Ren, B, La, QT, O'Brien, BA, Nassif, NT, Tan, Y, Gerace, D, Martiniello-Wilks, R, Torpy, F, Dane, AP, Alexander, IE & Simpson, AM 2018, 'Partial pancreatic transdifferentiation of primary human hepatocytes in the livers of a humanised mouse model.', The journal of gene medicine, vol. 20, no. 5.View/Download from: UTS OPUS or Publisher's site
Gene therapy is one treatment that may ultimately cure type 1 diabetes. We have previously shown that the introduction of furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes resulted in the reversal of diabetes and partial pancreatic transdifferentiation of liver cells. The present study investigated whether streptozotocin-diabetes could be reversed in FRG mice in which chimeric mouse-human livers can readily be established and, in addition, whether pancreatic transdifferentiation occurred in the engrafted human hepatocytes.Engraftment of human hepatocytes was confirmed by measuring human albumin levels. Following delivery of the empty vector or the INS-FUR vector to diabetic FRG mice, mice were monitored for weight and blood glucose levels. Intraperitoneal glucose tolerance tests (IPGTTs) were performed. Expression levels of pancreatic hormones and transcription factors were determined by a reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry.Diabetes was reversed for a period of 60 days (experimental endpoint) after transduction with INS-FUR. IPGTTs of the insulin-transduced animals were not significantly different from nondiabetic animals. Immunofluorescence microscopy revealed the expression of human albumin and insulin in transduced liver samples. Quantitative RT-PCR showed expression of human and mouse endocrine hormones and β-cell transcription factors, indicating partial pancreatic transdifferentiation of mouse and human hepatocytes. Nonfasting human C-peptide levels were significantly higher than mouse levels, suggesting that transdifferentiated human hepatocytes made a significant contribution to the reversal of diabetes.These data show that human hepatocytes can be induced to undergo partial pancreatic transdifferentiation in vivo, indicating that the technology holds promise for the treatment of type 1 diabetes.
Nguyen, LT, Saad, S, Tan, Y, Pollock, C & Chen, H 2017, 'Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus.', Journal of Molecular Endocrinology, vol. 59, no. 1, pp. 81-92.View/Download from: UTS OPUS or Publisher's site
Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.
Tan, Y, Kim, J, Cheng, J, Ong, M, Lao, W-G, Jin, X-L, Lin, Y-G, Xiao, L, Zhu, X-Q & Qu, X-Q 2017, 'Green tea polyphenols ameliorate non-alcoholic fatty liver disease through upregulating AMPK activation in high fat fed Zucker fatty rats', World Journal of Gastroenterology, vol. 23, no. 21, pp. 3805-3805.View/Download from: UTS OPUS or Publisher's site
To investigate protective effects and molecular mechanisms of green tea polyphenols (GTP) on non-alcoholic fatty liver disease (NAFLD) in Zucker fatty (ZF) rats.
Male ZF rats were fed a high-fat diet (HFD) for 2 wk then treated with GTP (200 mg/kg) or saline (5 mL/kg) for 8 wk, with Zucker lean rat as their control. At the end of experiment, serum and liver tissue were collected for measurement of metabolic parameters, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), inflammatory cytokines and hepatic triglyceride and liver histology. Immunoblotting was used to detect phosphorylation of AMP-activated protein kinase (AMPK) acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein 1c (SREBP1c).
Genetically obese ZF rats on a HFD presented with metabolic features of hepatic pathological changes comparable to human with NAFLD. GTP intervention decreased weight gain (10.1%, P = 0.052) and significantly lowered visceral fat (31.0%, P < 0.01). Compared with ZF-controls, GTP treatment significantly reduced fasting serum insulin, glucose and lipids levels. Reduction in serum ALT and AST levels (both P < 0.01) were observed in GTP-treated ZF rats. GTP treatment also attenuated the elevated TNFα and IL-6 in the circulation. The increased hepatic TG accumulation and cytoplasmic lipid droplet were attenuated by GTP treatment, associated with significantly increased expression of AMPK-Thr172 (P < 0.05) and phosphorylated ACC and SREBP1c (both P < 0.05), indicating diminished hepatic lipogenesis and triglycerides out flux from liver in GTP treated rats.
The protective effects of GTP against HFD-induced NAFLD in genetically obese ZF rats are positively correlated to reduction in hepatic lipogenesis through upregulating the AMPK pathway.
Kamal, MA, Shakil, S, Nawaz, MS, Yu, QS, Tweedie, D, Tan, Y, Qu, X & Greig, NH 2017, 'Inhibition of butyrylcholinesterase with fluorobenzylcymserine, an experimental Alzheimer's drug candidate: Validation of enzoinformatics results by classical and innovative enzyme kinetic analyses', CNS and Neurological Disorders - Drug Targets, vol. 16, no. 7, pp. 820-827.View/Download from: UTS OPUS or Publisher's site
© 2017 Bentham Science Publishers. Background: Selective butyrylcholinesterase (BuChE)-inhibition, increases acetylcholine (ACh) levels. In rodents, this inhibition is known to boost cognition. Also, this occurs without the typical unwanted adverse effects of acetylcholinesterase-inhibitors or AChE-Is. The novel compound, fluorobenzylcymserine (FBC), is derived from our effort to design a selective BuChE-inhibitor. Also, we wanted to check whether butyrylcholinesterase-inhibitors (BuChE-Is) possessed an edge over AChE-Is in Alzheimer's disease (AD) in terms of efficacy and/or tolerance. Method: FBC was synthesized as reported earlier while enzymatic activity of BuChE was calculated by Ellman-technique. Molecular docking was performed using Autodock4.2. We applied classical as well as innovative analyses of enzyme-kinetics for exploring 'FBC:human BuChE-interaction'. The mode of inhibition and kinetic parameters were also determined. Results: Docking results displayed two strong interacting sites for FBC. One of these binding sites was previously identified as a deep narrow groove having polar aromatic residues while a second site was identified during this study which displayed better interaction and was lined with aliphatic and sulphur containing residues. At low concentrations of BuChE, the IC 50 was found to be very low i.e. 4.79 and 6.10 nM for 12 and 36 μg, respectively, whereas it increased exponentially by increasing the units of BuChE. Conclusion: These analyses indicate that FBC is an interesting AD drug candidate that could provide a potent and partial mixed type of inhibition of human BuChE.
Lao, W, Jin, X, Tan, Y, Xiao, L, Padula, M, Bishop, D, Reedy, B, Ong, M, Kamal, M & Qu, X 2016, 'Characterisation of Bone Beneficial Components from Australian Wallaby Bone', Medicines, vol. 3, pp. 1-13.View/Download from: UTS OPUS or Publisher's site
Background: Osteoporosis is a condition in which the bones become brittle, increasing the risk of fractures. Complementary medicines have traditionally used animal bones for managing bone disorders, such as osteoporosis. This study aimed to discover new natural products for these types of conditions by determining mineral and protein content of bone extracts derived from the Australian wallaby. Methods: Inductively coupled plasma-mass spectrometry and Fourier transform infrared spectroscopic analysis were used for mineral tests, proteome analysis was using LC/MS/MS and the effects of wallaby bone extracts (WBE)s on calcium deposition and alkaline phosphatase activity were evaluated in osteogenic cells derived from adipose tissue-derived stem cells (ADSCs). Results: Concentrations of calcium and phosphorus were 26.21% and 14.72% in WBE respectively. Additionally, minerals found were wide in variety and high in concentration, while heavy metal concentrations of aluminium, iron, zinc and other elements were at safe levels for human consumption. Proteome analysis showed that extracts contained high amounts of bone remodelling proteins, such as osteomodulin, osteopontin and osteoglycin. Furthermore, in vitro evaluation of WBEs showed increased deposition of calcium in osteoblasts with enhanced alkaline phosphatase activity in differentiated adipose-derived stem cells. Conclusion: Our results demonstrate that wallaby bone extracts possess proteins and minerals beneficial for bone metabolism. WBEs may therefore be used for developing natural products for conditions such as osteoporosis and further investigation to understand biomolecular mechanism by which WBEs prevent osteoporosis is warranted.
Tan, Y, Jin, XL, Lao, W, Kim, J, Xiao, L & Qu, X 2015, 'Antiresistin RNA Oligonucleotide Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Attenuating Proinflammatory Cytokines', BIOMED RESEARCH INTERNATIONAL.View/Download from: UTS OPUS or Publisher's site
Lao, W, Tan, Y, Jin, X, Xiao, L, Kim, JJY & Qu, X 2015, 'Comparison of Cytotoxicity and the Anti-Adipogenic Effect of Green Tea Polyphenols with Epigallocatechin-3-Gallate in 3T3-L1 Preadipocytes', AMERICAN JOURNAL OF CHINESE MEDICINE, vol. 43, no. 6, pp. 1177-1190.View/Download from: UTS OPUS or Publisher's site
Gadau, M, Yeung, W-F, Liu, H, Zaslawski, C, Tan, Y-S, Wang, F-C, Bangrazi, S, Chung, K-F, Bian, Z-X & Zhang, S-P 2014, 'Acupuncture and moxibustion for lateral elbow pain: a systematic review of randomized controlled trials', BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE, vol. 14.View/Download from: UTS OPUS or Publisher's site
Aliev, G, Shahida, K, Gan, SH, Firoz, C, Khan, A, Abuzenadah, AM, Kamal, W, Kamal, MA, Tan, Y, Qu, X & Reale, M 2014, 'Alzheimer disease and type 2 diabetes mellitus: the link to tyrosine hydroxylase and probable nutritional strategies.', CNS and Neurological Disorders - Drug Targets, vol. 13, no. 3, pp. 467-477.View/Download from: Publisher's site
Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) are chronic health disorders that affect millions of people around the world. According to recent studies, there are molecular similarities in the inflammatory pathways involved in both AD and T2DM, which opens a new avenue for researchers with different perspectives to target the cause of these diseases rather than their obvious symptoms. Several links between inflammation, cardiovascular disease, T2DM and central nervous system disorders such as AD and Parkinson's disease have been elucidated. Mutations in the hippocampal-β-amyloid precursor protein gene in genetically high-risk individuals have been shown to cause the early onset of AD symptoms. The overexpression of β-amyloid protein in the hippocampal region and the synaptotoxicity that occurs as a result have been considered a typical feature of AD and leads to neuronal loss and cognitive decline. However, the identity of the cellular components that cause the late onset of the disease seen in the majority of the cases is still unknown. Synaptic insults associated with neuronal dysfunction may involve several cascades and molecules, one of which has been hypothesized to be tyrosine hydroxylase (TH). The axons of the noradrenergic cells that project to the hippocampus appear to be affected by the β-amyloid protein, which subsequently contributes to TH loss in Alzheimer brain cells. In this review, we attempt to shed light on the important mechanisms involved in AD as well as T2DM such as inflammatory factors, abnormalities in the insulin signaling system and the possible role of the endocrine enzyme TH.
Tan, Y, Lao, W, Xiao, LH, Wang, Z, Wei, X, Kamal, M, Seale, JP & Qu, X 2013, 'Managing The Combination Of Nonalcoholic Fatty Liver Disease And Metabolic Syndrome With Chinese Herbal Extracts In High-fat-diet Fed Rats', Evidence-based Complementary And Alternative Medicine, vol. 2013, no. 1, pp. 1-10.View/Download from: UTS OPUS or Publisher's site
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome (MetS). The aim of the study was to evaluate the effects of Chinese herbal extracts from Salvia miltiorrhiza and Gardenia jasminoides (SGE) on the combination of NAFLD and MetS induced by a high-fat diet (HFD) in rats. After 6 weeks of HFD feeding, rats ( each group) were treated with saline, rosiglitazone (RSG), and SGE for 4 weeks. HFD rats were obese, hyperinsulinemic, hyperlipidemic and increased hepatic enzymes with the histological images of NAFLD. Treatment with SGE significantly reduced serum triglycerides (TG), nonesterified fatty acids and enhanced insulin sensitivity, and ameliorated the elevated serum hepatic enzymes compared with HFD-saline group. SGE treatment also attenuated hepatic TG by 18.5% (). Histological stains showed SGE decreased lipids droplets in hepatocytes () and normalized macrovesicular steatosis in HFD rats. Significant reduction of TNF-a and IL6 in adipose tissue was detected in SGE treated rats. The anti-inflammatory action may be, at least in part, the mechanism of SGE on MetS associated with NAFLD. This study discovered that SGE is capable of managing metabolic and histological abnormalities of NAFLD and MetS. SGE may be an optimal treatment for the combination of NAFLD and MetS.
Kim, JJY, Tan, Y, Xiao, L, Sun, Y-L & Qu, X 2013, 'Green Tea Polyphenol Epigallocatechin-3-Gallate Enhance Glycogen Synthesis and Inhibit Lipogenesis in Hepatocytes', BIOMED RESEARCH INTERNATIONAL.View/Download from: UTS OPUS or Publisher's site
Xiao, LH, Lao, W, Tan, Y & Qu, X 2012, 'In Vitro Investigation Of Anti-diabetic Effect Of Taxus Cuspidate Extracts By Ultrasound Assisted Method', The American Journal of Chinese Medicine, vol. 40, no. 6, pp. 1205-1215.View/Download from: UTS OPUS or Publisher's site
Extracting active components from Chinese medicinal herbs efficiently is a key step in the investigation of their pharmacological effects and modes of action. In this project, we compared the ultrasound-assisted method and the conventional solvent method
Tan, Y, Sun, L, Kamal, M, Wang, X, Seale, J & Qu, X 2011, 'Suppression Of Retinol-binding Protein 4 With Rna Oligonucleotide Prevents High-fat Diet-induced Metabolic Syndrome And Non-alcoholic Fatty Liver Disease In Mice', Biochimica et Biophysica Acta, vol. 1811, no. 12, pp. 1045-1053.View/Download from: UTS OPUS or Publisher's site
Conflicting data have been reported regarding the role of retinol-binding protein (RBP4) in insulin resistance, obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In this study, we used pharmacological methods to investigate the role
Tan, Y, Kamal, M, Wang, Z, Xiao, W, Seale, JP & Qu, X 2011, 'Chinese herbal extracts (SK0506) as a potential candidate for the therapy of the metabolic syndrome', Clinical Science, vol. 120, no. 7-8, pp. 297-305.View/Download from: UTS OPUS or Publisher's site
The metabolic syndrome has reached epidemic proportions worldwide, but currently there is a lack of effective therapies for this multifactorial endocrine disease. TCM (traditional Chinese medicine) has been utilized to treat a wide variety of diseases for centuries in the People's Republic of China, subsequently becoming a promising source for the development of new therapeutic agents. Chinese medicinal herbs Gynostemma pentaphyllum, Coptis chinensis and Salvia miltiorrhiza have been shown to have anti-atherosclerotic and antidiabetic properties. In this study, we have investigated the metabolic effects of a mixture of these three herbal extracts (SK0506) in a rodent model of the metabolic syndrome induced by an HFD (high-fat diet). SD (Sprague-Dawley) rats that were fed on an HFD for 4 weeks gained 33% more weight compared with chow-fed rats (P<0.05). Four weeks treatment with SK0506 prevented weight gain with decreased visceral fat (P<0.01 compared with vehicle treatment). SK0506 also significantly reduced plasma triacylglycerols (triglycerides), NEFAs (non-esterified fatty acids) and cholesterol. SK0506 exerted similar effects to RSG (rosiglitazone) on impaired glucose intolerance. SK0506 also significantly enhanced glucose uptake and glycogen synthesis in adipose tissue during hyperinsulinaemic euglycaemic clamp. Western blotting analysis revealed that SK0506 enhanced GLUT4 (glucose transporter 4) expression in adipose tissue, and RSG markedly up-regulated GLUT4 translocation in skeletal muscle. Overall, the present study has discovered that SK0506 can reverse several components of the metabolic syndrome primarily through acting on hyperlipidaemia and visceral obesity. The results from the present study suggest that it is worthwhile to conduct a randomized clinical trial to confirm the potential that SK0506 may be a new oral agent for treating the metabolic syndrome and preventing Type 2 diabetes.
Kamal, M, Tan, Y, Seale, JP & Qu, X 2009, 'Targeting Buche-Inflammatory Pathway By Sk0506 To Manage Type 2 Diabetes And Alzheimer Disease', Neurochemical Research, vol. 34, no. 12, pp. 2163-2169.View/Download from: UTS OPUS or Publisher's site
Type 2 diabetes mellitus (T2DM) and Alzheimers disease (AD) affect a large percent of the population worldwide. Experimental studies have revealed that T2DM and AD share several molecular processes that underlie their respective degenerative pathology. Based on this information, we quantified TNF-?, IL-6 levels, serum glucose, serum triglyceride, hepatic triglyceride, serum AST, serum ALT and butyrylcholinesterase (BuChE) in various rat tissues. HFD was fed to rats resulting in increased body weight, fasting blood glucose, IL-6, TNF-? levels, hepatic triglyceride, serum AST, serum ALT and BuChE. SK0506 treatment significantly prevented weight gain induced by HFD feeding. SK0506, but not Rosiglitazone, significantly reduced serum and hepatic triglycerides levels. Treatment with SK0506 also ameliorated elevated levels of both inflammatory markers (TNF-? and IL-6) and serum liver enzymes (ALT and AST) significantly in HFD fed rats. BuChE activity also reduced in skeletal muscle and adipose tissues of rats treated by SK0506. In conclusion, current study has opened new potential avenues towards research for management of T2DM and AD by Chinese herbal extracts, SK0506.
Kim, JK, Xiao, H, Tan, Y, Wang, Z, Seale, JP & Qu, X 2009, 'The Effects And Mechanism Of Saponins Of Panax Notoginseng On Glucose Metabolism In 3T3-L1 Cells', The American Journal of Chinese Medicine, vol. 37, no. 6, pp. 1179-1189.View/Download from: UTS OPUS or Publisher's site
This study was carried out to determine the effect of saponins of Panax notoginseng (SPN), a naturally occurring cardiovascular agent, on: (1) glucose uptake, (2) GLUT4 translocation and (3) glycogen synthesis in 3T3-L1 adipocytes. Electrospray ionization-Mass spectrometry (ESI-MS) was used to determine the structural characterization of the major active components of SPN. 3T3-L1 adipocytes were cultured and treated with 100 nM insulin alone or with 10, 50 and 100 ?g/ml of SPN. [3H]2-deoxyglucose glucose uptake, GLUT4 immunofluorescence imaging and glycogen synthesis assay were carried out to determine the effects of SPN on glucose metabolism. Under insulin stimulation, SPN significantly increased glucose uptake in a dose-dependent manner; 50 ?g/ml of SPN increased glucose uptake by 64% (p < 0.001). Immunofluorescence imaging and analysis have revealed that 50 and 100 ?g/ml of SPN increased GLUT4 in the plasma membrane by 3-fold and 6-fold respectively (p < 0.001). Furthermore, the incorporation of D-[U-14C] glucose into glycogen was enhanced by 53% in 3T3-L1 cells treated with 100 ?g/ml of SPN (p < 0.01 vs. insulin stimulation alone). SPN, a naturally occurring agent used to treat ischemic cardio-cerebral vascular disease in China, enhanced insulin-stimulated glucose uptake and glycogen synthesis in adipocytes. The results of this study indicate that SPN may have a therapeutic potential for hyperglycaemia in type 2 diabetes.
Kamal, M, Qu, X, Yu, Q, Tweedie, D, Holloway, H, Li, Y, Tan, Y & Greig, N 2008, 'Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis', Journal Of Neural Transmission, vol. 115, no. 6, pp. 889-898.View/Download from: UTS OPUS or Publisher's site
Synaptic loss, particularly related to the forebrain cholinergic system, is considered to be an early event that leads to Alzheimer's disease (AD) and has led to the development of acetylcholinesterase inhibitors (AChE-Is) as the mainstay of treatment fo
Ren, B, La, QT, O'Brien, BA, Nassif, NT, Tan, Y, Gerace, D, Martiniello-Wilks, R, Torpy, F, Dane, AP, Alexander, IE & Simpson, AM 2017, 'EXPRESSION OF HUMAN PANCREATIC TRANSCRIPTION FACTORS IN THE LIVERS OF FRG MICE', JOURNAL OF GENE MEDICINE, Joint 10th Annual Scientific Meeting of the Australian-Gene-and-Cell-Therapy-Society (AGCTS) and Australasian-Society-for-Stem-Cell-Research (ASSCR), WILEY, Univ Technol Sydney, Sydney, AUSTRALIA.View/Download from: UTS OPUS
Simpson, A, Ren, B, O'Brien, BA, Alexander, IE, Nassif, NT, Tan, Y & Martiniello-Wilks, R 2015, 'Gene therapy for diabetes: reversal of diabetes in the humanised FRG mouse model', XENOTRANSPLANTATION, IPITA/IXA/CTS Joint Congress, WILEY-BLACKWELL, Melbourne, AUSTRALIA, pp. S41-S42.View/Download from: UTS OPUS
Ren, B, O'Brien, BA, Alexander, IE, Nassif, NT, Tan, Y, Martiniello-Wilks, R & Simpson, AM 2015, 'Pancreatic Transdiffereniation of Human Hepatocytes in the Livers of a Humanized Mouse Model', MOLECULAR THERAPY, 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), NATURE PUBLISHING GROUP, New Orleans, LA, pp. S110-S110.View/Download from: UTS OPUS or Publisher's site
Tan, Y & Qu, X 2008, 'RNA oligonucleotides improve metabolic syndrome by targeting retinol binding protein 4 gene in high fat fed mice.', 44th The European Association for the Study of Diabetes., Rome, Italy.