfusion (I/R)-induced brain injury and its underlying mechanism are still poorly understood. Herein, we constructed an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury and an in vitro model of oxygen and glucose deprivation and reperfusion (OGD/R) injury. After administration of amifostine, we found significant improvements in neurological deficits, infarct size, and cerebral oedema. Moreover, amifostine alleviated histopathological alteration and increased the number of surviving neurons. Biochemical analysis showed that treatment with amifostine obviously improved the brain damage of MCAO/R mice, as manifested by a decrease in reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and an increase in superoxide dismutase (SOD) activity. Moreover, amifostine decreased the mitochondrial membrane potential (m) loss, and cytochrome c escaping to cytoplasm, but increased the ATP level. In vitro, amifostine also showed an antioxidant effect, which was reflected by the reduced ROS generation, decreased mitochondrial superoxide generation, increased total SOD, SOD1 (Cu/Zn SOD, cytoplasmic SOD), and SOD2 (mitochondrial SOD) activities, and decreased m loss. Furthermore, amifostine suppressed neuronal apoptosis, accompanied by the reduction of Bax, cleaved caspase-9, cleaved caspase-3, and Bcl-2 upregulation. Amifostine also reduced the expression of p-p38 (Thr 180/Tyr 182) in vivo and in vitro. In short, amifostine exhibits a protective effect on cerebral I/R damage through modulating p38-related oxidative stress, mitochondrial dysfunction, and apoptosis.
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http://dx.doi.org/10.5114/fn.2020.102436DOI Listing
January 2020

Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease.

Neuropharmacology 2018 05 17;133:385-394. Epub 2018 Feb 17.

Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China; Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster, LA1 4YQ, UK.

Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM. We have tested 3 novel dual receptor agonists DA-JC1, DA-JC4 and DA-CH5 in comparison with the GLP-1 analogue liraglutide (all drugs at 25 nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD (4 × 25 mg/kg ip). In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was the best drug to reverse this. Pro-inflammatory cytokines were best reduced by DA-CH5, while expression levels of the neuroprotective growth factor Glial-Derived Neurotrophic Factor (GDNF) was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects. These results show that a combination of GLP-1 and GIP receptor activation is more efficient compared to single GLP-1 receptor activation. We conclude that dual agonists are a promising novel treatment for PD. The GLP-1 mimetic exendin-4 has previously shown disease modifying effects in two clinical trials in Parkinson patients.
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http://dx.doi.org/10.1016/j.neuropharm.2018.02.012DOI Listing
May 2018

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease.

Eur J Pharmacol 2017 Oct 27;812:82-90. Epub 2017 Jun 27.

Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China; Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster LA1 4YQ, UK.

Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.
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http://dx.doi.org/10.1016/j.ejphar.2017.06.029DOI Listing
October 2017

Effects of storage solutions on the viability of human umbilical cord mesenchymal stem cells for transplantation.

Cell Transplant 2013 4;22(6):1075-86. Epub 2012 Oct 4.

Department of Respiratory Medicine, The Second Clinical Medical College, Shanxi Medical University, Taiyuan, China.

Human umbilical cord-derived mesenchymal stem cell (UC-MSC) transplantation has shown promise for the treatment of various diseases. For clinical applications, UC-MSCs have been stored in 0.9% saline, 5% dextrose, dextrose and sodium chloride injection, Plasma-Lyte A, 1% human serum albumin (1% HSA), or 5% HSA before administration, but the effect of storage conditions on the viability and biological function of the cells remains unknown. Freshly harvested UC-MSCs were resuspended and incubated in these solutions for 2, 4, or 6 h at 4°C or room temperature (24°C). Cell viability, apoptotic/necrotic fraction, poststorage growth potential, immunophenotype, immunosuppressive capacity, and differentiation capacity were analyzed. When stored in parenteral solutions, UC-MSCs showed progressive deterioration in survival viability and adhesion ability. After 6-h storage, the best viability and attachment rate of UC-MSCs decreased to 83.0 ± 1.6% and 71.8 ± 3.2%, respectively. Our results suggested that UC-MSCs in these conditions lose their viability in a short time. However, it seems that the other biological functions of the surviving UC-MSCs were little affected. Since UC-MSCs suspended in these mediums lose their survival viability in a short time to levels significantly below the permissible limits (70%) by FDA, precautions need to be taken on using these solutions as suspension medium and further studies on the optimal methods for preservation are urgent.
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http://dx.doi.org/10.3727/096368912X657602DOI Listing
February 2014

Intravenous umbilical cord mesenchymal stem cell infusion for the treatment of combined malnutrition nonunion of the humerus and radial nerve injury.

Regen Med 2011 Nov;6(6):733-41

Department of Endocrinology, The Second Clinical Medical College, Shanxi Medical University, Taiyuan, China.

Nonunion and nerve injury are the most severe and common complications of bone fracture treatments. There is still no ideal therapy for these two complications. In this report, we first applied umbilical cord mesenchymal stem cell (UC-MSC) therapy to one patient with both nonunion and nerve injury, and observed the therapeutic effects. UC-MSCs were produced and expanded according to a clinical-grade technique using serum-free medium enriched in human platelet lysate. Flow cytometry was performed to evaluate the purity of UC-MSCs, which were then intravenously injected. At 60 days postinjection, clinical examinations were performed to evaluate the therapeutic effects. Compared with before treatment, the patient's nerve reflex was present, and their muscle tone and strength increased, and x-ray and electromyography analysis further showed that the fracture gap disappeared and the nerve conduction velocity increased with shorter latency and higher amplitude. Furthermore, the clinical evolution was favorable and no side effects were observed during the 1-year follow-up. Overall, this novel treatment might open up a new strategy for the treatment of bone fracture complications.
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http://dx.doi.org/10.2217/rme.11.83DOI Listing
November 2011
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