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  • 1.
    Aasa, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Vare, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Motwani, Hitesh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Jenssen, Dag
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Törnqvist, Margareta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions2016Inngår i: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 805, s. 38-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glycidol (Gly) is an electrophilic low-molecular weight epoxide that is classified by IARC as probably carcinogenic to humans. Humans might be exposed to Gly from food, e.g. refined vegetable oils, where Gly has been found as a food process contaminant. It is therefore important to investigate and quantify the genotoxicity of Gly as a primary step towards cancer risk assessment of the human exposure. Here, quantification of the mutagenic potency expressed per dose (AUC: area under the concentration time curve) of Gly has been performed in Chinese hamster ovary (CHO) cells, using the HPRT assay. The dose of Gly was estimated in the cell exposure medium by trapping Gly with a strong nucleophile, cob(I)alamin, to form stable cobalamin adducts for analysis by LC-MS/MS. Gly was stable in the exposure medium during the time for cell treatment, and thus the dose in vitro is the initial concentration x cell treatment time. Gly induced mutations in the hprt-gene at ante of 0.08 +/- 0:01 mutations/10(5) cells/mMh. Through comparison with the effect of ionizing radiation in the same system a relative mutagenic potency of 9.5 rad-eq./mMh was obtained, which could be used for comparison of genotoxicity of chemicals and between test systems and also in procedures for quantitative cancer risk assessment. Gly was shown to induce strand breaks, that were repaired by base excision repair. Furthermore, Gly-induced lesions, present during replication, were found to delay the replication fork elongation. From experiments with repair deficient cells, homologous recombination repair and the ERCC1-XPF complex were indicated to be recruited to support in the repair of the damage related to the stalled replication elongation. The type of DNA damage responsible for the mutagenic effect of Gly could not be concluded from the present study.

  • 2. Abd El-Wahed, Aida A.
    et al.
    Farag, Mohamed A.
    Eraqi, Walaa A.
    Mersal, Gaber A. M.
    Zhao, Chao
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    El-Seedi, Hesham R.
    Unravelling the beehive air volatiles profile as analysed via solid-phase microextraction (SPME) and chemometrics2021Inngår i: Journal of King Saud University – Science, ISSN 1018-3647, Vol. 33, nr 5, artikkel-id 101449Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Beehive air therapy is recognized as a potential remedy for treating asthma, bronchitis, lung fibrosis, and respiratory tract infections. Developed countries in which beehive air therapy is currently authorized include Germany, Hungary, Slovenia, and Austria. However, scientific proof of its efficacy is lacking which warrants further chemical and biological analyses as a proof of concept. In this study, beehive air volatile profile was determined for the first time along with its individual components (bees, venom, honey, and beeswax).

    Methods: Volatile compounds were collected from beehive air using solid phase micro-extraction (SPME) coupled to gas chromatography-mass spectrometry (GC–MS). Antimicrobial assay of the air released from 4 beehive products was further performed against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and multi drug-resistant Staphylococcus aureus (MRSA) using the in vitro agar-well diffusion and microtiter plate assays.

    Results and conclusions: A total of 56 volatile compounds were identified from beehive air, venom, bee insect and wax air including 6 fatty acids, 6 alcohols, 10 aldehydes, 5 esters, 1 ether, 9 hydrocarbons, 1 phenol, 7 ketones, 1 nitrogenous compound and 10 terpenes. The most abundant constituents were short-chain fatty acids (26.32%) while the lowest were the nitrogenous compounds (0.82%). The principal component analysis (PCA) scores plot of the UPLC/MS dataset showed the similarity of the beehive air to the insect bee's aroma profile. With regards to antimicrobial assay, beehive air and venom exerted the strongest antimicrobial activity among the examined bee products against S. aureus, K. pneumoniae, A. baumannii, and MRSA in agar-well diffusion assay but failing to exert an effect using microtiter plate assay as in case of bee venom against the aforementioned bacteria.

  • 3. Abd El-Wahed, Aida A.
    et al.
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Elashal, Mohamed H.
    Musharraf, Syed G.
    Saeed, Aamer
    Khatib, Alfi
    Tahir, Haroon Elrasheid
    Zou, Xiaobo
    Al Naggar, Yahya
    Mehmood, Arshad
    Wang, Kai
    El-Seedi, Hesham R.
    Cosmetic Applications of Bee Venom2021Inngår i: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 13, nr 11, artikkel-id 810Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Bee venom (BV) is a typical toxin secreted by stingers of honeybee workers. BV and BV therapy have long been attractive to different cultures, with extensive studies during recent decades. Nowadays, BV is applied to combat several skin diseases, such as atopic dermatitis, acne vulgaris, alopecia, vitiligo, and psoriasis. BV is used extensively in topical preparations as cosmetics and used as dressing for wound healing, as well as in facemasks. Nevertheless, the safety of BV as a therapeutic choice has always been a concern due to the immune system reaction in some people due to BV use. The documented unfavorable impact is explained by the fact that the skin reactions to BV might expand to excessive immunological responses, including anaphylaxis, that typically resolve over numerous days. This review aims to address bee venom therapeutic uses in skin cosmetics.

  • 4. Abd El-Wahed, Aida
    et al.
    Yosri, Nermeen
    Sakr, Hanem H.
    Du, Ming
    Algethami, Ahmed F. M.
    Zhao, Chao
    Abdelazeem, Ahmed H.
    Tahir, Haroon Elrasheid
    Masry, Saad H. D.
    Abdel-Daim, Mohamed M.
    Musharraf, Syed Ghulam
    El-Garawani, Islam
    Kai, Guoyin
    Al Naggar, Yahya
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    El-Seedi, Hesham R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Menoufia University, Egypt; Jiangsu University, China; Uppsala University, Sweden.
    Wasp Venom Biochemical Components and Their Potential in Biological Applications and Nanotechnological Interventions2021Inngår i: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 13, nr 3, artikkel-id 206Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Wasps, members of the order Hymenoptera, are distributed in different parts of the world, including Brazil, Thailand, Japan, Korea, and Argentina. The lifestyles of the wasps are solitary and social. Social wasps use venom as a defensive measure to protect their colonies, whereas solitary wasps use their venom to capture prey. Chemically, wasp venom possesses a wide variety of enzymes, proteins, peptides, volatile compounds, and bioactive constituents, which include phospholipase A2, antigen 5, mastoparan, and decoralin. The bioactive constituents have anticancer, antimicrobial, and anti-inflammatory effects. However, the limited quantities of wasp venom and the scarcity of advanced strategies for the synthesis of wasp venom’s bioactive compounds remain a challenge facing the effective usage of wasp venom. Solid-phase peptide synthesis is currently used to prepare wasp venom peptides and their analogs such as mastoparan, anoplin, decoralin, polybia-CP, and polydim-I. The goal of the current review is to highlight the medicinal value of the wasp venom compounds, as well as limitations and possibilities. Wasp venom could be a potential and novel natural source to develop innovative pharmaceuticals and new agents for drug discovery.

  • 5. Abd-El Azeem, Hoda H.
    et al.
    Osman, Gamalat Y.
    El-Seedi, Hesham R.
    Fallatah, Ahmed M.
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Gharib, Mohamed M.
    Antifungal Activity of Soft Tissue Extract from the Garden Snail Helix aspersa (Gastropoda, Mollusca)2022Inngår i: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 27, nr 10, artikkel-id 3170Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gastropods comprise approximately 80% of molluscans, of which land snails are used variably as food and traditional medicines due to their high protein content. Moreover, different components from land snails exhibit antimicrobial activities. In this study, we evaluated the antifungal activity of soft tissue extracts from Helix aspersa against Candida albicans, Aspergillus flavus, and Aspergillus brasiliensis by identifying extract components using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Two concentrations of three extracts (methanol, acetone, and acetic acid) showed antifungal activity. Both acetone (1 g/3 mL) and acetic acid extracts (1 g/mL) significantly inhibited C. albicans growth (p = 0.0001, 5.2 +/- 0.2 mm and p = 0.02, 69.7 +/- 0.6 mm, respectively). A. flavus and A. brasiliensis growth were inhibited by all extracts at 1 g/mL, while inhibition was observed for acetic acid extracts against A. brasiliensis (p = 0.02, 50.3 +/- 3.5 mm). The highest growth inhibition was observed for A. flavus using acetic acid and acetone extracts (inhibition zones = 38 +/- 1.7 mm and 3.1 +/- 0.7 mm, respectively). LC-MS-MS studies on methanol and acetone extracts identified 11-α-acetoxyprogesterone with a parent mass of 372.50800 m/z and 287.43500 m/z for luteolin. Methanol extracts contained hesperidin with a parent mass of 611.25400 m/z, whereas linoleic acid and genistein (parent mass = 280.4 and 271.48900 m/z, respectively) were the main metabolites.

  • 6. Abend, M.
    et al.
    Amundson, S. A.
    Badie, C.
    Brzoska, K.
    Hargitai, R.
    Kriehuber, R.
    Schüle, S.
    Kis, E.
    Ghandhi, S. A.
    Lumniczky, K.
    Morton, S. R.
    O'Brien, G.
    Oskamp, D.
    Ostheim, P.
    Siebenwirth, C.
    Shuryak, I.
    Szatmári, T.
    Unverricht-Yeboah, M.
    Ainsbury, E.
    Bassinet, C.
    Kulka, U.
    Oestreicher, U.
    Ristic, Y.
    Trompier, F.
    Wójcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Waldner, L.
    Port, M.
    Inter-laboratory comparison of gene expression biodosimetry for protracted radiation exposures as part of the RENEB and EURADOS WG10 2019 exercise2021Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikkel-id 9756Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Large-scale radiation emergency scenarios involving protracted low dose rate radiation exposure (e.g. a hidden radioactive source in a train) necessitate the development of high throughput methods for providing rapid individual dose estimates. During the RENEB (Running the European Network of Biodosimetry) 2019 exercise, four EDTA-blood samples were exposed to an Iridium-192 source (1.36 TBq, Tech-Ops 880 Sentinal) at varying distances and geometries. This resulted in protracted doses ranging between 0.2 and 2.4 Gy using dose rates of 1.5-40 mGy/min and exposure times of 1 or 2.5 h. Blood samples were exposed in thermo bottles that maintained temperatures between 39 and 27.7 degrees C. After exposure, EDTA-blood samples were transferred into PAXGene tubes to preserve RNA. RNA was isolated in one laboratory and aliquots of four blinded RNA were sent to another five teams for dose estimation based on gene expression changes. Using an X-ray machine, samples for two calibration curves (first: constant dose rate of 8.3 mGy/min and 0.5-8 h varying exposure times; second: varying dose rates of 0.5-8.3 mGy/min and 4 h exposure time) were generated for distribution. Assays were run in each laboratory according to locally established protocols using either a microarray platform (one team) or quantitative real-time PCR (qRT-PCR, five teams). The qRT-PCR measurements were highly reproducible with coefficient of variation below 15% in >= 75% of measurements resulting in reported dose estimates ranging between 0 and 0.5 Gy in all samples and in all laboratories. Up to twofold reductions in RNA copy numbers per degree Celsius relative to 37 degrees C were observed. However, when irradiating independent samples equivalent to the blinded samples but increasing the combined exposure and incubation time to 4 h at 37 degrees C, expected gene expression changes corresponding to the absorbed doses were observed. Clearly, time and an optimal temperature of 37 degrees C must be allowed for the biological response to manifest as gene expression changes prior to running the gene expression assay. In conclusion, dose reconstructions based on gene expression measurements are highly reproducible across different techniques, protocols and laboratories. Even a radiation dose of 0.25 Gy protracted over 4 h (1 mGy/min) can be identified. These results demonstrate the importance of the incubation conditions and time span between radiation exposure and measurements of gene expression changes when using this method in a field exercise or real emergency situation.

  • 7. Abend, M.
    et al.
    Amundson, S. A.
    Badie, C.
    Brzoska, K.
    Kriehuber, R.
    Lacombe, J.
    López-Riego, Milagrosa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lumniczky, K.
    Endesfelder, D.
    O'Brien, G.
    Doucha-Senf, S.
    Ghandhi, S. A.
    Hargitai, R.
    Kis, E.
    Lundholm, Lovisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Oskamp, D.
    Ostheim, P.
    Schüle, S.
    Schwanke, D.
    Shuryak, I.
    Siebenwith, C.
    Unverricht-Yeboah, M.
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Yang, J.
    Zenhausern, F.
    Port, M.
    RENEB Inter-Laboratory Comparison 2021: The Gene Expression Assay2023Inngår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 199, nr 6, s. 598-615Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Early and high-throughput individual dose estimates are essential following large-scale radiation exposure events. In the context of the Running the European Network for Biodosimetry and Physical Dosimetry (RENEB) 2021 exercise, gene expression assays were conducted and their corresponding performance for dose-assessment is presented in this publication. Three blinded, coded whole blood samples from healthy donors were exposed to 0, 1.2 and 3.5 Gy X-ray doses (240 kVp, 1 Gy/min) using the X-ray source Yxlon. These exposures correspond to clinically relevant groups of unexposed, low dose (no severe acute health effects expected) and high dose exposed individuals (requiring early intensive medical health care). Samples were sent to eight teams for dose estimation and identification of clinically relevant groups. For quantitative reverse transcription polymerase chain reaction (qRT-PCR) and microarray analyses, samples were lysed, stored at 20°C and shipped on wet ice. RNA isolations and assays were run in each laboratory according to locally established protocols. The time-to-result for both rough early and more precise later reports has been documented where possible. Accuracy of dose estimates was calculated as the difference between estimated and reference doses for all doses (summed absolute difference, SAD) and by determining the number of correctly reported dose estimates that were defined as ±0.5 Gy for reference doses <2.5 Gy and ±1.0 Gy for reference doses >3 Gy, as recommended for triage dosimetry. We also examined the allocation of dose estimates to clinically/diagnostically relevant exposure groups. Altogether, 105 dose estimates were reported by the eight teams, and the earliest report times on dose categories and estimates were 5 h and 9 h, respectively. The coefficient of variation for 85% of all 436 qRT-PCR measurements did not exceed 10%. One team reported dose estimates that systematically deviated several-fold from reported dose estimates, and these outliers were excluded from further analysis. Teams employing a combination of several genes generated about two-times lower median SADs (0.8 Gy) compared to dose estimates based on single genes only (1.7 Gy). When considering the uncertainty intervals for triage dosimetry, dose estimates of all teams together were correctly reported in 100% of the 0 Gy, 50% of the 1.2 Gy and 50% of the 3.5 Gy exposed samples. The order of dose estimates (from lowest to highest) corresponding to three dose categories (unexposed, low dose and highest exposure) were correctly reported by all teams and all chosen genes or gene combinations. Furthermore, if teams reported no exposure or an exposure >3.5 Gy, it was always correctly allocated to the unexposed and the highly exposed group, while low exposed (1.2 Gy) samples sometimes could not be discriminated from highly (3.5 Gy) exposed samples. All teams used FDXR and 78.1% of correct dose estimates used FDXR as one of the predictors. Still, the accuracy of reported dose estimates based on FDXR differed considerably among teams with one team's SAD (0.5 Gy) being comparable to the dose accuracy employing a combination of genes. Using the workflow of this reference team, we performed additional experiments after the exercise on residual RNA and cDNA sent by six teams to the reference team. All samples were processed similarly with the intention to improve the accuracy of dose estimates when employing the same workflow. Re-evaluated dose estimates improved for half of the samples and worsened for the others. In conclusion, this inter-laboratory comparison exercise enabled (1) identification of technical problems and corrections in preparations for future events, (2) confirmed the early and high-throughput capabilities of gene expression, (3) emphasized different biodosimetry approaches using either only FDXR or a gene combination, (4) indicated some improvements in dose estimation with FDXR when employing a similar methodology, which requires further research for the final conclusion and (5) underlined the applicability of gene expression for identification of unexposed and highly exposed samples, supporting medical management in radiological or nuclear scenarios. 

  • 8. Abildgaard, Amanda B.
    et al.
    Voutsinos, Vasileios
    Petersen, Søren D.
    Larsen, Fia B.
    Kampmeyer, Caroline
    Johansson, Kristoffer E.
    Stein, Amelie
    Ravid, Tommer
    Andréasson, Claes
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    Jensen, Michael K.
    Lindorff-Larsen, Kresten
    Hartmann-Petersen, Rasmus
    HSP70-binding motifs function as protein quality control degrons2023Inngår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 80, nr 1, artikkel-id 32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding. 

  • 9. Abosedera, Dalia A.
    et al.
    Emara, S. A.
    Tamam, Omar A. S.
    Badr, Osama M.
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    El-Seedi, Hesham R.
    Refaey, Mohamed S.
    Metabolomic profile and in vitro evaluation of the cytotoxic activity of Asphodelus microcarpus against human malignant melanoma cells A3752022Inngår i: Arabian Journal of Chemistry, ISSN 1878-5352, E-ISSN 1878-5379 , Vol. 15, nr 10, artikkel-id 104174Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Melanoma is a huge worldwide health problem that must be handled more effectively with better therapeutic options. As a result, new treatment drugs are required to treat this condition. The goal of this study was to investigate the cytotoxic activity of the anthraquinone-rich fractions obtained from Asphodelus microcarpus against human melanoma cell A375. On these melanoma cell lines; the cytotoxicity of these fractions had never been studied before. Liquid chromatography linked to mass spectrometry (LC-MS-MS) and Nuclear Magnetic Resonance was used to determine the chemical profiles of these fractions. The cytotoxicity of the fractions studied was determined by measuring cell viability and calculating IC50 values. Both ethyl acetate (EtOAC) and the precipitate fractions (PPT) exhibited selective cytotoxicity on human melanoma A 375 cell line with IC50 values of 83 and 65 µg/mL, respectively. The antiproliferative properties of EtOAc fraction and PPT were supported by a noticeable decrease in cell numbers during the G2/M cell cycle arrest. Our findings suggest that the anthraquinone content of A. microcarpus tubers is responsible for its anti-proliferative and apoptotic properties and that further in vivo investigations should be conducted to establish the viability of using them to treat human melanomas.

  • 10.
    Abramsson-Zetterberg, Lilianne
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ilback, Nils-Gunnar
    The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo2013Inngår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 59, s. 86-89Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic.

  • 11.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Regulation and measurement of brown adipose tissue blood flow2014Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Brown adipose tissue (BAT) is an organ specialized in macromolecule combustion in order to produce heat. Because of its high capacity to dissipate energy, it is currently among the best hopes for future treatments of obesity and diabetes. BAT is permeated by a vast capillary network that delivers blood rich in oxygen and nutrients to supply the high metabolic needs of the tissue. At the same time, metabolites, carbon dioxide and warm blood are drained back into systemic circulation. Blood flow is in fact a limiting factor for thermogenesis. Therefore, understanding BAT blood flow regulation is a crucial step for describing the tissue function. This thesis aims to summarize anatomical descriptions, to discuss the methodological evolution of the field, and to synthetize what we have learned about mechanistic regulation of BAT blood flow during the last half century. Manuscript I introduces a new method (high-resolution laser-doppler imaging) for the measurement of BAT blood flow, and gives mechanistic insights about its physiological regulation. Manuscript II focuses on the influence of bombesin receptor subtype-3 on the neurological control of body temperature and thermogenesis.

  • 12.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Thermal physiology and metabolism: Interplay between heat generation and energy homeostasis2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Mammal metabolism is intimately connected to the maintenance of body temperature. While metabolic pathways invariably produce heat as a by-product, the natural heat present in the environment also plays a role in defining the adaptive metabolism and general physiology of an organism. This thesis aims to discuss basic aspects of energy expenditure and their interactions with energy stores and body composition. In Paper I, we apply a new technique – high-resolution laser-Doppler imaging – to describe physiological regulatory features of adrenergically-stimulated blood flow in brown adipose tissue, and evaluate the validity of blood flow as a parameter to estimate nonshivering thermogenesis. Paper II focuses on the central regulation of body temperature. In the absence of bombesin receptor subtype-3, mice present an altered neurological body temperature setpoint, while peripheral thermogenic capacity remains intact. We conclude that brown adipose tissue malfunction is not the cause of the hypothermia observed in this mouse model. Paper III incorporates measurements of body temperature to the energy expenditure of different sources: basal metabolic rate, physical activity, thermic effect of food, and cold-induced thermogenesis. We describe basic aspects of dynamic insulation, energetic costs of circadian variation and hypothesize that physical activity may change the body temperature setpoint. Paper IV describes methodological issues related to glucose tolerance tests in obese mice. We conclude that the erroneous scaling of doses may affect the interpretation of metabolic health in mouse models, and suggest a new methodology. Paper V describes the outcomes caused by the expression of the human Cidea protein in adipose tissue of mice and suggests that this protein may clarify the link between adipose tissue expansion and healthy obesity. Paper VI explores the dissociation between thiazolidinedione-induced adipose tissue “browning” and reduced blood glycaemia. We demonstrate that although this pharmacological class tends to induce some level of brown adipose tissue recruitment, this phenomenon does not define its antidiabetic effects.

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  • 13.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    On adequate procedures for glucose tolerance tests in obese animals: Measurement of glucose tolerance in obesityManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Routine procedures for glucose tolerance test in rodents utilize an amount of injected glucose that is proportional to total body weight (normally 2 mg per g body weight). Obese mice consist of much more chemically inert lipid than lean mice but have only marginal increases in lean body mass (the only compartment where glucose is distributed). Present procedures thus inevitably lead to a diagnosis of impaired glucose tolerance and enhanced insulin levels in obesity. Routine procedures should use fixed glucose amounts per lean body mass (or per mouse).

  • 14.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fischer, Alexander W.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Hamburg, Germany.
    Mattsson, Charlotte
    de Jong, Jasper M. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ryden, Mikael
    Laurencikiene, Jurga
    Arner, Peter
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cidea improves the metabolic profile through expansion of adipose tissue2015Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 6, artikkel-id 7433Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.

  • 15.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hagberg, Carolina E.
    Spalding, Kirsty L.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis: Regulation of brown adipose tissue blood flow2015Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 308, nr 9, s. E822-E829Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen, and for the distribution of the generated heat to the rest of the body. It is therefore fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive, in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner, and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine, despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycaemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel non-invasive method to detect BAT perfusion, we demonstrate that adrenergically-stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and is therefore not a reliable parameter for the estimation of BAT activation and heat generation.

  • 16.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kalinovich, Anastasia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Novel thiazolidinediones distinguish between (UCP1-independent) antidiabetic effects (MSDC-0602) and adipogenic and browning-inducing effects (MSDC-0160) of classical thiazolidinediones (rosiglitazone)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Thiazolinediones (TZDs), also called glitazones, are a class of drugs traditionally used forimproving glucose tolerance in type II diabetes mellitus. The beneficial effects ofthiazolidinedione are believed to be caused by the drug binding to the nuclear receptor PPARγ,which in turn triggers a general adipogenic program in white adipose tissue, and apparentthermogenic recruitment of brown and brite/beige fat. Here, we present a comparison of thephysiological effects of three thiazolidinediones (rosiglitazone, MSDC-0602, and MSDC-0160)in C57BL/6 mice fed high-fat diet and housed at thermoneutrality. Rosiglitazone and MSDC-0160 caused the classically-described thiazolidinedione effects of increased fat mass,hyperphagia, and increased UCP1 levels in brown adipose tissue. MSDC-0602 and rosiglitazoneimproved glucose tolerance but MSDC-0602 did not induce increased fat mass, hyperphagia, orincreased UCP1 levels in brown fat. The beneficial effects of thiazolidinediones were fullypresent even in UCP1-KO mice, providing evidence for a dissociation between thiazolidinedioneinducedadipose tissue browning and their antidiabetic effects. We conclude that even structurallysimilar thiazolidinediones can act through distinct pathways, and that the glucose-loweringeffects of this class do not seem to rely on PPAR-γ-induced browning of adipose tissues.

  • 17.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA.
    Xiao, Cuiying
    Gavrilova, Oksana
    Reitman, Marc L.
    Integration of body temperature into the analysis of energy expenditure in the mouse2015Inngår i: Molecular Metabolism, ISSN 2212-8778, Vol. 4, nr 6, s. 461-470Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: We quantified the effect of environmental temperature on mouse energy homeostasis and body temperature.Methods: The effect of environmental temperature (4e33 C) on body temperature, energy expenditure, physical activity, and food intake invarious mice (chow diet, high-fat diet, Brs3-/y, lipodystrophic) was measured using continuous monitoring.Results: Body temperature depended most on circadian phase and physical activity, but also on environmental temperature. The amounts ofenergy expenditure due to basal metabolic rate (calculated via a novel method), thermic effect of food, physical activity, and cold-inducedthermogenesis were determined as a function of environmental temperature. The measured resting defended body temperature matchedthat calculated from the energy expenditure using Fourier’s law of heat conduction. Mice defended a higher body temperature during physicalactivity. The cost of the warmer body temperature during the active phase is 4e16% of total daily energy expenditure. Parameters measured indiet-induced obese and Brs3-/y mice were similar to controls. The high post-mortem heat conductance demonstrates that most insulation in miceis via physiological mechanisms.Conclusions: At 22 C, cold-induced thermogenesis isw120% of basal metabolic rate. The higher body temperature during physical activity isdue to a higher set point, not simply increased heat generation during exercise. Most insulation in mice is via physiological mechanisms, with littlefrom fur or fat. Our analysis suggests that the definition of the upper limit of the thermoneutral zone should be re-considered. Measuring bodytemperature informs interpretation of energy expenditure data and improves the predictiveness and utility of the mouse to model human energyhomeostasis.

  • 18. Acheva, Anna
    et al.
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Caen Normandy, France.
    Sollazzo, Alice
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Launonen, Virpi
    Kamarainen, Meerit
    Presence of Stromal Cells Enhances Epithelial-to-Mesenchymal Transition (EMT) Induction in Lung Bronchial Epithelium after Protracted Exposure to Oxidative Stress of Gamma Radiation2019Inngår i: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, Vol. 2019, artikkel-id 4120379Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of the study was to investigate the role of a microenvironment in the induction of epithelial-to-mesenchymal transition (EMT) as a sign of early stages of carcinogenesis in human lung epithelial cell lines after protracted low-dose rate gamma-radiation exposures. BEAS-2B and HBEC-3KT lung cell lines were irradiated with low-dose rate gamma-rays (Cs-137, 1.4 or 14 mGy/h) to 0.1 or 1 Gy with or without adding TGF-beta. TGF-beta-treated samples were applied as positive EMT controls and tested in parallel to find out if the radiation has a potentiating effect on the EMT induction. To evaluate the effect of the stromal component, the epithelial cells were irradiated in cocultures with stromal MRC-9 lung fibroblasts. On day 3 post treatment, the EMT markers: alpha-SMA, vimentin, fibronectin, and E-cadherin, were analyzed. The oxidative stress levels were evaluated by 8-oxo-dG analysis in both epithelial and fibroblast cells. The protracted exposure to low Linear Energy Transfer (LET) radiation at the total absorbed dose of 1 Gy was able to induce changes suggestive of EMT. The results show that the presence of the stromal component and its signaling (TGF-beta) in the cocultures enhances the EMT. Radiation had a minor cumulative effect on the TGF-beta-induced EMT with both doses. The oxidative stress levels were higher than the background in both epithelial and stromal cells post chronic irradiation (0.1 and 1 Gy); as for the BEAS-2B cell line, the increase was statistically significant. We suggest that the induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure and the presence of stromal component might enhance the effect through free radical production and accumulation.

  • 19.
    Adam, Lucille
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    López-González, Moisés
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Björk, Albin
    Pålsson, Sandra
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Poux, Candice
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wahren-Herlenius, Marie
    Fernández, Carmen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Spetz, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Early Resistance of Non-virulent Mycobacterial Infection in C57BL/6 Mice Is Associated With Rapid Up-Regulation of Antimicrobial Cathelicidin Camp2018Inngår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, artikkel-id 1939Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Early clearance of tuberculosis is the successful eradication of inhaled bacteria before the development of an adaptive immune response. We previously showed, by utilizing a non-virulent mycobacteria infection model, that C57BL/6 mice are more efficient than BALB/c in their control of bacterial growth in the lungs during the first weeks of the infection. Here, we assessed early (within 1-3 days) innate immune events locally in the lungs to identify factors that may contribute to the control of non-virulent mycobacterial burden. We confirmed that C57BL/6 mice are more resistant to infection compared with BALB/c after intranasal inoculation with mycobacterium. Transcriptomic analyses revealed a remarkably silent signature in C57BL/6 mice despite effective control of bacterial growth. In contrast, BALB/c mice up-regulated genes associated with neutrophil and myeloid cell chemotaxis and migration. Flow cytometry analyses corroborated the transcriptomic analyses and demonstrated influx of both neutrophil and myeloid cell populations in BALB/c mice, while these did not increase in C57BL/6 mice. We further detected increased release of TNF-alpha from BALB/c lung cells but limited release from C57BL/6-derived cells. However, C57BL/6 mice showed a marked early up-regulation of the Camp gene, encoding the cathelicidin CRAMP peptide, post-mycobacterial exposure. CRAMP (LL-37 in human) expression in the lungs was confirmed using immunofluorescence staining. Altogether, these findings show that C57BL/6 mice can clear the mycobacterial infection early and that this early control is associated with high CRAMP expression in the lungs without concomitant influx of immune cells. The role of CRAMP/LL-37 during mycobacterial infection may be relevant for novel protective strategies, and warrants further studies of human cohorts.

  • 20. Adam, Lucille
    et al.
    Tchitchek, Nicolas
    Todorova, Biliana
    Rosenbaum, Pierre
    Joly, Candie
    Poux, Candice
    Chapon, Catherine
    Spetz, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ustav, Mart
    Le Grand, Roger
    Martinon, Frédéric
    Innate Molecular and Cellular Signature in the Skin Preceding Long-Lasting T Cell Responses after Electroporated DNA Vaccination2020Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 204, nr 12, s. 3375-3388Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNA vaccines delivered with electroporation (EP) have shown promising results in preclinical models and are evaluated in clinical trials. In this study, we aim to characterize early mechanisms occurring in the skin after intradermal injection and EP of the auxoGTUmultiSIV DNA vaccine in nonhuman primates. First, we show that EP acts as an adjuvant by enhancing local inflammation, notably via granulocytes, monocytes/macrophages, and CD1a(int)-expressing cell recruitment. EP also induced Langerhans cell maturation, illustrated by CD86, CD83, and HLA-DR upregulation and their migration out of the epidermis. Second, we demonstrate the crucial role of the DNA vaccine in soluble factors release, such as MCP-1 or IL-15. Transcriptomic analysis showed that EP played a major role in gene expression changes postvaccination. However, the DNA vaccine is required to strongly upregulate several genes involved in inflammatory responses (e.g., Saa4), cell migration (e.g., Ccl3, Ccl5, or Cxcl10), APC activation (e.g., Cd86), and IFN-inducible genes (e.g., Ifit3, Ifit5, Irf7, Isg15, orMx1), illustrating an antiviral response signature. Also, AIM-2, a cytosolic DNA sensor, appeared to be strongly upregulated only in the presence of the DNA vaccine and trends to positively correlate with several IFN-inducible genes, suggesting the potential role of AIM-2 in vaccine sensing and the subsequent innate response activation leading to strong adaptive T cell responses. Overall, these results demonstrate that a combined stimulation of the immune response, in which EP and the auxoGTUmultiSIV vaccine triggered different components of the innate immunity, led to strong and persistent cellular recall responses.

  • 21. Adia, Madina Mohamed
    et al.
    Emami, Seyedeh Noushin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Byamukama, Robert
    Faye, Ingrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Borg-Karlson, Anna-Karin
    Antiplasmodial activity and phytochemical analysis of extracts from selected Ugandan medicinal plants2016Inngår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 186, s. 14-19Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ethnopharmacological relevance: Resistance of the parasites to known antimalarial drugs has provided the necessity to find new drugs from natural products against malaria. The aim of the study was to evaluate the in vitro antiplasmodial activity of some plants used by Traditional Medical Practitioners (TMPs) of Prometra and Rukararwe in malaria treatment in Uganda to provide scientific proof of the efficacies claimed by these Herbalists.

    Materials and methods: The air dried samples of Clerodendrum rotundifolium (leaves), Microglossa pyrifolia (leaves), Momordica foetida (leaves) and Zanthoxylum chalybeum (stem bark) used for malaria treatment by TMPs were successively extracted with ethyl acetate, methanol and water to yield twelve extracts. The extracts were tested against the chloroquine-sensitive (NF54) and chloroquine-resistant (FCR3) Plasmodium falciparum strains in vitro using the micro Mark III test which is based on assessing the inhibition of schizont maturation. A compound A was extracted and purified from the stem bark of Z. chalybeum and its structure was identified and confirmed by spectroscopic methods.

    Results: Most of the extracts tested (92%) showed an antiplasmodial activity with IC50 < 50 mu g/mL. In spite of successive extractions with different solvents, potent anti-plasmodial activity (IC50 < 5 mu g/mL) was observed in the ethyl acetate, methanol and aqueous extracts of M. pyrifolia and C. rotundifolium. Preferential enrichments of activity into water (IC50 < 15 mu g/mL) and Ethyl acetate (IC50 < 5 mu g/mL) were seen in the case of M. foetida and Z chalybeum respectively. The most active extracts were from C rotundifolium and M. pyrifolia with IC50 values less than 2 mu g/mL. Phytochemical analysis of the extracts revealed the presence of saponins, tannins, flavonoids, alkaloids and cardiac glycocides. Fagaramide isolated from Z chalybeum had a higher activity (IC50 2.85 mu g/mL) against the chloroquine-resistant strain than against the chloroquine-senstive (IC50 16.6 mu g/mL) strain used in the study.

    Conclusion: The plant extracts analysed in this study presented an average antiplasmodial activity (58%). This study revealed for the first time the antiplasmodial activity of the plant C. rotundofolium. It's the first time the compound fagaramide (N-isobutyl-3-(3,4-methylene dioxyphenyl) - 2E-propenamide) has been isolated from Z. chalybeum as one of the compounds that contribute to the activity of this plant against P. falciparum.

  • 22. Adori, Monika
    et al.
    Bhat, Sadam
    Gramignoli, Roberto
    Valladolid-Acebes, Ismael
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Uhlèn, Mathias
    Adori, Csaba
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Karolinska Institutet, Sweden.
    Hepatic Innervations and Nonalcoholic Fatty Liver Disease2023Inngår i: Seminars in liver disease (Print), ISSN 0272-8087, E-ISSN 1098-8971, Vol. 43, nr 02, s. 149-162Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.

  • 23. Ai, Jiaoyu
    et al.
    Wörmann, Sonja M.
    Görgülü, Kıvanç
    Vallespinos, Mireia
    Zagorac, Sladjana
    Alcala, Sonia
    Wu, Nan
    Kabacaoglu, Derya
    Berninger, Alexandra
    Navarro, Diego
    Kaya-Aksoy, Ezgi
    Ruess, Dietrich A.
    Ciecielski, Katrin J.
    Kowalska, Marlena
    Demir, Ihsan Ekin
    Ceyhan, Güralp O.
    Heid, Irina
    Braren, Rickmer
    Riemann, Marc
    Schreiner, Sabrina
    Hofmann, Samuel
    Kutschke, Maria
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jastroch, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Slotta-Huspenina, Julia
    Muckenhuber, Alexander
    Schlitter, Anna Melissa
    Schmid, Roland M.
    Steiger, Katja
    Diakopoulos, Kalliope N.
    Lesina, Marina
    Sainz Jr, Bruno
    Algül, Hana
    Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes2021Inngår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 161, nr 1, s. 318-332Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background & Aims: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown.

    Methods: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes.

    Results: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes.

    Conclusions: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.

  • 24. Ainsbury, Elizabeth A.
    et al.
    Al-hafidh, Jenna
    Bajinskis, Ainars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Barnard, Stephen
    Barquinero, Joan Francesc
    Beinke, Christina
    de Gelder, Virginie
    Gregoire, Eric
    Jaworska, Alicja
    Lindholm, Carita
    Lloyd, David
    Moquet, Jayne
    Nylund, Reetta
    Oestreicher, Ursula
    Roch-Lefevre, Sandrine
    Rothkamm, Kai
    Romm, Horst
    Scherthan, Harry
    Sommer, Sylwester
    Thierens, Hubert
    Vandevoorde, Charlot
    Vral, Anne
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Inter- and intra-laboratory comparison of a multibiodosimetric approach to triage in a simulated, large scale radiation emergency2014Inngår i: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 90, nr 2, s. 193-202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The European Union's Seventh Framework Programme-funded project 'Multi-disciplinary biodosimetric tools to manage high scale radiological casualties' (MULTIBIODOSE) has developed a multiparametric approach to radiation biodosimetry, with a particular emphasis on triage of large numbers of potentially exposed individuals following accidental exposures. In November 2012, an emergency exercise took place which tested the capabilities of the MULTIBIODOSE project partners. The exercise described here had a dual purpose: Intercomparison of (i) three biodosimetric assays, and (ii) the capabilities of the seven laboratories, with regards to provision of triage status for suspected radiation exposed individuals. Materials and methods: Three biological dosimetry tools - the dicentric, micronucleus and gamma-H2AX (the phosphorylated form of member X of histone H2A, in response to DNA double-strand breaks) foci assays - were tested, in addition to provision of the triage status results (low exposure: <1 Gy; medium exposure: 1-2 Gy; high exposure: >2 Gy) by the MULTIBIODOSE software. The exercise was run in two modes: An initial triage categorisation of samples (based on the first dose estimates for each assay received from each laboratory) followed by collation of the full set of estimated doses (all the results from all modes of each assay carried out by the participating laboratories) calculated using as many modes of operation as possible of the different assays developed during the project. Simulated acute whole body and partial body exposures were included. Results: The results of the initial triage categorisation and the full comparison of assays and methods within and between laboratories are presented here. Conclusions: The data demonstrate that the MULTIBIODOSE approach of applying multiparametric tools to radiation emergencies is valid and effective.

  • 25. Ainsbury, Elizabeth A.
    et al.
    Barnard, Stephen
    Barrios, Lleonard
    Fattibene, Paola
    de Gelder, Virginie
    Gregoire, Eric
    Lindholm, Carita
    Lloyd, David
    Nergaard, Inger
    Rothkamm, Kai
    Romm, Horst
    Scherthan, Harry
    Thierens, Hubert
    Vandevoorde, Charlot
    Woda, Clemens
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    MULTIBIODOSE RADIATION EMERGENCY TRIAGE CATEGORIZATION SOFTWARE2014Inngår i: Health Physics, ISSN 0017-9078, E-ISSN 1538-5159, Vol. 107, nr 1, s. 83-89Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this note, the authors describe the MULTIBIODOSE software, which has been created as part of the MULTIBIODOSE project. The software enables doses estimated by networks of laboratories, using up to five retrospective (biological and physical) assays, to be combined to give a single estimate of triage category for each individual potentially exposed to ionizing radiation in a large scale radiation accident or incident. The MULTIBIODOSE software has been created in Java. The usage of the software is based on the MULTIBIODOSE Guidance: the program creates a link to a single SQLite database for each incident, and the database is administered by the lead laboratory. The software has been tested with Java runtime environment 6 and 7 on a number of different Windows, Mac, and Linux systems, using data from a recent intercomparison exercise. The Java program MULTIBIODOSE_1.0.jar is freely available to download from http://www.multibiodose.eu/software or by contacting the software administrator: MULTIBIODOSE-software@gmx.com.

  • 26. Ainsbury, Elizabeth A.
    et al.
    Higueras, Manuel
    Puig, Pedro
    Einbeck, Jochen
    Samaga, Daniel
    Francesc Barquinero, Joan
    Barrios, Lleonard
    Brzozowska, Beata
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Warsaw, Poland.
    Fattibene, Paola
    Gregoire, Eric
    Jaworska, Alicja
    Lloyd, David
    Oestreicher, Ursula
    Romm, Horst
    Rothkamm, Kai
    Roy, Laurence
    Sommer, Sylwester
    Terzoudi, Georgia
    Thierens, Hubert
    Trompier, Francois
    Vral, Anne
    Woda, Clemens
    Uncertainty of fast biological radiation dose assessment for emergency response scenarios2017Inngår i: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 93, nr 1, s. 127-135Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Reliable dose estimation is an important factor in appropriate dosimetric triage categorization of exposed individuals to support radiation emergency response. Materials and methods: Following work done under the EU FP7 MULTIBIODOSE and RENEB projects, formal methods for defining uncertainties on biological dose estimates are compared using simulated and real data from recent exercises. Results: The results demonstrate that a Bayesian method of uncertainty assessment is the most appropriate, even in the absence of detailed prior information. The relative accuracy and relevance of techniques for calculating uncertainty and combining assay results to produce single dose and uncertainty estimates is further discussed. Conclusions: Finally, it is demonstrated that whatever uncertainty estimation method is employed, ignoring the uncertainty on fast dose assessments can have an important impact on rapid biodosimetric categorization.

  • 27. Ainsbury, Elizabeth
    et al.
    Badie, Christophe
    Barnard, Stephen
    Manning, Grainne
    Moquet, Jayne
    Abend, Michael
    Antunes, Ana Catarina
    Barrios, Lleonard
    Bassinet, Celine
    Beinke, Christina
    Bortolin, Emanuela
    Bossin, Lily
    Bricknell, Clare
    Brzoska, Kamil
    Buraczewska, Iwona
    Huertas Castano, Carlos
    Cemusova, Zina
    Christiansson, Maria
    Mateos Cordero, Santiago
    Coster, Guillaume
    Della Monac, Sara
    Desangles, Francois
    Discher, Michael
    Dominguez, Inmaculada
    Doucha-Senf, Sven
    Eakins, Jon
    Fattibene, Paola
    Filippi, Silvia
    Frenzel, Monika
    Georgieva, Dimka
    Gregoire, Eric
    Guogyte, Kamile
    Hadjidekova, Valeria
    Hadjiiska, Ljubomira
    Hristova, Rositsa
    Karakosta, Maria
    Kis, Eniko
    Kriehuber, Ralf
    Lee, Jungil
    Lloyd, David
    Lumniczky, Katalin
    Lyng, Fiona
    Macaeva, Ellina
    Majewski, Matthaeus
    Vanda Martins, S.
    McKeever, Stephen W. S.
    Meade, Aidan
    Medipally, Dinesh
    Meschini, Roberta
    M'kacher, Radhia
    Gil, Octavia Monteiro
    Montero, Alegria
    Moreno, Mercedes
    Noditi, Mihaela
    Oestreicher, Ursula
    Oskamp, Dominik
    Palitti, Fabrizio
    Palma, Valentina
    Pantelias, Gabriel
    Pateux, Jerome
    Patrono, Clarice
    Pepe, Gaetano
    Port, Matthias
    Jesus Prieto, Maria
    Quattrini, Maria Cristina
    Quintens, Roel
    Ricoul, Michelle
    Roy, Laurence
    Sabatier, Laure
    Sebastia, Natividad
    Sholom, Sergey
    Sommer, Sylwester
    Staynova, Albena
    Strunz, Sonja
    Terzoudi, Georgia
    Testa, Antonella
    Trompier, Francois
    Valente, Marco
    Van Hoey, Olivier
    Veronese, Ivan
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Woda, Clemens
    Integration of new biological and physical retrospective dosimetry methods into EU emergency response plans - joint RENEB and EURADOS inter-laboratory comparisons2017Inngår i: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 93, nr 1, s. 99-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: RENEB, 'Realising the European Network of Biodosimetry and Physical Retrospective Dosimetry,' is a network for research and emergency response mutual assistance in biodosimetry within the EU. Within this extremely active network, a number of new dosimetry methods have recently been proposed or developed. There is a requirement to test and/or validate these candidate techniques and inter-comparison exercises are a well-established method for such validation. Materials and methods: The authors present details of inter-comparisons of four such new methods: dicentric chromosome analysis including telomere and centromere staining; the gene expression assay carried out in whole blood; Raman spectroscopy on blood lymphocytes, and detection of radiation induced thermoluminescent signals in glass screens taken from mobile phones. Results: In general the results show good agreement between the laboratories and methods within the expected levels of uncertainty, and thus demonstrate that there is a lot of potential for each of the candidate techniques. Conclusions: Further work is required before the new methods can be included within the suite of reliable dosimetry methods for use by RENEB partners and others in routine and emergency response scenarios.

  • 28.
    Akar, Roya
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fink, Matthias J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jonas, Kristina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Regulation of the ECF sigma factor SigT by Lon-mediated proteolysisManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The Lon protease is widely conserved in both prokaryotic and eukaryotic species in which it fulfils important regulatory functions. Nevertheless, the number of identified Lon substrates is limited in most organisms and the precise role of Lon in regulating these proteins poorly understood. Previous quantitative proteomics data classified the general stress response sigma factor SigT as a promising putative Lon substrate in the dimorphic bacterium Caulobacter crescentus. Here, we confirm that SigT abundance is directly regulated by Lon. We show that downregulation of SigT levels during recovery from sucrose-induced osmotic stress is delayed in the absence of Lon, while its upregulation at the onset of stress functions normally. Furthermore, the presence of the Lon regulator LarA enhances Lon-mediated degradation of SigT in vitro and reduces SigT levels in vivo indicating a role of LarA in regulating Lon-mediated degradation of SigT. Together, our results emphasize the importance of Lon during the recovery phase following stress exposure by adjusting the concentration of the general stress response regulator SigT.

  • 29.
    Akar, Roya
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Fink, Matthias J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Omnus, Deike J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Regulation of the general stress response sigma factor σT by Lon-mediated proteolysis2023Inngår i: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 205, nr 11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Lon protease is widely conserved in both prokaryotic and eukaryotic organisms and fulfills important regulatory functions. Nevertheless, the number of identified Lon substrates is limited in most organisms, and the precise role of Lon in regulating these proteins is poorly understood. Here, we describe the α-proteobacterial general stress response sigma factor σT as a novel Lon substrate in Caulobacter crescentus. Based on previously published quantitative proteomics data, we find σT to be a promising putative Lon substrate and confirm a direct role of Lon in degrading σT. We show that Lon contributes to the downregulation of σT abundance under optimal conditions and during recovery from sucrose-induced osmotic stress. Furthermore, the presence of the Lon activity regulator LarA enhances Lon-mediated degradation of σT in vitro and reduces σT levels in vivo indicating a role of LarA in modulating Lon-mediated degradation of σT. Together, our results highlight the importance of Lon during the recovery phase following stress exposure by adjusting the concentrations of critical regulators of stress responses.

  • 30.
    Akuwudike, Pamela
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lopez Riego, Milagrosa
    Marczyk, Michal
    Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
    Brückner, Fabian
    Biberach University of Applied Sciences.
    Polanska, Joanna
    Department of Data Science and Engineering, Silesian University of Technology, .
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Institute of Biology, Jan Kochanowski University, Kielce, Poland.
    Lundholm, Lovisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Short- and long-term effects of radiation exposure  at low dose and low dose rate on normal human  VH10 fibroblastsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Experimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and dose rate effectiveness factor.  Here, human VH10 skin fibroblasts exposed to 25, 50 and 100 mGy of 137Cs gamma radiation at 1.6, 8, 12 mGy/h, and at a high dose rate of 23.4 Gy/h, were analyzed for radiation-induced short- and long-term effects. Two sample cohorts, i.e. discovery (n=30) and validation (n=12), were subjected to RNA sequencing. Results from the pool of those samples with shared conditions among six experiments constituted a third cohort (n=12). The 100 mGy-exposed cells at all the abovementioned dose rates, harvested at early and late time points after exposure, showed no strong gene expression changes. DMXL2, involved in the regulation of the NOTCH signalling pathway, presented a consistent upregulation among both the discovery and validation cohorts. Gene set enrichment analysis revealed that the NOTCH pathway was upregulated in the pooled cohort (p=0.76, NES=0.86). Apart from upregulated apical junction and downregulated DNA repair, few pathways were consistently changed across exposed cohorts. In agreement, cell viability assays, performed 1-, 3-, and 6-days post-irradiation, and colony forming assay, seeded just after exposure, did not reveal any statistically significant early effects in cell growth or survival patterns. Tendencies of increased growth and reduced colony size were observed at 12 mGy/h and 23.4 Gy/min. Furthermore, no long-term changes were observed in cell growth curves generated up to 70 days after exposure. In conclusion, low doses of gamma radiation given at low dose rates had no strong cytotoxic effects on VH10 cells.

  • 31.
    Akuwudike, Pamela
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    López Riego, Milagrosa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ginter, Józef
    Cheng, Lei
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wieczorek, Anna
    Życieńska, Katarzyna
    Łysek-Gładysińska, Małgorzata
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Brzozowska, Beata
    Lundholm, Lovisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mechanistic insights from high resolution DNA damage analysis to understand mixed radiation exposure2023Inngår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 130, artikkel-id 103554Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cells exposed to densely ionising high and scattered low linear energy transfer (LET) radiation (50 % dose of each) react more strongly than to the same dose of each separately. The relationship between DNA double strand break location inside the nucleus and chromatin structure was evaluated, using high-resolution transmission electron microscopy (TEM) in breast cancer MDA-MB-231 cells at 30 min post 5 Gy. Additionally, response to high and/or low LET radiation was assessed using single (1 ×1.5 Gy) versus fractionated dose delivery (5 ×0.3 Gy). By TEM analysis, the highest total number of γH2AX nanobeads were found in cells irradiated with alpha radiation just prior to gamma radiation (called mixed beam), followed by alpha, then gamma radiation. γH2AX foci induced by mixed beam radiation tended to be surrounded by open chromatin (lighter TEM regions), yet foci containing the highest number of beads, i.e. larger foci representing complex damage, remained in the heterochromatic areas. The γH2AX large focus area was also greater in mixed beam-treated cells when analysed by immunofluorescence. Fractionated mixed beams given daily induced the strongest reduction in cell viability and colony formation in MDA-MB-231 and osteosarcoma U2OS cells compared to the other radiation qualities, as well as versus acute exposure. This may partially be explained by recurring low LET oxidative DNA damage by every fraction together with a delay in recompaction of chromatin after high LET, demonstrated by low levels of heterochromatin marker H3K9me3 at 2 h after the last mixed beam fraction in MDA-MB-231. In conclusion, early differences in response to complex DNA damage may lead to a stronger cell kill induced by fractionated exposure, which suggest a therapeutic potential of combined high and low LET irradiation.

  • 32.
    Akuwudike, Pamela
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    López Riego, Milagrosa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Marczyk, Michal
    Kocibalova, Zuzana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Brückner, Fabian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Polańska, Joanna
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Jan Kochanowski University, Poland.
    Lundholm, Lovisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Short- and long-term effects of radiation exposure at low dose and low dose rate in normal human VH10 fibroblasts2023Inngår i: Frontiers In Public Health, ISSN 2296-2565, Vol. 11, artikkel-id 1297942Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Experimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and dose rate effectiveness factor.

    Methods: Human VH10 skin fibroblasts exposed to 25, 50, and 100 mGy of 137Cs gamma radiation at 1.6, 8, 12 mGy/h, and at a high dose rate of 23.4 Gy/h, were analyzed for radiation-induced short- and long-term effects. Two sample cohorts, i.e., discovery (n = 30) and validation (n = 12), were subjected to RNA sequencing. The pool of the results from those six experiments with shared conditions (1.6 mGy/h; 24 h), together with an earlier time point (0 h), constituted a third cohort (n = 12).

    Results: The 100 mGy-exposed cells at all abovementioned dose rates, harvested at 0/24 h and 21 days after exposure, showed no strong gene expression changes. DMXL2, involved in the regulation of the NOTCH signaling pathway, presented a consistent upregulation among both the discovery and validation cohorts, and was validated by qPCR. Gene set enrichment analysis revealed that the NOTCH pathway was upregulated in the pooled cohort (p = 0.76, normalized enrichment score (NES) = 0.86). Apart from upregulated apical junction and downregulated DNA repair, few pathways were consistently changed across exposed cohorts. Concurringly, cell viability assays, performed 1, 3, and 6 days post irradiation, and colony forming assay, seeded just after exposure, did not reveal any statistically significant early effects on cell growth or survival patterns. Tendencies of increased viability (day 6) and reduced colony size (day 21) were observed at 12 mGy/h and 23.4 Gy/min. Furthermore, no long-term changes were observed in cell growth curves generated up to 70 days after exposure.

    Discussion: In conclusion, low doses of gamma radiation given at low dose rates had no strong cytotoxic effects on radioresistant VH10 cells.

  • 33.
    Akuwudike, Pamela
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    López-Riego, Milagrosa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dehours, Cloé
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Polytech Angers l École d’Ingénieurs, France.
    Lundholm, Lovisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Jan Kochanowski University, Poland.
    Impact of fractionated cisplatin and radiation treatment on cell growth and accumulation of DNA damage in two normal cell types differing in origin2023Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 13, artikkel-id 14891Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Evidence on the impact of chemotherapy on radiotherapy-induced second malignant neoplasms is controversial. We estimated how cisplatin modulates the in vitro response of two normal cell types to fractionated radiation. AHH-1 lymphoblasts and VH10 fibroblasts were irradiated at 1 Gy/fraction 5 and 3 times per week during 12 and 19 days, respectively, and simultaneously treated with 0.1, 0.2, 0.4, 0.8, 1.7 and 3.3 µM of cisplatin twice a week. Cell growth during treatment was monitored. Cell growth/cell death and endpoints related to accumulation of DNA damage and, thus, carcinogenesis, were studied up to 21 days post treatment in cells exposed to radiation and the lowest cisplatin doses. Radiation alone significantly reduced cell growth. The impact of cisplatin alone below 3.3 µM was minimal. Except the lowest dose of cisplatin in VH10 cells, cisplatin reduced the inhibitory effect of radiation on cell growth. Delayed cell death was highest in the combination groups while the accumulation of DNA damage did not reveal a clear pattern. In conclusion, fractionated, concomitant exposure to radiation and cisplatin reduces the inhibitory effect of radiation on cell proliferation of normal cells and does not potentiate delayed effects resulting from accumulation of DNA damage.

  • 34.
    Akuwudike, Pamela
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tartas, Adrianna
    López-Riego, Milagrosa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Toma-Daşu, Iuliana
    Stockholms universitet, Naturvetenskapliga fakulteten, Fysikum. Karolinska Institutet, Sweden.
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Jan Kochanowski University, Poland.
    Lundholm, Lovisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cell Type-Specific Patterns in the Accumulation of DNA Damage Following Multifractional Radiation Exposure2022Inngår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, nr 21, artikkel-id 12861Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Predicting the risk of second malignant neoplasms is complicated by uncertainties regarding the shape of the dose–response relationship at high doses. Limited understanding of the competitive relationship between cell killing and the accumulation of DNA lesions at high doses, as well as the effects of other modulatory factors unique to radiation exposure during radiotherapy, such as dose heterogeneity across normal tissue and dose fractionation, contribute to these uncertainties. The aim of this study was to analyze the impact of fractionated irradiations on two cell systems, focusing on the endpoints relevant for cancer induction. To simulate the heterogeneous dose distribution across normal tissue during radiotherapy, exponentially growing VH10 fibroblasts and AHH-1 lymphoblasts were irradiated with 9 and 12 fractions (VH10) and 10 fractions (AHH-1) at 0.25, 0.5, 1, or 2 Gy per fraction. The effects on cell growth, cell survival, radiosensitivity and the accumulation of residual DNA damage lesions were analyzed as functions of dose per fraction and the total absorbed dose. Residual γH2AX foci and other DNA damage markers (micronuclei, nuclear buds, and giant nuclei) were accumulated at high doses in both cell types, but in a cell type-dependent manner. The competitive relationship between cell killing and the accumulation of carcinogenic DNA damage following multifractional radiation exposure is cell type-specific.

  • 35. Alberro-Brage, Andres
    et al.
    Kryvenko, Vitalii
    Malainou, Christina
    Guenther, Stefan
    Morty, Rory E.
    Seeger, Werner
    Herold, Susanne
    Samakovlis, Christos
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Vadasz, Istvan
    Influenza virus decreases albumin uptake and megalin expression in alveolar epithelial cells2023Inngår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, artikkel-id 1260973Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction

    Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.

    Methods

    To investigate whether IV infection impairs alveolar protein clearance, we examined albumin uptake and megalin expression in MLE-12 cells and alveolar epithelial cells (AEC) from murine precision-cut lung slices (PCLS) and in vivo, under IV infection conditions by flow cytometry and western blot. Transcriptional levels from AEC and broncho-alveolar lavage (BAL) cells were analyzed in an in-vivo mouse model by RNAseq.

    Results

    IV significantly downregulated albumin uptake, independently of activation of the TGF- β1/GSK3β axis that has been previously implicated in the regulation of megalin function. Decreased plasma membrane abundance, total protein levels, and mRNA expression of megalin were associated with this phenotype. In IV-infected mice, we identified a significant upregulation of matrix metalloproteinase (MMP)-14 in BAL fluid cells. Furthermore, the inhibition of this protease partially recovered total megalin levels and albumin uptake.

    Discussion

    Our results suggest that the previously described MMP-driven shedding mechanisms are potentially involved in downregulation of megalin cell surface abundance and clearance of excess alveolar protein. As lower alveolar edema protein concentrations are associated with better outcomes in respiratory failure, our findings highlight the therapeutic potential of a timely MMP inhibition in the treatment of IV-induced ARDS.

  • 36. Algethami, Jari S.
    et al.
    Abd El-Wahed, Aida A.
    Elashal, Mohamed H.
    Ahmed, Hanan R.
    Elshafiey, Esraa H.
    Omar, Eslam M.
    Al Naggar, Yahya
    Algethami, Ahmed F.
    Shou, Qiyang
    Alsharif, Sultan M.
    Xu, Baojun
    Shehata, Awad A.
    Guo, Zhiming
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wang, Kai
    El-Seedi, Hesham R.
    Bee Pollen: Clinical Trials and Patent Applications2022Inngår i: Nutrients, E-ISSN 2072-6643, Vol. 14, nr 14, artikkel-id 2858Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Bee pollen is a natural cocktail of floral nectar, flower pollen, enzymes, and salivary secretions produced by honeybees. Bee pollen is one of the bee products most enriched in proteins, polysaccharides, polyphenols, lipids, minerals, and vitamins. It has a significant health and medicinal impact and provides protection against many diseases, including diabetes, cancer, infectious, and cardiovascular. Bee pollen is commonly promoted as a cost-effective functional food. In particular, bee pollen has been applied in clinical trials for allergies and prostate illnesses, with a few investigations on cancer and skin problems. However, it is involved in several patents and health recipes to combat chronic health problems. This review aimed to highlight the clinical trials and patents involving bee pollen for different cases and to present the role of bee pollen as a supplementary food and a potential product in cosmetic applications.

  • 37. Ali, Kiran
    et al.
    Ali, Arslan
    Noman Khan, Muhammad
    Rahman, Saeedur
    Faizi, Shaheen
    Ali, Muhammad Shaiq
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    El-Seedi, Hesham R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Menoufia University, Egypt; Jiangsu University, China.
    Musharraf, Syed Ghulam
    Rapid Identification of Common Secondary Metabolites of Medicinal Herbs Using High-Performance Liquid Chromatography with Evaporative Light Scattering Detector in Extracts2021Inngår i: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 11, nr 8, artikkel-id 489Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The discovery and identification of novel natural products of medicinal importance in the herbal medicine industry becomes a challenge. The complexity of this process can be reduced by dereplication strategies. The current study includes a method based on high-performance liquid chromatography (HPLC), using the evaporative light scattering detector (ELSD) to identify the 12 most common secondary metabolites in plant extracts. Twelve compounds including rutin, taxifolin, quercetin, apigenin, kaempferol, betulinic acid, oleanolic acid, betulin, lupeol, stigmasterol, and beta-sitosterol were analyzed simultaneously. The polarity of the compounds varied greatly from highly polar (flavonoids) to non-polar (triterpenes and sterols). This method was also tested for HPLC-DAD and HPLC-ESI-MS/MS analysis. Oleanolic acid and ursolic acid could not be separated in HPLC-ELSD analysis but were differentiated using LC-ESI-MS/MS analysis due to different fragment ions. The regression values (R-2 > 0.996) showed good linearity in the range of 50-1000 mu g/mL for all compounds. The range of LOD and LOQ values were 7.76-38.30 mu g/mL and 23.52-116.06 mu g/mL, respectively. %RSD and % trueness values of inter and intraday studies were mostly <10%. This method was applied on 10 species of medicinal plants. The dereplication strategy has the potential to facilitate and shorten the identification process of common secondary metabolites in complex plant extracts.

  • 38. Alkadarou, Tayseer
    et al.
    Musa, Ahmed
    Alkadarou, Abedelgader
    Mahfouz, Mohamed S
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Elhassan, Ahmed M
    Elhassan, Ibrahim M
    Immunological characteristics of hyperreactive malarial splenomegaly syndrome in sudanese patients2013Inngår i: Journal of Tropical Medicine, ISSN 1687-9686, E-ISSN 1687-9694, Vol. 2013, s. 961051-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hyperreactive Malarial Splenomegaly (HMS) is defined as a massive enlargement of the spleen resulting from abnormal immune responses after repeated exposure to the malaria parasites. This study was carried out in Khartoum, Sudan. Sudan is considered to be one of the countries where HMS is quite prevalent. The objective of the study was to determine the incidence of HMS in patients who reported to the Omdurman Tropical Diseases Hospital (OMTDH) in Sudan and to investigate the basic laboratory and immunological characteristics of this condition in these patients. A cross-sectional study was carried out in OMTDH, and all patients with enlarged spleens were included in the study. Thirty-one out of 335 (9.3%) patients were diagnosed as having the HMS condition using international criteria for HMS diagnosis. The mean serum immunoglobulin M (IgM) levels in HMS patient groups were 14.3 ± 5 g/L, and this was significantly higher compared with geographically matched controls (P < 0.001). Immunoglobulin G (IgG) C anticircumsporozoite (CSP) antibody levels were higher in the HMS patients although the difference was not statistically significant, when compared with a group of patients with mild malaria. In comparison with naïve European controls, both the HMS and the mild malaria groups had significantly higher antimalarial antibody levels P < 0.001 and P < 0.01, respectively. Plasma levels of interleukin 10 (IL10) and interferon gamma (IFN γ ) were significantly increased in the HMS patients compared with the healthy control donors (P < 0.05 and P < 0.01) for IL10 and IFN γ , respectively. The findings of this study suggest that HMS is one of the significant causes of tropical splenomegaly in Sudan. HMS is associated with significant elevations of circulating IgM and antimalarial IgG antibodies as well as IL10 and IFN γ .

  • 39. Almuzzaini, Bader
    et al.
    Sarshad, Aishe A.
    Rahmanto, Aldwin S.
    Hansson, Magnus L.
    Von Euler, Anne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sangfelt, Olle
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Östlund Farrants, Ann-Kristin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Percipalle, Piergiorgio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    In beta-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects2016Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30, nr 8, s. 2860-2873Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Actin and nuclear myosin 1 (NM1) are regulators of transcription and chromatin organization. Using a genome-wide approach, we report here that beta-actin binds intergenic and genic regions across the mammalian genome, associated with both protein-coding and rRNA genes. Within the rDNA, the distribution of beta-actin correlated with NM1 and the other subunits of the B-WICH complex, WSTF and SNF2h. In beta-actin(-/-) mouse embryonic fibroblasts (MEFs), we found that rRNA synthesis levels decreased concomitantly with drops in RNA polymerase I (Pol I) and NM1 occupancies across the rRNA gene. Reintroduction of wild-type beta-actin, in contrast to mutated forms with polymerization defects, efficiently rescued rRNA synthesis underscoring the direct role for a polymerization-competent form of beta-actin in Pol I transcription. The rRNA synthesis defects in the beta-actin(-/-) MEFs are a consequence of epigenetic reprogramming with up-regulation of the repressive mark H3K4me1 (mono-methylation of lys4 on histone H3) and enhanced chromatin compaction at promoter-proximal enhancer (T0 sequence), which disturb binding of the transcription factor TTF1. We propose a novel genome-wide mechanism where the polymerase-associated beta-actin synergizes with NM1 to coordinate permissive chromatin with Pol I transcription, cell growth, and proliferation.

  • 40. Almuzzaini, Bader
    et al.
    Sarshad, Aishe A.
    Östlund Farrants, Ann-Kristin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Percipalle, Piergiorgio
    Nuclear myosin 1 contributes to a chromatin landscape compatible with RNA polymerase II transcription activation2015Inngår i: BMC Biology, E-ISSN 1741-7007, Vol. 13, artikkel-id 35Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Nuclear myosin 1c (NM1) is emerging as a regulator of transcription and chromatin organization. Results: Using chromatin immunoprecipitation and deep sequencing (ChIP-Seq) in combination with molecular analyses, we investigated the global association of NM1 with the mammalian genome. Analysis of the ChIP-Seq data demonstrates that NM1 binds across the entire mammalian genome with occupancy peaks correlating with distributions of RNA Polymerase II (Pol II) and active epigenetic marks at class II gene promoters. In mouse embryonic fibroblasts subjected to RNAi mediated NM1 gene silencing, we show that NM1 synergizes with polymerase-associated actin to maintain active Pol II at the promoter. NM1 also co-localizes with the nucleosome remodeler SNF2h at class II promoters where they assemble together with WSTF as part of the B-WICH complex. A high resolution micrococcal nuclease (MNase) assay and quantitative real time PCR shows that this mechanism is required for local chromatin remodeling. Following B-WICH assembly, NM1 mediates physical recruitment of the histone acetyl transferase PCAF and the histone methyl transferase Set1/Ash2 to maintain and preserve H3K9acetylation and H3K4trimethylation for active transcription. Conclusions: We propose a novel genome-wide mechanism where myosin synergizes with Pol II-associated actin to link the polymerase machinery with permissive chromatin for transcription activation.

  • 41. Al-Sayegh, M. A.
    et al.
    Mahmood, S. R.
    Abul Khair, S. B.
    Xie, X.
    El Gindi, M.
    Kim, T.
    Almansoori, A.
    Percipalle, Piergiorgio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. New York University Abu Dhabi (NYUAD), United Arab Emirates.
    β-actin contributes to open chromatin for activation of the adipogenic pioneer factor CEBPA during transcriptional reprograming2020Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 31, nr 23, s. 2511-2521Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adipogenesis is regulated by a cascade of signals that drive transcriptional reprogramming in adipocytes. Here, we report that nuclear actin regulates the chromatin states that establish tissue- specific expression during adipogenesis. To study the role of beta-actin in adipocyte differentiation, we conducted RNA sequencing on wild-type and beta-actin knockout mouse embryonic fibroblasts (MEFs) after reprograming to adipocytes. We found that beta-actin depletion affects induction of several adipogenic genes during transcriptional reprograming. This impaired regulation of adipogenic genes is linked to reduced expression of the pioneer factor Cebpa and is rescued by reintroducing NLS-tagged beta-actin. ATAC-Seq in knockout MEFs revealed that actin-dependent reduction of Cebpa expression correlates with decreased chromatin accessibility and loss of chromatin association of the ATPase Brg1. This, in turn, impairs CEBPB's association with its Cebpa promoter-proximal binding site during adipogenesis. We propose a role for the nuclear beta-actin pool in maintaining open chromatin for transcriptional reprogramming during adipogenic differentiation.

  • 42.
    Alvarez, Francisco J.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ryman, Kicki
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hooijmaijers, Cornelis
    Bulone, Vincent
    Ljungdahl, Per O.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Diverse Nitrogen Sources in Seminal Fluid Act in Synergy To Induce Filamentous Growth of Candida albicans2015Inngår i: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 81, nr 8, s. 2770-2780Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pathogenic fungus Candida albicans is the leading cause of vulvovaginal candidiasis (VVC). VVC represents a major quality- of-life issue for women during their reproductive years, a stage of life where the vaginal epithelium is subject to periodic hormonally induced changes associated with menstruation and concomitant exposure to serum as well as potential intermittent contact with seminal fluid. Seminal fluid potently triggers Candida albicans to switch from yeastlike to filamentous modes of growth, a developmental response tightly linked to virulence. Conversely, vaginal fluid inhibits filamentation. Here, we used artificial formulations of seminal and vaginal fluids that faithfully mimic genuine fluids to assess the contribution of individual components within these fluids to filamentation. The high levels of albumin, amino acids, and N-acetylglucosamine in seminal fluid act synergistically as potent inducers of filamentous growth, even at atmospheric levels of CO2 and reduced temperatures (30 degrees C). Using a simplified in vitro model that mimics the natural introduction of seminal fluid into the vulvovaginal environment, a pulse of artificial seminal fluid (ASF) was found to exert an enduring potential to overcome the inhibitory efficacy of artificial vaginal fluid (AVF) on filamentation. These findings suggest that a transient but substantial change in the nutrient levels within the vulvovaginal environment during unprotected coitus can induce resident C. albicans cells to engage developmental programs associated with virulent growth.

  • 43. Alvarez-Crespo, Mayte
    et al.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Martinez-Sanchez, Noelia
    Dieguez, Carlos
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lopez, Miguel
    Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance2016Inngår i: Molecular metabolism, ISSN 2212-8778, Vol. 5, nr 4, s. 271-282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Classically, metabolic effects of thyroid hormones (THs) have been considered to be peripherally mediated, i.e. different tissues in the body respond directly to thyroid hormones with an increased metabolism. An alternative view is that the metabolic effects are centrally regulated. We have examined here the degree to which prolonged, centrally infused triiodothyronine (T3) could in itself induce total body metabolic effects and the degree to which brown adipose tissue (BAT) thermogenesis was essential for such effects, by examining uncoupling protein 1 (UCP1) KO mice. Methods: Wildtype and UPC1 KO mice were centrally-treated with T3 by using minipumps. Metabolic measurements were analyzed by indirect calorimetry and expression analysis by RT-PCR or western blot. BAT morphology and histology were studied by immunohistochemistry. Results: We found that central T3-treatment led to reduced levels of hypothalamic AMP-activated protein kinase (AMPK) and elevated body temperature (0.7 degrees C). UCP1 was essential for the T3-induced increased rate of energy expenditure, which was only observable at thermoneutrality and notably only during the active phase, for the increased body weight loss, for the increased hypothalamic levels of neuropeptide Y (NPY) and agouti-related peptide (AgRP) and for the increased food intake induced by central T3-treatment. Prolonged central T3-treatment also led to recruitment of BAT and britening/beiging (browning) of inguinal white adipose tissue (iWAT). Conclusions: We conclude that UCP1 is essential for mediation of the central effects of thyroid hormones on energy balance, and we suggest that similar UCP1-dependent effects may underlie central energy balance effects of other agents.

  • 44. Amin, Fatin Aina Zulkhairi
    et al.
    Cheng, Mohamad Zulhafiz Shafiq
    Sabri, Suriana
    Ismail, Norsharina
    Chan, Kim Wei
    Esa, Norhaizan Mohd
    Lila, Mohd Azmi Mohd
    Nur-Fazila, Saulol Hamid
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    El-Seedi, Hesham R.
    Zawawi, Norhasnida
    In Vivo Toxicity Assessment of the Probiotic Bacillus amyloliquefaciens HTI-19 Isolated from Stingless Bee (Heterotrigona itama) Honey2023Inngår i: Nutrients, E-ISSN 2072-6643, Vol. 15, nr 10, artikkel-id 2390Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study evaluated the acute and sub-acute toxicity of B. amyloliquefaciens HTI-19 (isolated from stingless bee honey) in female Sprague Dawley rats. In an acute toxicity study, the rats received a low dosage (1 x 109 CFU center dot mL 1), medium dosage (3 x 10(9) CFU center dot mL(-1)), or high dosage (1 x 10(10) CFU center dot mL(-1)) of B. amyloliquefaciens HTI-19 daily orally by syringe-feeding for 14 days. For the subacute toxicity study, rats received a low dosage (1 x 10(9) CFU center dot mL(-1)) or a high dosage (1 x 10(10) CFU center dot mL(-1)) for 28 days. The probiotic feeding in acute and sub-acute toxicity studies showed no mortality or significant abnormalities in rats throughout the experimental period. In week 2 of the acute study, the body weight of the rats showed a significant increase (p < 0.05) compared to the control. By gross and microscopic examination of organs, no evidently significant changes were observed in the morphology of organs. Serum biochemical tests and blood hematology tests also revealed no treatment-related changes. Overall, these data indicated that oral administration of B. amyloliquefaciens HTI-19 up to 1 x 10(9) CFU center dot mL(-1) for 28 days can be considered safe.

  • 45. Amoako-Sakyi, Daniel
    et al.
    Adukpo, Selorme
    Kusi, Kwadwo A.
    Dodoo, Daniel
    Ofori, Michael F.
    Adjei, George O.
    Edoh, Dominic E.
    Asmah, Richard H.
    Brown, Charles
    Adu, Bright
    Obiri-Yeboah, Dorcas
    Futagbi, Godfred
    Abubakari, Sharif Buari
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Akanmori, Bartholomew D.
    Goka, Bamenla Q.
    Arko-Mensah, John
    Gyan, Ben A.
    A STAT6 Intronic Single-Nucleotide Polymorphism is Associated with Clinical Malaria in Ghanaian Children2016Inngår i: Genetics and Epigenetics, ISSN 1179-237X, Vol. 8, s. 7-14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Malaria pathogenesis may be influenced by IgE responses and cytokine cross-regulation. Several mutations in the IL-4/STAT6 signaling pathway can alter cytokine cross-regulation and IgE responses during a Plasmodium falciparum malarial infection. This study investigated the relationship between a STAT6 intronic single-nucleotide polymorphism (rs3024974), total IgE, cytokines, and malaria severity in 238 Ghanaian children aged between 0.5 and 13 years. Total IgE and cytokine levels were measured by ELISA, while genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (RFLP). Compared with healthy controls, heterozygosity protected against clinical malaria: uncomplicated malaria (odds ratios [OR] = 0.13, P < 0.001), severe malarial anemia (OR = 0.18, P, 0.001), and cerebral malaria (OR = 0.39, P = 0.022). Levels of total IgE significantly differed among malaria phenotypes (P = 0.044) and rs3024974 genotypes (P = 0.037). Neither cytokine levels nor IL-6/IL-10 ratios were associated with malaria phenotypes or rs3024974 genotypes. This study suggests a role for rs3024974 in malaria pathogenesis and offers further insights into an IL-4/STAT6 pathway mutation in malaria pathogenesis.

  • 46. Amr, Alaa
    et al.
    Abd El-Wahed, Aida
    El-Seedi, Hesham R.
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Augustyniak, Maria
    El-Samad, Lamia M.
    Abdel Karim, Ahmed E.
    El Wakil, Abeer
    UPLC-MS/MS Analysis of Naturally Derived Apis mellifera Products and Their Promising Effects against Cadmium-Induced Adverse Effects in Female Rats2023Inngår i: Nutrients, E-ISSN 2072-6643, Vol. 15, nr 1, artikkel-id 119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Honeybee products arouse interest in society due to their natural origin and range of important biological properties. Propolis (P) and royal jelly (RJ) attract scientists’ attention because they exhibit antioxidant, anti-inflammatory, anti-bacterial, anti-tumor, and immunomodulatory abilities. In this study, we tested whether P and RJ could mitigate the adverse effects of cadmium (Cd) exposure, with particular emphasis on the reproductive function in female rats. In this line, one week of pretreatment was established. Six experimental groups were created, including (i) the control group (without any supplementation), (ii) the Cd group (receiving CdCl2 in a dose of 4.5 mg/kg/day), (iii) the P group (50 mg of P/kg/day), (iv) RJ group (200 mg of RJ/kg/day), (v) P + Cd group (rats pretreated with P and then treated with P and Cd simultaneously), (vi) RJ + Cd group (animals pretreated with RJ before receiving CdCl2 simultaneously with RJ). Cd treatment of rats adversely affected a number of measured parameters, including body weight, ovarian structure and ultrastructure, oxidative stress parameters, increased ovarian Cd content and prolonged the estrous cycle. Pretreatment and then cotreatment with P or RJ and Cd alleviated the adverse effects of Cd, transferring the clusters in the PCA analysis chart toward the control group. However, clusters for cotreated groups were still distinctly separated from the control and P, or RJ alone treated groups. Most likely, investigated honeybee products can alter Cd absorption in the gut and/or increase its excretion through the kidneys and/or mitigate oxidative stress by various components. Undoubtedly, pretreatment with P or RJ can effectively prepare the organism to overcome harmful insults. Although the chemical composition of RJ and P is relatively well known, focusing on proportion, duration, and scheme of treatment, as well as the effects of particular components, may provide interesting data in the future. In the era of returning to natural products, both P and RJ seem valuable materials for further consideration as anti-infertility agents.

  • 47. Anantharaman, Aparna
    et al.
    Tripathi, Vidisha
    Khan, Abid
    Yoon, Je-Hyun
    Singh, Deepak K.
    Gholamalamdari, Omid
    Guang, Shuomeng
    Ohlson, Johan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wahlstedt, Helene
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Öhman, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jantsch, Michael F.
    Conrad, Nicholas K.
    Ma, Jian
    Gorospe, Myriam
    Prasanth, Supriya G.
    Prasanth, Kannanganattu V.
    ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins2017Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, nr 7, s. 4189-4201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adenosine deaminases acting on RNA (ADARs) catalyze the editing of adenosine residues to inosine (A-to-I) within RNA sequences, mostly in the introns and UTRs (un-translated regions). The significance of editing within non-coding regions of RNA is poorly understood. Here, we demonstrate that association of ADAR2 with RNA stabilizes a subset of transcripts. ADAR2 interacts with and edits the 3' UTR of nuclear-retained Cat2 transcribed nuclear RNA (Ctn RNA). In absence of ADAR2, the abundance and half-life of Ctn RNA are significantly reduced. Furthermore, ADAR2-mediated stabilization of Ctn RNA occurred in an editing-independent manner. Unedited Ctn RNA shows enhanced interaction with the RNA-binding proteins HuR and PARN [Poly(A) specific ribonuclease deadenylase]. HuR and PARN destabilize Ctn RNA in absence of ADAR2, indicating that ADAR2 stabilizes Ctn RNA by antagonizing its degradation by PARN and HuR. Transcriptomic analysis identified other RNAs that are regulated by a similar mechanism. In summary, we identify a regulatory mechanism whereby ADAR2 enhances target RNA stability by limiting the interaction of RNA-destabilizing proteins with their cognate substrates.

  • 48. Anchang-Kimbi, Judith K.
    et al.
    Achidi, Eric A.
    Apinjoh, Tobias O.
    Mugri, Regina N.
    Chi, Hanesh Fru
    Tata, Rolland B.
    Nkegoum, Blaise
    Mendimi, Joseph-Marie N.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Troye Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Antenatal care visit attendance, intermittent preventive treatment during pregnancy (IPTp) and malaria parasitaemia at delivery2014Inngår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 162-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The determinants and barriers for delivery and uptake of IPTp vary with different regions in sub-Saharan Africa. This study evaluated the determinants of ANC clinic attendance and IPTp-SP uptake among parturient women from Mount Cameroon Area and hypothesized that time of first ANC clinic attendance could influence uptake of IPTp-SP/dosage and consequently malaria parasite infection status at delivery. Methods: Two cross sectional surveys were carried out at the Government Medical Centre in the Mutengene Health Area, Mt Cameroon Area from March to October 2007 and June 2008 to April 2009. Consented parturient women were consecutively enrolled in both surveys. In 2007, socio-demographic data, ANC clinic attendance, gestational age, fever history and reported use/dosage of IPTp-SP were documented using a structured questionnaire. In the second survey only IPT-SP usage/dosage was recorded. Malaria parasitaemia at delivery was determined by blood smear microscopy and placental histology. Results and discussion: In 2007, among the 287 women interviewed, 2.2%, 59.7%, and 38.1% enrolled in the first, second and third trimester respectively. About 90% of women received at least one dose SP but only 53% received the two doses in 2007 and by 2009 IPTp-two doses coverage increased to 64%. Early clinic attendance was associated (P = 0.016) with fever history while being unmarried (OR = 2.2; 95% CI: 1.3-3.8) was significantly associated with fewer clinic visits (<4visits). Women who received one SP dose (OR = 3.7; 95% CI: 2.0-6.8) were more likely not to have attended >= 4visits. A higher proportion (P < 0.001) of women with first visit during the third trimester received only one dose, meanwhile, those who had an early first ANC attendance were more likely (OR = 0.4; 95% CI = 0.2 - 0.7) to receive two or more doses. Microscopic parasitaemia at delivery was frequent (P = 0.007) among women who enrolled in the third trimester and had received only one SP dose than in those with two doses. Conclusion: In the study area, late first ANC clinic enrolment and fewer clinic visits may prevent the uptake of two SP doses and education on early and regular ANC clinic visits can increase IPTp coverage.

  • 49. Anchang-Kimbi, Judith K.
    et al.
    Achidi, Eric Akum
    Nkegoum, Blaise
    Mendimi, Joseph-Marie N.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    IgG isotypic antibodies to crude Plasmodium falciparum blood-stage antigen associated with placental malaria infection in parturient Cameroonian women2016Inngår i: African Health Sciences, ISSN 1680-6905, E-ISSN 1729-0503, Vol. 16, nr 4, s. 1007-1017Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Few studies have reported an association between placental malaria (PM) infection and levels of isotypic antibodies against non-pregnancy associated antigens. Objective: To determine and evaluate IgG isotypic antibody levels to crude P. falciparum blood stage in women with and without PM infection. Methods: Levels of IgG (IgG1-IgG4) and IgM to crude P. falciparum blood stage antigen were measured by ELISA in 271 parturient women. Placental malaria infection was determined by placental blood microscopy and placental histology. Age, parity and intermittent preventive treatment during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) usage were considered during analysis. Results: P. falciparum-specific IgG1 (96.5%) and IgG3 (96.7%) antibodies were predominant compared with IgG2 (64.6%) and IgG4 (49.1%). Active PM infection was associated with significant increased levels of IgG1, IgG4 and IgM while lower levels of these antibodies were associated with uptake of two or more IPTp-SP doses. PM infection was the only independent factor associated with IgG4 levels. Mean IgG1 + IgG3/IgG2 + IgG4 and IgG1 + IgG2 + IgG3/IgG4 ratios were higher among the PM-uninfected group while IgG4/IgG2 ratio prevailed in the infected group. Conclusion: PM infection and IPTp-SP dosage influenced P. falciparum-specific isotypic antibody responses to blood stage antigens. An increase in IgG4 levels in response to PM infection is of particular interest.

  • 50. Andreassi, Maria Grazia
    et al.
    Haddy, Nadia
    Harms-Ringdahl, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Campolo, Jonica
    Borghini, Andrea
    Chevalier, François
    Schwenk, Jochen M.
    Fresneau, Brice
    Bolle, Stephanie
    Fuentes, Manuel
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. CEA-CNRS-ENSICAEN-University of Caen Normandy, France; Advanced Resource Center for HADrontherapy in Europe (ARCHADE), France.
    A Longitudinal Study of Individual Radiation Responses in Pediatric Patients Treated with Proton and Photon Radiotherapy, and Interventional Cardiology: Rationale and Research Protocol of the HARMONIC Project2023Inngår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, nr 9, artikkel-id 8416Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy (photon and proton) in Pediatrics (HARMONIC) is a five-year project funded by the European Commission that aimed to improve the understanding of the long-term ionizing radiation (IR) risks for pediatric patients. In this paper, we provide a detailed overview of the rationale, design, and methods for the biological aspect of the project with objectives to provide a mechanistic understanding of the molecular pathways involved in the IR response and to identify potential predictive biomarkers of individual response involved in long-term health risks. Biological samples will be collected at three time points: before the first exposure, at the end of the exposure, and one year after the exposure. The average whole-body dose, the dose to the target organ, and the dose to some important out-of-field organs will be estimated. State-of-the-art analytical methods will be used to assess the levels of a set of known biomarkers and also explore high-resolution approaches of proteomics and miRNA transcriptomes to provide an integrated assessment. By using bioinformatics and systems biology, biological pathways and novel pathways involved in the response to IR exposure will be deciphered.

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