Publications by authors named "Shakil Ahmad"

76 Publications

Climate change and hydrological regime of the high-altitude Indus basin under extreme climate scenarios.

Sci Total Environ 2021 Jan 2;768:144467. Epub 2021 Jan 2.

Water Systems and Global Change, Wageningen University and Research, the Netherlands; World Meteorological Organization, Switzerland.

Climate change is recognized as one of the greatest challenges of 21st century. This study investigated climate and hydrological regimes of the high-altitude Indus basin for the historical period and extreme scenarios of future climate during 21st century. Improved datasets of precipitation and temperature were developed and forced to a fully-distributed physically-based energy-balance Variable Infiltration Capacity (VIC) hydrological model to simulate the water balance at regional and sub-basin scale. Relative to historical baseline, the results revealed highly contrasting signals of climate and hydrological regime changes. Against an increase of 0.6 °C during the last 40 years, the median annual air temperature is projected to increase further between 0.8 and 5.7 °C by the end of 21st century. Similarly, a decline of 11.9% in annual precipitation is recorded, but future projections are highly conflicting and spatially variable. The Karakoram region is anticipated to receive more precipitation, while SW-Hindukush and parts of W-Himalayan region may experience decline in precipitation. The Model for Interdisciplinary Research On Climate version-5 (MIROC5) generally shows increases, while Max Planck Institute Earth System Model at base resolution (MPI-ESM-LR) indicates decreases in precipitation and river inflows under three Representative Concentration Pathways (RCPs) of 2.6, 4.5 and 8.5. Indus-Tarbela inflows are more likely to increase compared to Kabul, Jhelum and Chenab river inflows. Substantial increase in the magnitudes of peak flows and one-month earlier attainment is projected for all river gauges. High flows are anticipated to increase under most scenarios, while low flows may decrease for MPI-ESM-LR in Jhelum, Chenab and Kabul river basins. Hence, hydrological extremes are likely to be intensified. Critical modifications in the strategies and action plans for hydropower generation, construction and operation of storage reservoirs, irrigation withdrawals, flood control and drought management will be required to optimally manage water resources in the basin.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144467DOI Listing
January 2021

Synthesis and Photoactivated Toxicity of 2-Thiophenylfuranocoumarin Induce Midgut Damage and Apoptosis in Larvae.

J Agric Food Chem 2021 Jan 12;69(3):1091-1106. Epub 2021 Jan 12.

Key Laboratory of Green Prevention and Control of Tropical Plant Diseases and Pests, Ministry of Education, College of Plant Protection, Hainan University, Haikou, Hainan 570228, P.R. China.

Furanocoumarins are photoactive compounds derived from secondary plant metabolites. They possess many bioactivities, including antioxidative, anticancer, insecticidal, and bactericidal activities. Here, we designed a new scheme for synthesizing 2-arylfuranocoumarin derivatives by condensation, esterification, bromination, and Wittig reaction. We found that 2-thiophenylfuranocoumarin (Iy) had excellent photosensitive activity. Three Iy concentrations (LC, LC, and LC) were used to treat the fourth instar larvae of (). The photoactivated toxicity, sublethal dose, mitochondrial dysfunction, oxidative stress level, intestinal barrier dysfunction, and apoptosis were studied. The results showed that Iy induced reactive oxygen species (ROS) production in midgut cells under ultraviolet light. Ultrastructural analysis demonstrated that mitochondria were damaged, and the activities of related enzymes were inhibited. Ultimately, Iy exposure led to excessive ROS production followed by the inhibition of antioxidant enzymes, including SOD, CAT, GPx, and GR, which diminished ROS elimination and escalated oxidative stress in midgut cells, aggravating the degree of oxidative damage in these cells. Histopathological changes were observed in the midgut, which led to intestinal barrier dysfunction. When the elimination of ROS was blocked and it accumulated in cells, apoptosis-related genes, including , , and , were induced and activated. In addition, Iy affected the growth and development of at sublethal concentrations, and there was an obvious post-lethal effect. Thus, we found that Iy caused midgut damage and apoptosis in larvae under ultraviolet light, which preliminarily revealed the mode of action of Iy in .
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http://dx.doi.org/10.1021/acs.jafc.0c07237DOI Listing
January 2021

Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model.

Redox Biol 2021 Jan 28;38:101814. Epub 2020 Nov 28.

Mirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; King Fahad Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia; President's Office, University of Southampton, University Road, Southampton, UK. Electronic address:

An imbalance in angiogenic growth factors and poor utero-placental perfusion are strongly associated with preeclampsia. The reduced utero-placental perfusion (RUPP) model that mimics insufficient placental perfusion is used to study preeclampsia. The aim of this study was to develop a refined RUPP model in C57Bl/6 J mice to test the efficacy of MZe786 as a potential inhibitor of soluble Flt-1 for preeclampsia therapy. Murine RUPP (mRUPP) was induced through bilateral ligation of the ovarian arteries at E11.5 that resulted in typical preeclampsia symptoms including increase in mean arterial pressure (MAP), kidney injury and elevated soluble Flt-1 (sFlt-1) levels in the maternal plasma and amniotic fluid. The murine RUPP kidneys showed tubular and glomerular damage along with increased oxidative stress characterised by increased nitrotyrosine staining. The mRUPP displayed abnormal placental vascular histology, reduced expression of placental cystathionine γ-lyase (CSE), the hydrogen sulfide (HS) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (HS)-releasing compound MZe786 from E11.5 to E17.5 successfully prevented the development of preeclampsia. Specifically, MZe786 treatment reduced maternal MAP and kidney nitrotyrosine staining and improved fetal outcome. The circulation levels of sFlt-1 were dramatically decreased in MZe786 treated animals implying that HS released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial.
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http://dx.doi.org/10.1016/j.redox.2020.101814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744945PMC
January 2021

Bibliometric Analysis of Literature Published on Antibacterial Dental Adhesive from 1996-2020.

Polymers (Basel) 2020 Nov 29;12(12). Epub 2020 Nov 29.

Islamabad Model College for Boys, H-9, Islamabad 44000, Pakistan.

This study aimed to investigate the current state of research on antibacterial dental adhesives. The interest in this field can be drawn from an increasing number of scholarly works in this area. However, there is still a lack of quantitative measurement of this topic. The main aim of this study was to consolidate the research published on the antibacterial adhesive from 1996 to 2020 in Web of Science indexed journals. The bibliometric method, a quantitative study of investigating publishing trends and patterns, was used for this study. The result has shown that a gradual increase in research was found, whereby a substantial increase was observed from 2013. A total of 248 documents were published in 84 journals with total citations of 5107. The highly cited articles were published mainly in Q1 category journals. Most of the published articles were from the USA, China, and other developed countries; however, some developing countries contributed as well. The authorship pattern showed an interdisciplinary and collaborative approach among researchers. The thematic evaluation of keywords along with a three-factor analysis showed that 'antibacterial adhesives' and 'quaternary ammonium' have been used commonly. This bibliometric analysis can provide direction not only to researchers but also to funding organizations and policymakers.
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http://dx.doi.org/10.3390/polym12122848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761276PMC
November 2020

MZe786, a hydrogen sulfide-releasing aspirin prevents preeclampsia in heme oxygenase-1 haplodeficient pregnancy under high soluble flt-1 environment.

Redox Biol 2021 Jan 24;38:101768. Epub 2020 Oct 24.

Mirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Holt Street, Birmingham, B7 4BB, United Kingdom; Aston Medical Research Institute, Aston Medical School, Birmingham, United Kingdom; Department of Biochemistry, ESC Research Unit, Faculty of Science, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; President's Office, University of Southampton, University Road, Southampton, SO17 1BJ, UK. Electronic address:

Preeclampsia affects one in twelve of the 130 million pregnancies a year. The lack of an effective therapeutic to prevent or treat it is responsible for an annual global cost burden of 100 billion US dollars. Preeclampsia also affects these women later in life as it is a recognised risk factor for cardiovascular disease, stroke and vascular dementia. Our laboratory demonstrated that preeclampsia is associated with high soluble fms-like tyrosine kinase 1 (sFlt-1) and low heme oxygenase-1 (HO1/Hmox1) expression. Here we sought to determine the therapeutic value of a novel HS-releasing aspirin (MZe786) in HO-1 haploid deficient (Hmox1) pregnant mice in a high sFlt-1 environment. Pregnant Hmox1 mice were injected with adenovirus encoding sFlt-1 or control virus at gestation day E11.5. Subsequently, Hmox1 dams were treated daily with a number of treatment regimens until E17.5, when maternal and fetal outcomes were assessed. Here we show that HO-1 compromised mice in a high sFlt-1 environment during pregnancy exhibit severe preeclampsia signs and a reduction in antioxidant genes. MZe786 ameliorates preeclampsia by reducing hypertension and renal damage possibly by stimulating antioxidant genes. MZe786 also improved fetal outcome in comparison with aspirin alone and appears to be a better therapeutic agent at preventing preeclampsia than aspirin alone.
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http://dx.doi.org/10.1016/j.redox.2020.101768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610044PMC
January 2021

Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells.

Sci Rep 2020 09 25;10(1):15810. Epub 2020 Sep 25.

Aston Medical Research Institute, Aston Medical School, Birmingham, UK.

Endothelial dysfunction is a hallmark of preeclampsia, a life-threatening complication of pregnancy characterised by hypertension and elevated soluble Fms-Like Tyrosine Kinase-1 (sFlt-1). Dysregulation of hydrogen sulfide (HS) by inhibition of cystathionine γ-lyase (CSE) increases sFlt-1 and soluble endoglin (sEng) release. We explored whether compromise in CSE/HS pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative status. We investigated whether these effects were linked to CSE-induced sFlt-1 and sEng production in endothelial cells. Here, we demonstrate that CSE/HS pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increases the production of mitochondrial-specific superoxide. As a compensatory effect, low CSE environment enhances the reliance on glycolysis. The mitochondrial-targeted HS donor, AP39, suppressed the antiangiogenic response and restored the mitochondrial bioenergetics in endothelial cells. AP39 revealed that upregulation of sFlt-1, but not sEng, is independent of the mitochondrial HS metabolising enzyme, SQR. These data provide new insights into the molecular mechanisms for antiangiogenic upregulation in a mitochondrial-driven environment. Targeting HS to the mitochondria may be of therapeutic benefit in the prevention of endothelial dysfunction associated with preeclampsia.
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http://dx.doi.org/10.1038/s41598-020-72371-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519095PMC
September 2020

MZe786 Rescues Cardiac Mitochondrial Activity in High sFlt-1 and Low HO-1 Environment.

Antioxidants (Basel) 2020 Jul 9;9(7). Epub 2020 Jul 9.

Aston Medical Research Institute, Aston Medical School, Birmingham B4 7ET, UK.

Hypertensive disorder in pregnancy is a major cause of maternal and perinatal mortality worldwide. Women who have had preeclampsia are at three to four times higher risk in later life of developing high blood pressure and heart disease. Soluble Flt-1 (sFlt-1) is elevated in preeclampsia and may remain high postpartum in women with a history of preeclampsia. Heme oxygenase-1 (Hmox1/HO-1) exerts protective effects against oxidative stimuli and is compromised in the placenta of pregnant women with preeclampsia. We hypothesized that sFlt-1 inhibits cardiac mitochondrial activity in HO-1 deficient mice. HO-1 haplo-insufficient mice (Hmox1) were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) or control virus (Ad-CMV). Subsequently, they were treated daily with either placebo or MZe786 for six days, when the heart tissue was harvested to assess cardiac mitochondrial activity. Here, we show that the loss of HO-1 disturbed cardiac mitochondrial respiration and reduced mitochondrial biogenesis. The overexpression of sFlt-1 resulted in the inhibition of the cardiac mitochondrial activity in Hmox1 mice. The present study demonstrates that the hydrogen sulfide (HS) releasing molecule, MZe786, rescues mitochondrial activity by stimulating cardiac mitochondrial biogenesis and antioxidant defense in Hmox1 mice and in Hmox1 mice exposed to a high sFlt-1 environment.
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http://dx.doi.org/10.3390/antiox9070598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402164PMC
July 2020

Contribution of the neuronal sodium channel Na1.8 to sodium- and calcium-dependent cellular proarrhythmia.

J Mol Cell Cardiol 2020 07 11;144:35-46. Epub 2020 May 11.

Department of Cardiology and Pneumology, University Hospital, Georg-August University Göttingen, and DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany; Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany. Electronic address:

Objective: In myocardial pathology such as heart failure a late sodium current (I) augmentation is known to be involved in conditions of arrhythmogenesis. However, the underlying mechanisms of the I generation are not entirely understood. By now evidence is growing that non-cardiac sodium channel isoforms could also be involved in the I generation. The present study investigates the contribution of the neuronal sodium channel isoform Na1.8 to arrhythmogenesis in a clearly-defined setting of enhanced I by using anemone toxin II (ATX-II) in the absence of structural heart disease.

Methods: Electrophysiological experiments were performed in order to measure I, action potential duration (APD), SR-Ca-leak and cellular proarrhythmic triggers in ATX-II exposed wild-type (WT) and SCN10A mice cardiomyocytes. In addition, WT cardiomyocytes were stimulated with ATX-II in the presence or absence of Na1.8 inhibitors. I was measured by using the whole cell patch clamp method.

Results: In WT cardiomyocytes exposure to ATX-II augmented I prolonged APD, increased SR-Ca-leak and induced proarrhythmic triggers such as early afterdepolarizations (EADs) and Ca-waves. All of them could be significantly reduced by applying Na1.8 blockers PF-01247324 and A-803467. Both blockers had no relevant effects on cellular electrophysiology of SCN10A cardiomyocytes. Moreover, in SCN10A-cardiomyocytes, the ATX-II-dependent increase in I, SR-Ca-leak and APD prolongation was less than in WT and comparable to the results which were obtained with WT cardiomyocytes being exposed to ATX-II and Na1.8 inhibitors in parallel. Moreover, we found a decrease in reverse mode NCX current and reduced CaMKII-dependent RyR2-phosphorylation after application of PF-01247324 as an underlying explanation for the Na-mediated Ca-dependent proarrhythmic triggers.

Conclusion: The current findings demonstrate that Na1.8 is a significant contributor for I-induced arrhythmic triggers. Therefore, Na1.8 inhibition under conditions of an enhanced I constitutes a promising antiarrhythmic strategy which merits further investigation.
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http://dx.doi.org/10.1016/j.yjmcc.2020.05.002DOI Listing
July 2020

Inhibition of Na1.8 prevents atrial arrhythmogenesis in human and mice.

Basic Res Cardiol 2020 02 20;115(2):20. Epub 2020 Feb 20.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (Na1.8) in atrial electrophysiology. This study investigated the role and involvement of Na1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking Na1.8. Na1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of Na1.8 and Na1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of Na1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of Na1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that Na1.8 significantly contributes to late Na current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca leak in human atrial cardiomyocytes. Selective pharmacological inhibition of Na1.8 potently reduced late Na current, proarrhythmic diastolic Ca release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A mice (genetic ablation of Na1.8). Pharmacological Na1.8 inhibition showed no effects in SCN10A mice. Importantly, in vivo experiments in SCN10A mice showed that genetic ablation of Na1.8 protects against atrial fibrillation induction. This study demonstrates that Na1.8 is expressed in the murine and human atria and contributes to late Na current generation and cellular arrhythmogenesis. Blocking Na1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.
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http://dx.doi.org/10.1007/s00395-020-0780-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033079PMC
February 2020

Taxonomic study of one generic and two new species record to the flora of Pakistan using multiple microscopic techniques.

Microsc Res Tech 2020 Apr 2;83(4):345-353. Epub 2019 Dec 2.

Key laboratory of Green Prevention and Control of Tropical Plant Diseases and Pests, Hainan University Haikou, China.

Recent field exploration and collections has led to the findings of several new species in Pakistan. Here we reported two new species Ajuga reptance L and Sphagneticola trilobata (L.) Prusk for the first time in Pakistan flora as these species were neither listed in any other literature nor identified before in Pakistan. These species were found as a result of taxonomic studies performed in the year 2019 in District Rawalpindi and Islamabad, Pakistan. Microscopic techniques were used for the confirmation of foliar epidermal and pollen micromorphological features. Detailed study (morphological, palynological, and foliar epidermal) was provided for the correct identification and delimitation of the species using both light and scanning electron microscopy. Morphological results were compared with the flora of Taiwan and China.
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http://dx.doi.org/10.1002/jemt.23420DOI Listing
April 2020

Effects of SiO content on the nanomechanical properties of CoCrPt-SiO granular films.

Sci Rep 2019 Nov 26;9(1):17580. Epub 2019 Nov 26.

Department of Mechanical Engineering, Texas A&M University, College Station, TX, 77843, USA.

CoCrPt material is used for perpendicular magnetic recording media due to its high magneto-crystalline anisotropy that brings good thermal stability on the media. The addition of SiO between the CoCrPt grains offers benefits including lower noise and better thermal stability. It has been reported that the SiO content has strong effects on the media's recording performance such as coercivity, anisotropy and noise. In this work, we focus on studying the effects of the SiO content on the nanomechanical properties of the media which are critical for the head-disk interface reliability. Variations of these properties with SiO content provide guidelines for optimum designs considering both recording and mechanical interface performance.
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http://dx.doi.org/10.1038/s41598-019-54093-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879606PMC
November 2019

Climatic and hydrological projections to changing climate under CORDEX-South Asia experiments over the Karakoram-Hindukush-Himalayan water towers.

Sci Total Environ 2020 Feb 3;703:135010. Epub 2019 Nov 3.

School of Civil and Environmental Engineering (SCEE), National University of Sciences and Technology (NUST), Islamabad, Pakistan. Electronic address:

The complex snow and glacier (cryosphere) dynamics over the "third pole" mountainous regions of the Karakoram-Hindukush-Himalayas (HKH) makes this region challenging for accurate hydrological predictions. The objective of this study is to investigate the impacts of climate change on major hydrological components (precipitation-runoff, snow- and glacier-runoff, evapotranspiration and inter-annual change in streamflows) over the Hunza-, Gilgit- and Astore-River basins, located in HKH. For this purpose, three different hydrological models (snowmelt runoff (SRM), HEC-HMS and HBV are tested over snow- and glacier-covered river basins. These are subsequently integrated with the climate projections simulated from regional climate models (RCMs) developed under CORDEX-SA experiments. The basin-wide RCM-simulations for future scenarios exhibited an increase in precipitation but decline in intensity of rise over high-altitude zones. The temperature rise showed a maximum increase during monsoon by 4.18 °C, 4.37 °C and 4.34 °C over Hunza-, Gilgit- and Astore-River basins, respectively, for the period 2071-2099 (2090s) and a high emission scenario (RCP8.5). Further, in response to rise in precipitation and temperature, the SRM simulations showed a significant increase in snow- glacier-melt runoff (49%, 42% and 46% for SRM) and precipitation runoff (23.8%, 15.7% and 27% for HEC-HMS) in the Hunza-, Gilgit- and Astore-River basins, respectively, for the 2090s under RCP8.5. The streamflow projections for SRM showed a shift in hydrological regime with an increase by 369 (168.4%), 216.5 (74.8%) and 131.8 m/s (82%) during pre-monsoon in the Hunza-, Gilgit- and Astore-River basins, respectively and then decline by -73.2 m/s (-13.9%) and -45.4 m/s (23.4%) during monsoon of the 2090s, in the Hunza- and Astore-River basins, respectively, under RCP8.5. Overall, the projections show that the pre-monsoon and monsoon seasons are expected to be strongly influenced by climate change, through alterations in snow- and glacier-accumulation, and melt regimes with substantial consequences for river runoff in the region.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135010DOI Listing
February 2020

Application of tuned liquid column ball damper (TLCBD) for improved vibration control performance of multi-storey structure.

PLoS One 2019 24;14(10):e0224436. Epub 2019 Oct 24.

School of Civil & Environmental Engineering, National University of Science and Technology (NUST), Sector H-12, Islamabad, Pakistan.

Tuned liquid column ball damper (TLCBD) is a passive control device used for controlling the building vibrations induced from wind or earthquakes. TLCBD is a modified form of conventional tuned liquid column damper (TLCD). This paper studies the effect of TLCBD on the four-storey steel frame structure. The performance of the TLCBD is also compared with conventional TLCD. The analytical model of both TLCD and TLCBD is presented here. The effectiveness of these analytical models is examined experimentally by series of shaking table tests under different excitation levels including harmonic loadings and seismic excitations. In TLCBD, the vibration is reduced significantly as compared to TLCD by using steel ball as a moving orifice. The difference in diameter of steel ball and tube, containing the liquid column, acts as an orifice which moves with the movement of the ball. This moving orifice phenomenon enhanced the vibration reduction effect by resisting the water motion in the TLCBD. Root mean square (RMS) and peak values of acceleration were calculated for each loading and each storey of uncontrolled and controlled structures. Comparison of the time histories of controlled and uncontrolled structures for different loadings is also reported. Results indicate that the TLCBD is more effective in the earthquake scenarios as compared to the harmonic excitations. The TLCBD controls the vibration of the primary structure significantly in vibration reduction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224436PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812827PMC
March 2020

Establishment of porcine and human expanded potential stem cells.

Nat Cell Biol 2019 06 3;21(6):687-699. Epub 2019 Jun 3.

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Stem Cell and Regenerative Medicine Consortium, Pokfulam, Hong Kong.

We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.
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http://dx.doi.org/10.1038/s41556-019-0333-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035105PMC
June 2019

Cell death induced by α-terthienyl via reactive oxygen species-mediated mitochondrial dysfunction and oxidative stress in the midgut of Aedes aegypti larvae.

Free Radic Biol Med 2019 06 22;137:87-98. Epub 2019 Apr 22.

Key Laboratory of Green Prevention and Control of Tropical Plant Diseases and Pests, Hainan University, Ministry of Education, Haikou, Hainan 570228, PR China. Electronic address:

α-Terthienyl (α-T) is a photosensitizer that produces many reactive oxygen species (ROS) under ultraviolet light. Here, we aimed to evaluate the oxidation mechanism of the 25%, 50%, and 75% lethal concentrations in Aedes aegypti larvae; the lethal concentration of α-T was used as the test value. The effects on mitochondria, oxidative stress, and cell death patterns caused by ROS were evaluated. The results showed that α-T mainly produced large amounts of ROS in the midgut of larvae. Moreover, mitochondrial ROS were increased in midgut cells, and the production of ROS sites, such as complex enzymes, was inhibited, resulting in enhanced production of ROS. Ultrastructural analysis of mitochondria revealed significant vacuolation, decreased activity of tricarboxylic acid cycle enzymes, and reduced ATP content and mitochondrial membrane potential in the high concentration group compared with those in the control group. Additionally, mitochondrial biosynthesis was blocked in the high concentration group. Thus, exposure to α-T disrupted mitochondrial function, although the mitochondrial DNA content may have increased because of mitochondrial self-protection mechanisms against oxidative stress. Furthermore, high concentrations of α-T aggravated oxidative stress and increased the number of intracellular oxidative damage products. Reverse transcription polymerase chain reaction and fluorescence staining showed that ROS induced by low α-T concentrations upregulated apoptotic genes, including Dronc (P < 0.05), thereby promoting apoptosis. Moderate concentrations of α-T promoted autophagy through induction of ROS, inhibited apoptosis, and induced necrosis. In contrast, high α-T concentrations induced high levels of ROS, which caused mitochondrial dysfunction and increased cytoplasmic Ca concentration, directly inducing cell necrosis. We also found that α-T may disrupt the permeability of the peritrophic membrane, leading to intestinal barrier dysfunction. These results provided insights into the mode of action of α-T in Aedes aegypti.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.04.021DOI Listing
June 2019

Modulation of Chemokine- and Adhesion-Molecule Gene Expression and Recruitment of Neutrophil Granulocytes in Rat and Mouse Liver after a Single Gadolinium Chloride or Zymosan Treatment.

Int J Mol Sci 2018 Dec 5;19(12). Epub 2018 Dec 5.

Department of Gastroenterology and Endocrinology, University Hospital, Georg-August University Goettingen, 37075 Goettingen, Germany.

Kupffer cells are professional phagocytes of the liver clearing bacteria from portal blood. Their clearance capacity, however, can be overwhelmed, transforming them into critical mediators of hepatic-injury. We investigated the consequences of selective Kupffer cell-overload by intraperitoneally administering pyrogen-free gadolinium chloride (GdCl₃) or Zymosan into rats and into endotoxin-resistant mice (C3H/HeJ). The number of myeloperoxidase-positive (MPO⁺) cells increased at 3 h mainly around the portal vessel after both GdCl₃ and Zymosan treatment. Simultaneously, GdCl₃ administration reduced detectability of ED-1⁺ (but not ED-2) cells near the portal vessel. Serum chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2 and chemokine (C-C motif) ligand 2 (CCL-2) showed a peak at 3 h after both treatment regimens although at a higher extent after Zymosan administration. Accordingly, CXCL-1, CXCL-5 and CCL-2 gene expression in the liver was up-regulated after GdCl₃ treatment at 3 h. After Zymosan administration a significant up-regulation of CXCL-1, CXCL-2, CXCL-10, CCL-2, CCL-3 and CCL-20 gene expression in liver at 3 h was observed. After Zymosan administration intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) gene expression was up-regulated in rat liver tissue. In C3H/HeJ mice both treatment regimens up-regulated CCL-2 and ICAM-1 gene expression after 3 h and down-regulated platelet endothelial cell adhesion molecule 1 (PECAM-1) gene expression. In conclusion, phagocytosis overload of Kupffer cells causes induction of several CXC, CC-chemokines, upregulation of "positive" adhesion molecule gene expression, down-regulation of the "negative" adhesion molecule PECAM-1 and a recruitment of neutrophil granulocytes in the portal area of the liver of treated rats and mice mainly in close contact to the liver macrophages.
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http://dx.doi.org/10.3390/ijms19123891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321201PMC
December 2018

The functional consequences of sodium channel Na 1.8 in human left ventricular hypertrophy.

ESC Heart Fail 2019 02 30;6(1):154-163. Epub 2018 Oct 30.

Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.

Aims: In hypertrophy and heart failure, the proarrhythmic persistent Na current (I ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na 1.8 in human hypertrophied myocardium.

Methods And Results: Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of Na 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent I was significantly reduced after addition of novel Na 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca leak and SR-Ca spark frequency after exposure to both Na 1.8 inhibitors.

Conclusions: We show for the first time that the neuronal sodium channel Na 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na 1.8 reduced augmented I , abbreviated the action potential duration, and decreased the SR-Ca leak. The findings of our study suggest that Na 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.
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http://dx.doi.org/10.1002/ehf2.12378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352890PMC
February 2019

S100P enhances the motility and invasion of human trophoblast cell lines.

Sci Rep 2018 07 31;8(1):11488. Epub 2018 Jul 31.

School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.

S100P has been shown to be a marker for carcinogenesis where its expression in solid tumours correlates with metastasis and a poor patient prognosis. This protein's role in any physiological process is, however, unknown. Here we first show that S100P is expressed both in trophoblasts in vivo as well as in some corresponding cell lines in culture. We demonstrate that S100P is predominantly expressed during the early stage of placental formation with its highest expression levels occurring during the first trimester of gestation, particularly in the invading columns and anchoring villi. Using gain or loss of function studies through overexpression or knockdown of S100P expression respectively, our work shows that S100P stimulates both cell motility and cellular invasion in different trophoblastic and first trimester EVT cell lines. Interestingly, cell invasion was seen to be more dramatically affected than cell migration. Our results suggest that S100P may be acting as an important regulator of trophoblast invasion during placentation. This finding sheds new light on a hitherto uncharacterized molecular mechanism which may, in turn, lead to the identification of novel targets that may explain why significant numbers of confirmed human pregnancies suffer complications through poor placental implantation.
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http://dx.doi.org/10.1038/s41598-018-29852-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068119PMC
July 2018

Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart.

Cardiovasc Res 2018 11;114(13):1728-1737

Clinic for Cardiology & Pneumology, Georg-August University Goettingen, DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany.

Aims: In heart failure (HF), enhanced persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel NaV1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy.

Methods And Results: By western blot, we found that NaV1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform NaV1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of NaV1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of NaV1.8 on INaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. NaV1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased INaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of NaV1.8 (SCN10A-/-), were associated with reduced INaL and abbreviated APD.

Conclusion: We provide first evidence of differential regulation of NaV1.8 and NaV1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of INaL. We propose inhibition of NaV1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.
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http://dx.doi.org/10.1093/cvr/cvy152DOI Listing
November 2018

Improvement of the Patient Safety Culture in the Primary Health Care Corporation - Qatar.

J Patient Saf 2018 Apr 17. Epub 2018 Apr 17.

From the Quality Management Department, Primary Health Care Corporation, Doha, Qatar.

Objectives: Primary Health Care Corporation (PHCC) is the public primary health care provider in Qatar. Having a patient safety culture (PSC) is the keystone to enabling a continuous process to improve the quality of services and to reduce errors. The objective of this study was to assess the impact of accreditation, quality improvement trainings, and patient safety (PS) trainings on the improvement of the PSC at the PHCC in Qatar.

Methods: The Medical Office Survey on Patient Safety Culture from the Agency for Healthcare Research and Quality was used in 2012 and 2015 to assess the culture of PS and health care quality in the 21 health centers. The results of the two surveys were compared using the χ test. A P value of less than 0.05 was considered significant.

Results: Out of 2689 staff working in the 21 health centers, 1810 (67.3%) completed the survey in 2012, and 2616 (70.0%) of 3735 completed the survey in 2015. The comparison between 2012 and 2015 survey's results showed a statistically significant improvement for all the 10 dimensions (P < 0.05). Although a statistically significant difference was observed between 2012 and 2015 results for work pressure and pace, three of the four questions of the work pressure and pace dimension presented nonsignificant differences.

Conclusions: The survey was a good tool to raise awareness on PS and quality issues at PHCC. There is evidence that the implementation of accreditation program, the quality improvement trainings, and PS trainings helped the organization improve its PS culture.
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http://dx.doi.org/10.1097/PTS.0000000000000489DOI Listing
April 2018

Mediators of hypoxia in a rat model of sterile-induced acute liver injury.

Int J Clin Exp Pathol 2017 1;10(12):11471-11479. Epub 2017 Dec 1.

Department of Gastroenterology and Endocrinology, University Medical Center, Georg-August University Robert-Koch-Str. 40, D-37075 Goettingen, Germany.

Background: The liver plays a key role in iron homeostasis during injury and hypoxia.

Methods: For induction of liver injury, thioacetamide (TAA) was administered intraperitoneally to male Sprague Dawley rats. Animals were sacrificed at 0, 1, 3, 6, 12, 24, 48, 72 and 96 h. Serum, liver, spleen and heart tissues were collected from control and TAA-treated rats. Tissue sections were prepared for immunohistochemical studies. Nuclear and cytoplasmic proteins were isolated for Western blot analysis.

Results: Hypoxia inducible factor (HIF)-1α and ED1 positive cells accumulated around the portal field and the interlobular space within 12 hours after TAA administration. Accordingly, Western blot analysis of liver tissue showed an early increase of HIF1α followed by a decrease at 48 h to 96 h. For Erythropoietin (EPO), as well as for HIF1- and -2α, a time-dependent translocation was observed from the cytoplasmic to the nuclear compartment.

Conclusion: Our data suggest that the TAA-induced acute liver damage generates HIF-1α dependent rescue mechanisms with translocation of EPO from the cytoplasmic to the nuclear compartment. Enhanced iron transport into the liver could be necessary for increased metabolic activities during repair processes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966030PMC
December 2017

Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial.

J Am Heart Assoc 2017 Sep 8;6(9). Epub 2017 Sep 8.

Norwich Medical School, University of East Anglia, Norwich, UK

Background: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.

Methods And Results: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, =0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, =0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L, <0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, =0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation.

Conclusions: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.
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http://dx.doi.org/10.1161/JAHA.117.006478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634294PMC
September 2017

Inhibition of Late Sodium Current as an Innovative Antiarrhythmic Strategy.

Curr Heart Fail Rep 2017 06;14(3):179-186

Clinic for Cardiology and Pneumology/Heart Center, University Medical Center Goettingen, DZHK (German Centre for Cardiovascular Research), Goettingen, Germany.

Purpose Of Review: Over the last years, evidence is accumulating that enhanced late sodium current (I) in cardiac pathologies has fundamental consequences for cellular electrophysiology. This review discusses the underlying mechanisms of I-induced arrhythmias and the significance of I-inhibition as a possible therapeutic approach.

Recent Findings: Inhibition of enhanced I, e.g., by ranolazine, was shown to reverse these effects in different myocardial diseases including heart failure. The antianginal drug ranolazine has already been examined in larger clinical trials with promising antiarrhythmic actions. Enhanced I was found to be present in several cardiac pathologies like ischemia, long QT syndromes, hypertrophic cardiomyopathy, and heart failure. In settings of enhanced I, a sodium-dependent calcium overload leads to severe impairment of excitation-contraction coupling and therefore has a high proarrhythmogenic potential. Experimental data showed that inhibition of I has a high antiarrhythmic potential which could be confirmed in further clinical trials.
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http://dx.doi.org/10.1007/s11897-017-0333-0DOI Listing
June 2017

Angiopoietin-1 promotes atherosclerosis by increasing the proportion of circulating Gr1+ monocytes.

Cardiovasc Res 2017 01;113(1):81-89

Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, U.K;

Aims: Atherosclerosis is a chronic inflammatory disease occurring within the artery wall. A crucial step in atherogenesis is the infiltration and retention of monocytes into the subendothelial space of large arteries induced by chemokines and growth factors. Angiopoietin-1 (Ang-1) regulates angiogenesis and reduces vascular permeability and has also been reported to promote monocyte migration in vitro. We investigated the role of Ang-1 in atherosclerosis-prone apolipoprotein-E (Apo-E) knockout mouse.

Methods And Results: Apo-E knockout (Apo-E) mice fed a western or normal chow diet received a single iv injection of adenovirus encoding Ang-1 or control vector. Adenovirus-mediated systemic expression of Ang-1 induced a significant increase in early atherosclerotic lesion size and monocyte/macrophage accumulation compared with control animals receiving empty vector. Ang-1 significantly increased plasma MCP-1 and VEGF levels as measured by ELISA. FACS analysis showed that Ang-1 selectively increased inflammatory Gr1monocytes in the circulation, while the cell-surface expression of CD11b, which mediates monocyte emigration, was significantly reduced.

Conclusions: Ang-1 specifically increases circulating Gr1inflammatory monocytes and increases monocyte/macrophage retention in atherosclerotic plaques, thereby contributing to development of atherosclerosis.
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http://dx.doi.org/10.1093/cvr/cvw223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220674PMC
January 2017

A randomized double-blind placebo-controlled crossover trial of sodium nitrate in patients with stable angina INAS.

Future Cardiol 2016 11 12;12(6):617-626. Epub 2016 Oct 12.

School of Medicine & Dentistry, University of Aberdeen, Aberdeen, UK.

In an aging western population, a significant number of patients continue to suffer from angina once all revascularization and optimal medical treatment options are exhausted. Under experimental conditions, oral supplementation with inorganic nitrate was shown to exhibit a blood pressure-lowering effect, and has also been shown to promote angiogenesis, improve endothelial dysfunction and mitochondrial efficiency in skeletal muscle. It is unknown whether similar changes occur in cardiac muscle. In the current study, we investigate whether oral sodium nitrate treatment will improve myocardial ischemia in patients with stable angina.
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http://dx.doi.org/10.2217/fca-2016-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097453PMC
November 2016

Induction of Lipocalin2 in a Rat Model of Lung Irradiation.

Int J Mol Sci 2016 Apr 28;17(5). Epub 2016 Apr 28.

Clinic for Gastroenterology and Endocrinology, University Medical Center Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany.

Previously, we showed that lipocalin2 (LCN2) serum levels increased after liver irradiation and during acute-phase conditions. Here, we evaluate LCN2 expression and serum levels after single-dose lung irradiation with 25 Gy, percutaneously administered to the lung of randomly-paired male Wistar rats. Due to the concave anatomy of the lung recesses, the irradiation field included the upper part of the liver. No rat died due to irradiation. In control tissue, lung immunohistochemistry showed a high constitutive expression of LCN2+ granulocytes. LCN2 mRNA levels in lung tissue increased up to 24 h (9 ± 2.3-fold) after irradiation. However, serum LCN2 levels remained undetectable after lung irradiation. LCN2 expression in the upper part of the liver increased up to 4.2-fold after lung irradiation, but the lower liver showed an early decrease. Acute-phase cytokines (IL-1β and TNF-α) showed a significant increase on transcript level in both lung and upper liver, whilst the lower liver did not show any considerable increase. In conclusion, constitutive expression of LCN2 in local immune cells demonstrates its local role during stress conditions in the lung. The absence of LCN2 in the serum strengthens our previous findings that the liver is the key player in secreting LCN2 during stress conditions with liver involvement.
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http://dx.doi.org/10.3390/ijms17050637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881463PMC
April 2016

Ex vivo characterization of normal and adenocarcinoma colon samples by Mueller matrix polarimetry.

J Biomed Opt 2015 May;20(5):56012

Pakistan Institute of Engineering and Applied Sciences, Department of Physics and Applied Mathematics, Nilore, Islamabad 45650, Pakistan.

Mueller matrix polarimetry along with polar decomposition algorithm was employed for the characterization of ex vivo normal and adenocarcinoma human colon tissues by polarized light in the visible spectral range (425-725 nm). Six derived polarization metrics [total diattenuation (DT ), retardance (RT ), depolarization(ΔT ), linear diattenuation (DL), retardance (δ), and depolarization (ΔL)] were compared for normal and adenocarcinoma colon tissue samples. The results show that all six polarimetric properties for adenocarcinoma samples were significantly higher as compared to the normal samples for all wavelengths. The Wilcoxon rank sum test illustrated that total retardance is a good candidate for the discrimination of normal and adenocarcinoma colon samples. Support vector machine classification for normal and adenocarcinoma based on the four polarization properties spectra (ΔT , ΔL, RT ,and δ) yielded 100% accuracy, sensitivity, and specificity, while both DTa nd DL showed 66.6%, 33.3%, and 83.3% accuracy, sensitivity, and specificity, respectively. The combination of polarization analysis and given classification methods provides a framework to distinguish the normal and cancerous tissues.
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http://dx.doi.org/10.1117/1.JBO.20.5.056012DOI Listing
May 2015

Carbon monoxide inhibits sprouting angiogenesis and vascular endothelial growth factor receptor-2 phosphorylation.

Thromb Haemost 2015 Feb 30;113(2):329-37. Epub 2014 Oct 30.

Dr. Shakil Ahmad, Aston Medical School, Aston University, Birmingham B4 7ET, UK, Tel.: +44 121 204 4038, E-mail:

Carbon monoxide (CO) is a gaseous autacoid known to positively regulate vascular tone; however, its role in angiogenesis is unknown. The aim of this study was to investigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. Human umbilical vein endothelial cells (HUVECs) were cultured on growth factor-reduced Matrigel and treated with a CO-releasing molecule (CORM-2) or exposed to CO gas (250 ppm). Here, we report the surprising finding that exposure to CO inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell actin reorganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-mediated phosphorylation of VEGFR-2 at tyrosine residue 1175 and 1214 and basic fibroblast growth factor- (FGF-2) and VEGF-mediated Akt phosphorylation. Consistent with these data, mice exposed to 250 ppm CO (1h/day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p<0.05). These data establish a new biological function for CO in angiogenesis and point to a potential therapeutic use for CO as an anti-angiogenic agent in tumour suppression.
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http://dx.doi.org/10.1160/TH14-01-0002DOI Listing
February 2015

β-Cell-Specific Glucocorticoid Reactivation Attenuates Inflammatory β-Cell Destruction.

Front Endocrinol (Lausanne) 2014 14;5:165. Epub 2014 Oct 14.

Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.

Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1(tg/+) mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1(tg/+) mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1(tg/+) mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1(tg/+) islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.
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http://dx.doi.org/10.3389/fendo.2014.00165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196588PMC
October 2014