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Orthogonal assays for the identification of inhibitors of the single-stranded nucleic acid binding protein YB-1

Acta Pharmaceutica Sinica B 2019年第5期9卷 997-1007页

作者： Alexander J.Trevarton Yan Zhou Dehua Yang Gordon W.Rewcastle Jack U.Flanagan Antony Braithwaite Peter R.Shepherd Cristin G.Print Ming-Wei Wang Annette Lasham Department of Molecular Medicine and Pathology University of AucklandAucklandNew Zealand The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of Sciences(CAS)Shanghai201203China Auckland Cancer Society Research centre AucklandNew Zealand maurice wilkins centre for Molecular biodiscovery University of AucklandAucklandNew Zealand Department of Pathology Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand maurice wilkins centre for Molecular biodiscovery University of OtagoDunedinNew Zealand School of Pharmacy Fudan UniversityShanghai201203China

We have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be determined and its role in transcriptional regulation remains elusive. Drug targeting of transcription factors is often thought to be difficult and there are very few published high-throughput screening approaches. YB-1 predominantly binds to single-stranded nucleic acids, adding further difficulty to drug discovery. Therefore, we have developed two novel screening assays to detect compounds that interfere with the transcriptional activation properties of YB-1, both of which may be generalizable to screen for inhibitors of other nucleic acid binding molecules. The first approach is a cell-based luciferase reporter gene assay that measures the level of activation of a fragment of the E2 F1 promoter by YB-1. The second approach is a novel application of the Alpha Screen system, to detect interference of YB-1 interaction with a single-stranded DNA binding site. These complementary assays examine YB-1 binding to two discrete nucleic acid sequences using two different luminescent signal outputs and were employed sequentially to screen 7360 small molecule compounds leading to the identification of three putative YB-1 inhibitors.

关键词： Cancer YB-1 Luciferase Alpha Screen Transcription factor Single-stranded DNA

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Steatotic livers are susceptible to normothermic ischemiareperfusion injury from mitochondrial Complex-Ⅰ?dysfunction

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World Journal of Gastroenterology 2016年第19期22卷 4673-4684页

作者： Michael JJ Chu Rakesh Premkumar Anthony JR Hickey Yannan Jiang Brett Delahunt Anthony RJ Phillips Adam SJR Bartlett Department of Surgery University of Auckland School of Biological Sciences University of Auckland maurice wilkins centre for biodiscovery University of Auckland Department of Statistics University of Auckland Department of Pathology and Molecular Medicine Wellington School of Medicine University of Otago New Zealand Liver Transplant Unit Auckland City Hospital

AIM: To assess the effects of ischemic preconditioning(IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury(IRI).METHODS: Sixty male Sprague-Dawley rats were fed8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups(n = 10/group) for each dietary state were tested:(1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion;(2) the IPC group underwent IPC prior to same standard IRI; and(3) sham underwent t h e s a m e s u r g e r y w i t h o u t I R I o r I P C. H e p a t i c mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-Ⅰ, Complex-Ⅱ enzyme activity, serum alanine aminotransferase(ALT), and histological injury were ***: Steatotic-IRI livers had a greater increase in ALT(2476 ± 166 vs 1457 ± 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-Ⅰ?activity at baseline [78.4 ± 2.5 vs 116.4 ± 6.0 nmol/(*** protein), P < 0.001] and following IRI [28.0 ± 6.2 vs 104.3 ± 12.6 nmol/(*** protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-Ⅰ?function post-IRI compared to the lean liver IRI group. Complex-Ⅱ activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities. CONCLUSION: Warm IRI impairs steatotic liver Complex-Ⅰ?activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria.

关键词： Mitochondrial respiration Fatty liver Liver ischemia Oxidative phosphorylation Liver injury Hepatic steatosis Ischemic preconditioning

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BET inhibition prevents aberrant RUNX1 and ERG transcription in STAG2 mutant leukaemia cells

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Journal of Molecular Cell Biology 2020年第5期12卷 397-399页

作者： Jisha Antony Gregory Gimenez Terry Taylor Umaima Khatoon Robert Day Ian MMorison Julia AHorsfield Department of Pathology Dunedin School of MedicineUniversity of OtagoDunedin 9016New Zealand maurice wilkins centre for Molecular biodiscovery The University of AucklandPrivate Bag 92019AucklandNew Zealand Southern Community Laboratories Dunedin 9016New Zealand Department of Biochemistry University of OtagoDunedin 9054New Zealand

Cohesin is a multiprotein complex that not only is essential for cell division but also has key roles in genome organization that underpin its gene regulatory *** mutations of genes encoding cohesin subunits occur in myeloid malignancies at 10%–12%(Kon et al.,2013),and the frequency of cohesin mutation in Down syndrome-associated megakaryoblastic leukaemia is even higher(~50%)(Yoshida et al.,2013).Cohesin insufficiency reinforces stem cell programmes and impairs differentiation in haematopoietic stem cells(Mazumdar et al.,2015;Mullenders et al.,2015;Viny et al.,2015).The STAG2 subunit of cohesin is the most frequently mutated in myeloid malignancies(Kon et al.,2013).In contrast to other cohesin subunits,complete loss of STAG2 is tolerated due to partial compensation by ***2 and STAG1 have redundant roles in cell division(Benedetti et al.,2017;van der Lelij et al.,2017).However,cohesin-STAG1 and cohesin-STAG2 have non-redundant roles in facilitating 3D genome organization to delineate tissue-specific gene expression(Kojic et al.,2018).

关键词： function. redundant

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Targeting growth hormone function: strategies and therapeutic applications

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Signal Transduction and Targeted Therapy 2019年第1期4卷 614-624页

作者： Man Lu Jack U.Flanagan Ries J.Langley Michael P.Hay Jo K.Perry Liggins Institute University of AucklandAucklandNew Zealand Auckland Cancer Society Research centre School of Medical SciencesUniversity of AucklandAucklandNew Zealand maurice wilkins centre for Molecular biodiscovery AucklandNew Zealand Department of Molecular Medicine and Pathology School of Medical SciencesUniversity of AucklandAucklandNew Zealand

Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological *** is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these *** adults,hypersecretion of GH causes acromegaly,and strategies that block the release of GH or that inhibit GH receptor(GHR)activation are the primary forms of medical therapy for this *** of GH has also been linked to cancer and the microvascular complications that are associated with ***,studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited,most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in *** review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.

关键词： therapeutic pituitary diseases

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A dahlia flower extract has antidiabetic properties by improving insulin function in the brain

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Life Metabolism 2023年第4期2卷 39-50页

作者： Dominik Pretz Philip M.Heyward Jeremy Krebs Joel Gruchot Charles Barter Pat Silcock Nerida Downes Mohammed Zubair Rizwan Alisa Boucsein Julia Bender Elaine J.Burgess Geke Aline Boer Pramuk Keerthisinghe Nigel B.Perry Alexander Tups centre for Neuroendocrinology School of Biomedical SciencesUniversity of OtagoDunedin 9054New Zealand Department of Physiology School of Biomedical SciencesUniversity of OtagoDunedin 9054New Zealand maurice wilkins centre for Molecular biodiscovery University of AucklandAuckland 1010New Zealand Department of Medicine University of OtagoWellingtonWellington South 6242New Zealand centre for Endocrine Diabetes and Obesity Research Wellington Regional HospitalNewtownWellington 6021New Zealand Product Development Research centre University of OtagoDunedin 9054New Zealand Department of Chemistry The New Zealand Institute for Plant and Food ResearchUniversity of OtagoDunedin 9054New Zealand

Butein,a rare chalcone found in the toxic plant Toxicodendron vernicifluum,has been shown to regulate glucose homeostasis via inhibition of the nuclear factor kappa-B kinase subunit beta(IKKβ)/nuclear factor kappa B(NF-κB)pathway in the ***,we investigated whether the nonpoisonous plant Dahlia pinnata could be a source of butein as a potential treatment for type 2 diabetes(T2D).In mice fed a high-fat diet(HFD)to induce glucose intolerance,an oral *** petal extract improved glucose tolerance at doses of 3.3 mg/kg body weight and 10 mg/kg body ***,this effect was not mediated by butein alone but by butein combined with the closely related flavonoids,sulfuretin and/or ***,the extract improved systemic insulin *** of phosphatidylinositol 3-kinase to block insulin signaling in the brain abrogated the glucoregulatory effect of the orally administered *** extract reinstated central insulin signaling and normalized astrogliosis in the hypothalamus of HFD-fed *** NF-κB reporter zebrafish to determine IKKβ/NF-κB activity,a potent anti-inflammatory action of the extract was found.A randomized controlled crossover clinical trial on participants with predia-betes or T2D confirmed the safety and efficacy of the extract in *** conclusion,we identified an extract from the flower petals of *** as a novel treatment option for T2D,potentially targeting the central regulation of glucose homeostasis as a root cause of the disease.

关键词： inflammation hypothalamus signal transduction neuroendocrine arcuate nucleus

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结核分枝杆菌H37Ra FadD3基因克隆与表达研究

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云南大学学报（自然科学版） 2014年第4期36卷 600-605页

作者：袁方陈元晓 Stephanie Dawes Edward N.Baker 昆明医科大学基础医学院生物化学与分子生物学系云南昆明650500 昆明医科大学基础医学院细胞生物学与遗传学系云南昆明650500 maurice wilkins centre for Molecular biodiscovery and School of Biological Sciences University of Auckland

为探索FadD3在结核分枝杆菌胆固醇分解代谢中的作用,从结核分枝杆菌H37Ra的全基因组中克隆了FadD3基因,并在大肠杆菌BL21中表达.根据NCBI公布的结核分枝杆菌全基因组序列设计一对引物,PCR扩增FadD3基因.PCR扩增产物与克隆载体pGEM3Zf(+... 详细信息

为探索FadD3在结核分枝杆菌胆固醇分解代谢中的作用,从结核分枝杆菌H37Ra的全基因组中克隆了FadD3基因,并在大肠杆菌BL21中表达.根据NCBI公布的结核分枝杆菌全基因组序列设计一对引物,PCR扩增FadD3基因.PCR扩增产物与克隆载体pGEM3Zf(+)进行拼接,得到重组基因FadD3-pGEM3Zf(+),再转化到大肠杆菌DH5ɑ得到克隆.PCR检测阳性克隆,再与表达载体pYUB28b拼接,得到重组质粒FadD3-pYUB28b.阳性重组质粒亚克隆到大肠杆菌BL21宿主菌进行自体诱导表达.经过表型筛选及鉴定分析,已成功构建了重组表达质粒***-PAGE和Western blotting证实,重组基因FadD3-pYUB28b在大肠杆菌BL21中有表达产物.实验结果表明,以pYUB28b为表达载体,FadD3重组基因在大肠杆菌表达体系于温度分别为18,28℃有包涵体形式的表达蛋白,在37℃无表达产物.

关键词：结核分枝杆菌 H37Ra FadD3 基因克隆表达

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