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pregnane X receptor and constitutive androstane receptor modulate differently CYp3A-mediated metabolism in earlyand late-stage cholestasis

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World Journal of Gastroenterology 2017年第42期23卷 7519-7530页

作者： Daniela Gabbia arianna dalla pozza Laura Albertoni Roberta Lazzari Giorgia Zigiotto Maria Carrara Vincenzo Baldo Tatjana Baldovin Annarosa Floreani Sara De Martin Department of Pharmaceutical and Pharmacological Sciences University of Padova Department of Medicine General Pathology and Cytopathology UnitUniversity of Padova Department of Cardiac Thoracicand Vascular SciencesHygiene and Public Health UnitUniversity of Padova Department of Surgery Oncology and GastroenterologyUniversity of Padova

AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P < 0.01). At variance, m RNA and protein expression of CYP3 A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.

关键词： Cholestasis CYP3A Drug metabolism Pregnane X receptor Constitutive androstane receptor

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Prevalence of Bicuspid Aortic Valve in Turner Syndrome Patients Receiving Cardiac MRI and CT: A Meta-Analysis

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Congenital Heart Disease 2022年第2期17卷 129-140页

作者： Pengzhu Li Martina Bacova Robert dalla-pozza Nikolaus Alexander Haas Felix Sebastian Oberhoffer Department of Pediatric Cardiology and Intensive Care Medical Hospital of the University of MunichLudwig Maximilians University MunichMunichGermany

Turner syndrome(TS)is a rare disorder affecting 25–50 in 100000 female newborns.Bicuspid aortic valve(BAV)is assumed to be the most common congenital heart defect(CHD)in TS.In literature,reported BAV prevalence in TS ranges between 14%and 34%.The specific BAV prevalence in TS is still unknown.The aim of this study was to give a more precise estimation of BAV prevalence in TS by conducting a meta-analysis of TS-studies,which detected BAV by either cardiac magnetic resonance imaging(MRI)or cardiac computed tomography(CT).We searched PubMed,Cochrane Library,and Web of Science databases to collect observational studies including the prevalence of BAV identified by cardiac MRI or cardiac CT in TS patients up to June 4th,2021.After screening for inclusion,data extraction,and quality assessment by two independent reviewers,the meta-analysis was performed with R 4.1.1 software.Results are shown as proportion and weighted mean difference with 95%confidence intervals(95%CI).In total,11 studies involving 1177 patients were included.Pooled data showed that the prevalence of BAV in TS patients was 23.7%(95%CI:21.3%to 26.1%).No high heterogeneity was found between the included studies.The current meta-analysis reveals that BAVcan be detected in 23.7%of TS patients receiving cardiac MRI or cardiac CT.Therefore,BAV can be considered as the most common CHD in TS.Compared to TTE,cardiac MRI and cardiac CT might represent superior imaging modalities in BAV assessment of adult TS patients.

关键词： Turner syndrome bicuspid aortic valve magnetic resonance imaging(MRI) tomography X-ray computed(CT)

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Diagnosis of pervasive developmental disorders:when and how?An area-based study about health care providers

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World Journal of Pediatrics 2015年第1期11卷 48-53页

作者： Silvia Manea Laura Visonàdalla pozza Monica Mazzucato Oliviana Gelasio Paola Facchin Veneto Region Child&Mother Health Observatory Epidemiology and Community Medicine UnitDepartment of PediatricsPadua University

Background:Pervasive developmental disorders(PDDs)can be very difficult to diagnose in children and to communicate such a diagnosis to their parents.Families of children with PDD learn of their child's diagnosis long after the first symptoms are noted in the child's behavior.Methods:An area-based survey was conducted to assess all social and health care providers taking care of patients with PDDs in the Veneto Region(North-East Italy).Results:Only 28%of health care providers arrived at a definite diagnosis when the child was in his/her first year of age,51%when the child was 2-3 years old and 21%from age of 4 years and up.On average,the latency between the time of the diagnosis and its communication to the family was 6.9 months.However,a number of families did not ever have a diagnosis communicated to them.Sometimes,68%of the providers did not communicate a PDDs diagnosis to patient's families,and 4%of them quite commonly.Conclusion:The well-known delay in making a diagnosis of PDDs has two distinct components:one relating to the difficulty of confirming a diagnosis of PDDs,the other,hitherto unrecognized,relating to the family being notified.

关键词： autism,pervasive development disorders classification system communication diagnosis

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Hypercalcaemia after treatment with denosumab in children:bisphosphonates as an option for therapy and prevention?

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World Journal of Pediatrics 2020年第5期16卷 520-527页

作者： Carmen Sydlik Hans Roland Dürr Susanne Bechtold-dalla pozza Claudia Weiβenbacher Julia Roeb Heinrich Schmidt Department of Pediatric Endocrinology Dr.v.Haunersches Children's HospitalLudwig-Maximilian-University of MunichLindwurmstr.480337 MunichGermany Department of Orthopaedics Physical Medicine and RehabilitationUniversity HospitalLudwig-Maximilian-University of MunichMunichGermany

Background Pharmacologic options for treatment of osteolytic diseases especially in children are limited.Although not licensed for use,denosumab,a fully humanized antibody to RANKL,is used in children with good effects.Among others,one possible indication are giant cell tumors and aneurysmatic bone cysts.However,there are reports of severe hypercalcemia during weeks to months after termination of denosumab,that are rarely seen in adults.Methods We collected data of four patients,aged 6-17 years,who experienced severe hypercalcemia after completion of treatment with denosumab for unresectable giant cell tumors of bone or aneurysmal bone cysts and methods of their treatment.The detailed case information were described.Results One patient was treated with long-term,high-dose steroid therapy,leading to typical Cushing's syndrome.Another patient was restarted on denosumab repeatedly due to relapses of hypercalcemia after every stop.Finally,in two patients,hypercalcemia ceased definitely after treatment with bisphosphonates.However,several applications were necessary to stabilize calcium levels.Conclusions There is a considerable risk of hypercalcemia as an adverse effect after denosumab treatment in children.Therapeutic and,preferably,preventive strategies are needed.Bisphosphonates seem to be an option for both,but effective proceedings still remain to be established.

关键词： Aneurysmatic bone cyst Bisphosphonates Calcium homeostasis Denosumab Giant cell tumor of the bone

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Mitochondrial uncoupling protein 2 and pancreatic cancer:A new potential target therapy

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World Journal of Gastroenterology 2015年第11期21卷 3232-3238页

作者： Massimo Donadelli Ilaria Dando Elisa dalla pozza Marta Palmieri Department of Life and Reproduction Sciences Biochemistry SectionUniversity of Verona

Overall 5-years survival of pancreatic cancer patients is nearly 5%,making this cancer type one of the most lethal neoplasia.Furthermore,the incidence rate of pancreatic cancer has a growing trend that determines a constant increase in the number of deceases caused by this pathology.The poor prognosis of pancreatic cancer is mainly caused by delayed diagnosis,early metastasis of tumor,and resistance to almost all tested cytotoxic drugs.In this respect,the identification of novel potential targets for new and efficient therapies should be strongly encouraged in order to improve the clinical management of pancreatic cancer.Some studies have shown that the mitochondrial uncoupling protein 2(UCP2) is over-expressed in pancreatic cancer as compared to adjacent normal tissues.In addition,recent discoveries established a key role of UCP2 in protecting cancer cells from an excessive production of mitochondrial superoxide ions and in the promotion of cancer cell metabolic reprogramming,including aerobic glycolysis stimulation,promotion of cancer progression.These observations together with the demonstration that UCP2 repression can synergize with standard chemotherapy to inhibit pancreatic cancer cell growth provide the molecular rationale to consider UCP2 as a potential therapeutic target for pancreatic cancer.In this editorial,recent advances describing the relationship between cancer development and mitochondrial UCP2 activity are critically provided.

关键词： Uncoupling protein 2 Target therapy Reactive oxyge

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