Light triggered formation of photo-responsive epoxy based networks

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Simone Radl, Ignazio Roppolo, Karina Pölzl, Markus Ast, Josef Spreitz, Thomas Griesser, Wolfgang Kern, Sandra Schlögl, Marco Sangermano
Taking advantage of versatile o-nitrobenzyl chemistry, the present study highlights the design of photocurable epoxy networks that undergo spatially controlled bond cleavage in response to UV irradiation. The synthetic strategy involves the preparation of epoxy monomers with photolabile o-nitrobenzyl ester (o-NBE) links that are cured via photoinduced cationic ring opening reaction. Two different photoinitiation systems are employed which do not interfere with the absorbance of the o-NBE groups. The first initiation mechanism exploits the direct photolysis of N-hydroxynaphthalimide triflate upon deep UV exposure and the second mechanism follows a free radical promoted cationic polymerization upon visible light illumination. The crosslinking and cleavage kinetics of the photodegradable epoxy networks are characterized by spectroscopic techniques. In thin films, the UV induced increase in solubility is confirmed by sol-gel analysis and used for the fabrication of positive tone photoresists. Patterned films are obtained by photolithographic processes and microscopic analyses reveal that the resists provide a resolution of 4 μm and a good contrast behavior.

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Testing of a palatable bait and compatible vaccine carrier for the oral vaccination of European badgers (Meles meles) against tuberculosis

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Sonya Gowtage, Gareth A. Williams, Ray Henderson, Paul Aylett, Duncan MacMorran, Si Palmer, Andy Robertson, Sandrine Lesellier, Stephen P. Carter, Mark A. Chambers
The oral vaccination of wild badgers (Meles meles) with live Bacillus Calmette–Guérin (BCG) is one of the tools being considered for the control of bovine tuberculosis (caused by Mycobacterium bovis) in the UK. The design of a product for oral vaccination requires that numerous, and often competing, conditions are met. These include the need for a highly palatable, but physically stable bait that will meet regulatory requirements, and one which is also compatible with the vaccine formulation; in this case live BCG. In collaboration with two commercial bait companies we have developed a highly attractive and palatable bait recipe designed specifically for European badgers (Meles meles) that meets these requirements. The palatability of different batches of bait was evaluated against a standardised palatable control bait using captive badgers. The physical properties of the bait are described e.g. firmness and colour. The microbial load in the bait was assessed against European and US Pharmacopoeias. The bait was combined with an edible vaccine carrier made of hydrogenated peanut oil in which BCG vaccine was stable during bait manufacture and cold storage, demonstrating <0.5 log10 reduction in titre after 117weeks' storage at −20°C. BCG stability in bait was also evaluated at +4°C and under simulated environmental conditions (20°C, 98% Relative Humidity; RH). Finally, iophenoxic acid biomarkers were utilised as a surrogate for the BCG vaccine, to test variants of the vaccine-bait design for their ability to deliver biomarker to the gastrointestinal tract of individual animals. These data provide the first detailed description of a bait-vaccine delivery system developed specifically for the oral vaccination of badgers against Mycobacterium bovis using live BCG.



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The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Jennifer E. Cornick, Özlem Tastan Bishop, Feyruz Yalcin, Anmol M. Kiran, Benjamin Kumwenda, Chrispin Chaguza, Shanil Govindpershad, Sani Ousmane, Madikay Senghore, Mignon du Plessis, Gerd Pluschke, Chinelo Ebruke, Lesley McGee, Beutel Sigaùque, Jean-Marc Collard, Stephen D. Bentley, Aras Kadioglu, Martin Antonio, Anne von Gottberg, Neil French, Keith P. Klugman, Robert S. Heyderman, Mark Alderson, Dean B. Everett
Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype.



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Influenza in the Asia-Pacific region: Findings and recommendations from the Global Influenza Initiative

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Benjamin J. Cowling, Saverio Caini, Tawee Chotpitayasunondh, Samsuridjal Djauzi, Salvacion R. Gatchalian, Q. Sue Huang, Parvaiz A. Koul, Ping-Ing Lee, Abdul Razak Muttalif, Stanley Plotkin
The fourth roundtable meeting of the Global Influenza Initiative (GII) was held in Hong Kong, China, in July 2015. An objective of this meeting was to gain a broader understanding of the epidemiology, surveillance, vaccination policies and programs, and obstacles to vaccination of influenza in the Asia-Pacific region through presentations of data from Australia, Hong Kong, India, Indonesia, Malaysia, New Zealand, the Philippines, Taiwan, Thailand, and Vietnam.As well as a need for improved levels of surveillance in some areas, a range of factors were identified that act as barriers to vaccination in some countries, including differences in climate and geography, logistical challenges, funding, lack of vaccine awareness and education, safety concerns, perceived lack of vaccine effectiveness, and lack of inclusion in national guidelines. From the presentations at the meeting, the GII discussed a number of recommendations for easing the burden of influenza and overcoming the current challenges in the Asia-Pacific region. These recommendations encompass the need to improve surveillance and availability of epidemiological data; the development and publication of national guidelines, where not currently available and/or that are in line with those proposed by the World Health Organization; the requirement for optimal timing of vaccination programs according to local or country-specific epidemiology; and calls for advocacy and government support of vaccination programs in order to improve availability and uptake and coverage.In conclusion, in addition to the varied epidemiology of seasonal influenza across this diverse region, there are a number of logistical and resourcing issues that present a challenge to the development of optimally effective vaccination strategies and that need to be overcome to improve access to and uptake of seasonal influenza vaccines. The GII has developed a number of recommendations to address these challenges and improve the control of influenza.



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Replacement of in vivo human rabies vaccine potency testing by in vitro glycoprotein quantification using ELISA – Results of an international collaborative study

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Sylvie Morgeaux, Bertrand Poirier, C. Ian Ragan, Dianna Wilkinson, Ulrich Arabin, Françoise Guinet-Morlot, Robin Levis, Heidi Meyer, Patrice Riou, Shahjahan Shaid, Dmitriy Volokhov, Noël Tordo, Jean-Michel Chapsal
Three different ELISAs quantifying rabies glycoprotein were evaluated as in vitro alternatives to the National Institutes of Health (NIH) in vivo potency test for batch release of human rabies vaccines. The evaluation was carried out as an international collaborative study supported by the European Partnership for Alternatives to Animal Testing (EPAA). This pre-validation study, the results of which are presented in this paper, compared three different ELISA designs, assessing their within- and between-laboratory precision. One of the ELISA designs was proposed to the European Directorate for the Quality of Medicines & HealthCare (EDQM) and accepted for an international collaborative study under the umbrella of the Biological Standardisation Programme.



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Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Meliha C. Kapetanovic, Johanna Nagel, Inger Nordström, Tore Saxne, Pierre Geborek, Anna Rudin
BackgroundTreatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccination. The mechanisms by which MTX exerts these effects in RA are unknown. We aimed to evaluate whether MTX reduces vaccine-specific serum Ig levels and their functionality in RA patients following vaccination with pneumococcal conjugate vaccine, and if numbers of antigen-specific circulating plasmablasts are affected.MethodsTen patients with RA on MTX and 10 RA patients without disease modifying anti-rheumatic drug (DMARD) were immunized with a dose 13-valent pneumococcal conjugate vaccine (Prevenar13). Circulating plasmablasts producing total IgG and IgA as well as specific IgG and IgA against two pneumococcal capsular serotypes (6B and 23F) were enumerated using ELISPOT 6days after vaccination. IgG levels against both these serotypes were determined with ELISA before and 4–6weeks after vaccination. Positive antibody response was defined as ⩾2-fold increase of pre-vaccination antibody levels. The functionality of vaccine specific antibodies to serotype 23F was evaluated by measuring their ability to opsonize bacteria using opsonophagocytic assay (OPA) in 4 randomly chosen RA patients on MTX and 4 RA patients without DMARD.ResultsAfter vaccination, RA patients on MTX showed significant increase in pre- to postvaccination antibody levels for 6B (p<0.05), while patients without DMARD had significant increases for both 6B and 23F (p<0.05 and p<0.01, respectively). Only 10% of RA on MTX and 40% of RA patients without DMARD showed positive post-vaccination antibody responses for both serotypes. Increased opsonizing ability after vaccination was detected in 1 of 4 RA patients on MTX and 3 of 4 patients on RA without DMARD. However, numbers of circulating total and vaccine-specific IgG- or IgA-producing plasmablasts did not differ between RA patients with or without MTX.ConclusionsMTX treatment in RA leads to reduced vaccine-specific antibody responses and their functionality compared to untreated RA following pneumococcal vaccination using polysaccharide-protein conjugate vaccine. However, since there was no reduction in numbers of circulating total or vaccine-specific antibody-producing plasmablasts after vaccination this effect is probably not due to reduced activation of B cells in lymphoid tissue.Clinical trial registration: NCT02240888.



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Demand- and supply-side determinants of diphtheria-pertussis-tetanus nonvaccination and dropout in rural India

Publication date: Available online 9 January 2017
Source:Vaccine
Author(s): Arpita Ghosh, Ramanan Laxminarayan
BackgroundAlthough 93% of 12- to 23-month-old children in India receive at least one vaccine, typically Bacillus Calmette–Guérin, only 75% complete the recommended three doses of diphtheria-pertussis-tetanus (DPT, also referred to as DTP) vaccine. Determinants can be different for nonvaccination and dropout but have not been examined in earlier studies. We use the three-dose DPT series as a proxy for the full sequence of recommended childhood vaccines and examine the determinants of DPT nonvaccination and dropout between doses 1 and 3.MethodsWe analyzed data on 75,728 6- to 23-month-old children in villages across India to study demand- and supply-side factors determining nonvaccination with DPT and dropout between DPT doses 1 and 3, using a multilevel approach. Data come from the District Level Household and Facility Survey 3 (2007–08).ResultsIndividual- and household-level factors were associated with both DPT nonvaccination and dropout between doses 1 and 3. Children whose mothers had no schooling were 2.3 times more likely not to receive any DPT vaccination and 1.5 times more likely to drop out between DPT doses 1 and 3, compared with children whose mothers had 10 or more years of schooling. Although supply-side factors related to availability of public health facilities and immunization-related health workers in villages were not correlated with dropout between DPT doses 1 and 3, children in districts where 46% or more villages had a healthcare subcentre were 1.5 times more likely to receive at least one dose of DPT vaccine compared with children in districts where 30% or fewer villages had subcentres.ConclusionsNonvaccination with DPT in India is influenced by village- and district-level contextual factors over and above individuals' background characteristics. Dropout between DPT doses 1 and 3 is associated more strongly with demand-side factors than with village- and district-level supply-side factors.



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Perfusion of the uterine junctional zone in nulliparous and primiparous women assessed by DCE-MRI, as a function of menstrual cycle and hormonal contraception

Publication date: May 2017
Source:Magnetic Resonance Imaging, Volume 38
Author(s): L.J. Meylaerts, L. Wijnen, M. Bazot, M. Grieten, W. Ombelet, M. Vandersteen
PurposeTo evaluate the perfusion parameters of inner and outer myometrium in healthy nulliparous and primiparous women who are and who are not currently using hormonal contraceptives by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Material and methodsWe performed pelvic 1.5T DCE-MRI on 98 women: 18 nulliparous non-users, 30 nulliparous users, 12 primiparous non-users and 38 primiparous users of hormonal contraception (mean age respectively 26.4, 25.8, 30.23 and 28.18years). The nulliparous non-users underwent DCE-MRI investigations during their follicular, ovulatory and luteal phase. Perfusion parameters (iAUC/volume, Ktrans, Kep and Ve) were assessed in the anterior and posterior junctional zone (JZ), outer myometrium and cervix.ResultsIn nulliparous non-users, the mean Ktrans and iAUC/volume showed a decrease from follicular to luteal phase (0.82 vs 0.55min⁻¹ for Ktrans, p=0/027 and 1.28 vs 0.68 for iAUC/volume, p<0.001). The anterior JZ demonstrated lower Ktrans (p=0.050) and higher Kep (p=0.012), in nulliparous non-users, lower Ktrans in nulliparous users (p<0.001) and lower Ve in primiparous users (p=0.012) than the anterior outer myometrium. Ktrans at the anterior and posterior JZ wall in nulliparous users was lower than in non-users (p=0.001 and p=0.013) and Ve at the anterior JZ wall in primiparous users was lower than in non-users (p=0.044).ConclusionThis study provides data on normal perfusion parameters of inner and outer myometrium, which may be potentially useful in assisted reproductive therapy.



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Spectral characterization, thermal and biological activity studies of Schiff base complexes derived from 4,4′-Methylenedianiline, ethanol amine and benzil

Publication date: 15 April 2017
Source:Journal of Molecular Structure, Volume 1134
Author(s): Sanaa Moustafa Emam
Some new metal(II) complexes of asymmetric Schiff base ligand were prepared by template technique. The shaped complexes are in binuclear structures and were explained through elemental analysis, molar conductivity, various spectroscopic methods (IR, U.V–Vis, XRD, ESR), thermal (TG) and magnetic moment measurements. The IR spectra were done demonstrating that the Schiff base ligand acts as neutral tetradentate moiety in all metal complexes. The electronic absorption spectra represented octahedral geometry for all complexes, while, the ESR spectra for Cu(II) complex showed axially symmetric g-tensor parameter with g׀׀ > g⊥ > 2.0023 indicating to ²B1g ground state with (dx2−y2)¹ configuration. The nature of the solid residue created from TG estimations was affirmed utilizing IR and XRD spectra. The biological activity of the prepared complexes was studied against Land Snails. Additionally, the in vitro antitumor activity of the synthesized complexes with Hepatocellular Carcinoma cell (Hep-G2) was examined. It was observed that Zn(II) complex (5), exhibits a high inhibition of growth of the cell line with IC50 of 7.09 μg/mL.

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Hassle free synthesis of nanodimensional Ni, Cu and Zn sulfides for spectral sensing of Hg, Cd and Pb: A comparative study

Publication date: 5 April 2017
Source:Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 176
Author(s): Zarina Ansari, Shib Shankar Singha, Abhijit Saha, Kamalika Sen
A simple room temperature synthesis method of Ni, Cu and Zn sulfide nanoparticles (NPs) in aqueous medium is reported here. The NPs stabilized in aqueous medium by the citrate ions were characterized by UV–vis, ζ potentials, TEM and Raman spectroscopic techniques. The solid NPs could be isolated from the aqueous medium when allowed to stand for a prolonged time (~20h). The solids were also characterized by IR and powder X-ray analysis. The nanoparticles were further used for the development of facile optical sensing and detection of heavy metal ions at trace scale. Alterations in the absorption spectra of the generated NPs were indicative of their interactions with heavy metal ions. Raman spectral measurements further validate the detection technique. It is found that out of the three synthesized nanoparticles, nickel sulfide NP is a specific sensor for mercury ions whereas zinc sulfide and copper sulfide NPs act as sensors for Hg²⁺, Cd²⁺ and Pb²⁺.

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Novel synthesis of metal sulfides-loaded porous carbon as anode materials for lithium-ion batteries

Publication date: 15 April 2017
Source:Chemical Engineering Journal, Volume 314
Author(s): Siqi Zhang, Rong Lin, Wenbo Yue, Fangzhou Niu, Jie Ma, Xiaojing Yang
Many metal sulfides with high theoretical capacities are potential anode materials for lithium-ion batteries. However, the low electronic conductivity and large volume change of metal sulfides during cycling seriously hamper their practical applications. Herein, we report a novel and scalable strategy to synthesize well-dispersed Ni3S2 (∼5nm) inside porous carbon (CMK-3) by using mesoporous silica (SBA-15) as the template. CMK-3 offers not only good electronic conductivity but also mesopores to accommodate the volume variation of Ni3S2, leading to outstanding electrochemical performance of Ni3S2-loaded CMK-3. To show the versatility of this novel method, ZnS-loaded CMK-3 is also prepared. However, most ZnS nanoparticles are formed outside the pores of CMK-3 with regard to high loading amount. It is inferred that the intermediate product Zn would melt and migrate to the outer surface of CMK-3 prior to the formation of ZnS. This novel synthesis method may offer an attractive pathway to metal sulfide-loaded porous carbon with high lithium storage capacity.

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Ameliorating Effects of Herbal Formula Hemomine on Experimental Subacute Hemorrhagic Anemia in Rats

Publication date: Available online 9 January 2017
Source:Journal of Ethnopharmacology
Author(s): Sae Kwang Ku, Hyemee Kim, Joo Wan Kim, Ki Sung Kang, Hae-Jeung Lee
Ethnopharmacological relevanceHemomine (HM) is an herbal mixture consisting of 5 varieties of the hematopoietic herbal extracts (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia lactiflora Pall., Rehmannia glutinosa Liboschitz ex Stueudel, Glycyrrhiza uralensis Fischer).Aim of the studyAnemia has been treated with iron supplements, whereas it could cause adverse side effects such as digestive discomfort. In the present study, HM was applied to SHA rats to test for several activities so as to verify its therapeutic potentials on anemia and digestive discomfort.Materials and methodsSprague-Dawley rats were assigned to seven groups: (Two controls, two references (ferric hydroxide polymatose (FM) and ferritin extract glycerin hydrate (FA)), three different concentrations of HM, n=8 per groups), and induced subacute hemorrhagic anemia (SHA) through blood exsanguinations once a day for 7 days.ResultsThe SHA animal model showed changes in the markers related to classic iron-deficient and regenerative anemia in this experiment. However, the SHA related anemic signs were dose-dependently inhibited by the administration of HM 2, 1, and 0.5ml/kg for 7 days, and more favorably than the equal dosages of FM and FA. In addition, FM and FA showed the typical constipation signs, including reduction of in thickness of the colonic mucosa, in contrast, HM 2, 1, and 0.5ml/kg groups had no effects on the gastrointestinal motilities and the colonic mucous components when compared to the controls. The results suggested that the HM significantly showed to have therapeutic effects in the experimental SHA in rats, and is more potent than the commercial iron supplement through the proliferation of hematopoietic stem cells with reduced digestive discomfort.ConclusionsTherefore, Hemomine may prove to be a promising hematopoietic and therapeutic agent for anemia.

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A characterization of the antimalarial activity of the bark of Cylicodiscus gabunensis Harms

Publication date: Available online 9 January 2017
Source:Journal of Ethnopharmacology
Author(s): Omar Aldulaimi, Fidelia I. Uche, Hamza Hameed, Haddijatou Mbye, Imran Ullah, Falko Drijfhout, Timothy D.W. Claridge, Paul Horrocks, Wen-Wu Li
Ethnopharmacological relevance and aimA decoction of the bark of Cylicodiscus gabunensis Harms is used as a traditional medicine in the treatment of malaria in Nigeria. This study aims to validate the antimalarial potency of this decoction in vitro against Plasmodium falciparum and define potential bioactive constituents within the C. gabunensis bark.Materials and methodsA bioassay-guided separation and fractionation protocol was applied to C. gabunensis extracts, exploiting the use of a Malaria Sybr Green I Fluorescence assay method to monitor antiproliferative effects on parasites as well as define 50% inhibition concentrations. Spectroscopic techniques, including GC-MS, TOF LC-MS and ¹H NMR were used to identify phytochemicals present in bioactive fractions. Analogues of gallic acid were synthesized de novo to support the demonstration of the antimalarial action of phenolic acids identified in C. gabunensis bark. In vitro cytotoxicity of plant extracts, fractions and gallate analogues was evaluated against the HepG2 cell line.ResultsThe antimalarial activity of ethanolic extracts of C. gabunensis bark was confirmed in vitro, with evidence for phenolic acids, primarily gallic acid and close analogues such as ethyl gallate, likely providing this effect. Further fraction produced the most potent fraction with a 50% inhibitory concentration of 4.7µg/ml. Spectroscopic analysis, including ¹H NMR, LC-MS and GC-MS analysis of this fraction and its acid hydrolyzed products, indicated the presence of conjugates of gallic acid with oligosaccharides. The extracts/fractions and synthetic alkyl gallate showed moderate selectivity against P. falciparum.ConclusionsThese results support the use of the bark of C. gabunensis as a traditional medicine in the treatment of human malaria, with phenolic acid oligosaccharide complexes evident in the most bioactive fractions.

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Role of cAMP/PKA pathway and T-type calcium channels in the mechanism of action of serotonin in human adrenocortical cells

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Estelle Louiset, Céline Duparc, Sébastien Lenglet, Celso E. Gomez-Sanchez, Hervé Lefebvre
In human adrenal, serotonin (5-HT), produced by mast cells located in zona glomerulosa, stimulates production of corticosteroids through a paracrine mechanism involving the 5-HT receptor type 4 (5-HT4). The aim of the present study was to investigate the transduction mechanisms associated with activation of 5-HT4 receptors in human adrenocortical cells. Our results show that 5-HT4 receptors are present in the outer adrenal cortex, both in glomerulosa and fasciculata zonae. In the zona glomerulosa. 5-HT4 receptor was detected both in immunopositive and immunonegative cells for 11β-hydroxylase, an enzyme involved in cortisol synthesis. The data demonstrate that 5-HT4 receptors are positively coupled to adenylyl cyclases and cAMP-dependent protein kinases (PKA). The activation of the cAMP-PKA pathway is associated with calcium influx through T-type calcium channels. Both the adenylyl cyclase/PKA pathway and the calcium influx are involved in 5-HT-induced cortisol secretion.

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GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Julia Dörner, Verena Martinez Rodriguez, Ricarda Ziegler, Theresa Röhrig, Rebecca S. Cochran, Ronni M. Götz, Mark D. Levin, Marjut Pihlajoki, Markku Heikinheimo, David B. Wilson
As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1⁺ progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Gli1-creER^T2) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1⁺ cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1⁺ progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1⁺ progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Amhr2, Foxl2) in response to GDX. These findings support the premise that GLI1⁺ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue.



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Electrochemistry of cytochrome P450 17α-hydroxylase/17,20-lyase (P450c17)

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Lisandra L. Martin, Clemens Kubeil, Alexandr N. Simonov, Vladimir L. Kuznetsov, C. Jo Corbin, Richard J. Auchus, Alan J. Conley, Alan M. Bond, Raymond J. Rodgers
Within the superfamily of cytochrome P450 enzymes (P450s), there is a small class which is functionally employed for steroid biosynthesis. The enzymes in this class appear to have a small active site to accommodate the steroid substrates specifically and snuggly, prior to the redox transformation or hydroxylation to form a product. Cytochrome P450c17 is one of these and is also a multi-functional P450, with two activities, the first 17α-hydroxylation of pregnenolone is followed by a subsequent 17,20-lyase transformation to dehydroepiandrosterone (DHEA) as the dominant pathways to cortisol precursors or androgens in humans, respectively. How P450c17 regulates these two redox reactions is of special interest. There is a paucity of direct electrochemical studies on steroidogenic P450s, and in this mini-review we provide an overview of these studies with P450c17. Historical consideration as to the difficulties in obtaining reliable electrochemistry due to issues of handling proteins on an electrode, together with advances in the electrochemical techniques are addressed. Recent work using Fourier transformed alternating current voltammetry is highlighted as this technique can provide both catalytic information simultaneously with the underlying redox transfer with the P450 haem.



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Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Ai Tamura, Koshiro Nishimoto, Tsugio Seki, Yoko Matsuzawa, Jun Saito, Masao Omura, Celso E. Gomez-Sanchez, Kohzoh Makita, Seishi Matsui, Nobukazu Moriya, Atsushi Inoue, Maki Nagata, Hironobu Sasano, Yasuhiro Nakamura, Yuto Yamazaki, Yasuaki Kabe, Kuniaki Mukai, Takeo Kosaka, Mototsugu Oya, Sachiko Suematsu, Tetsuo Nishikawa
We report a case of non-familial juvenile primary aldosteronism (PA). Super-selective adrenal venous sampling identified less aldosterone production in the right inferior adrenal segment than others. Bilateral adrenalectomy sparing the segment normalized blood pressure and improved PA. Both adrenals had similar histologies, consisting of a normal adrenal cortex and aldosterone synthase-positive hyperplasia/adenoma. An aldosterone-driving KCNJ5 mutation was detected in the lesions, but not in the histologically normal cortex. After taking into account that the two adrenal glands displayed a similar histological profile, as well as the fact that hyperplastic lesions in both glands exhibited a common KCNJ5 mutation, we conclude that the specific mutation may have occurred at an adrenal precursor mesodermal cell, at an early stage of development; its daughter cells were mixed with non-mutant cells and dispersed into both adrenal glands, resulting into a form of the condition known as genetic mosaicism.



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A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Elzette Pretorius, Wiebke Arlt, Karl-Heinz Storbeck
The abundant adrenal C19 steroid 11β-hydroxyandrostenedione (11OHA4) has been written off as a dead-end product of adrenal steroidogenesis. However, recent evidence has demonstrated that 11OHA4 is the precursor to the potent androgenic 11-oxygenated steroids, 11-ketotestosterone and 11-ketodihydrotestosterone, that bind and activate the human androgen receptor similarly to testosterone and DHT. The significance of this discovery becomes apparent when considering androgen dependent diseases such as castration resistant prostate cancer and diseases associated with androgen excess, e.g. congenital adrenal hyperplasia and polycystic ovary syndrome. In this review we describe the production and metabolism of 11-oxygenated steroids. We subsequently discuss their androgenic activity and highlight the putative role of these androgens in disease states.



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Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Nesa Marti, José A. Galván, Amit V. Pandey, Mafalda Trippel, Coya Tapia, Michel Müller, Aurel Perren, Christa E. Flück
Recently, dihydrotestosterone biosynthesis through the backdoor pathway has been implicated for the human testis in addition to the classic pathway for testosterone (T) synthesis. In the human ovary, androgen precursors are crucial for estrogen synthesis and hyperandrogenism in pathologies such as the polycystic ovary syndrome is partially due to ovarian overproduction. However, a role for the backdoor pathway is only established for the testis and the adrenal, but not for the human ovary. To investigate whether the backdoor pathway exists in normal and PCOS ovaries, we performed specific gene and protein expression studies on ovarian tissues.We found aldo-keto reductases (AKR1C1-1C4), 5α-reductases (SRD5A1/2) and retinol dehydrogenase (RoDH) expressed in the human ovary, indicating that the ovary might produce dihydrotestosterone via the backdoor pathway. Immunohistochemical studies showed specific localization of these proteins to the theca cells. PCOS ovaries show enhanced expression, what may account for the hyperandrogenism.

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Regulation of zonation and homeostasis in the adrenal cortex

Publication date: 5 February 2017
Source:Molecular and Cellular Endocrinology, Volume 441
Author(s): Emanuele Pignatti, Sining Leng, Diana L. Carlone, David T. Breault
The adult adrenal cortex is organized into concentric zones, each specialized to produce distinct steroid hormones. Cellular composition of the cortex is highly dynamic and subject to diverse signaling controls. Cortical homeostasis and regeneration rely on centripetal migration of steroidogenic cells from the outer to the inner cortex, which is accompanied by direct conversion of zona glomerulosa (zG) into zona fasciculata (zF) cells. Given the important impact of tissue structure and growth on steroidogenic function, it is essential to understand the mechanisms governing adrenal zonation and homeostasis. Towards this end, we review the distinctions between each zone by highlighting their morphological and ultra-structural features, discuss key signaling pathways influencing zonal identity, and evaluate current evidence for long-term self-renewing stem cells in the adult cortex. Finally, we review data supporting zG-to-zF transdifferentiation/direct conversion as a major mechanism of adult cortical renewal.



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