| 11. |
- Al-Adwani, S, et al.
(author)
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Studies on citrullinated LL-37: detection in human airways, antibacterial effects and biophysical properties
- 2020
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 2376-
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Journal article (peer-reviewed)abstract
- Arginine residues of the antimicrobial peptide LL-37 can be citrullinated by peptidyl arginine deiminases, which reduce the positive charge of the peptide. Notably, citrullinated LL-37 has not yet been detected in human samples. In addition, functional and biophysical properties of citrullinated LL-37 are not fully explored. The aim of this study was to detect citrullinated LL-37 in human bronchoalveolar lavage (BAL) fluid and to determine antibacterial and biophysical properties of citrullinated LL-37. BAL fluid was obtained from healthy human volunteers after intra-bronchial exposure to lipopolysaccharide. Synthetic peptides were used for bacterial killing assays, transmission electron microscopy, isothermal titration calorimetry, mass-spectrometry and circular dichroism. Using targeted proteomics, we were able to detect both native and citrullinated LL-37 in BAL fluid. The citrullinated peptide did not kill Escherichia coli nor lysed human red blood cells. Both peptides had similar α-helical secondary structures but citrullinated LL-37 was more stable at higher temperatures, as shown by circular dichroism. In conclusion, citrullinated LL-37 is present in the human airways and citrullination impaired bacterial killing, indicating that a net positive charge is important for antibacterial and membrane lysing effects. It is possible that citrullination serves as a homeostatic regulator of AMP-function by alteration of key functions.
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| 12. |
- Forslund, Sofia K., et al.
(author)
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Combinatorial, additive and dose-dependent drug–microbiome associations
- 2021
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505
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Journal article (peer-reviewed)abstract
- During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
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| 13. |
- Engdahl, Elin, et al.
(author)
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Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)
- 2021
-
In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:11
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Journal article (peer-reviewed)abstract
- The breast cancer resistance protein (BCRP) is an important efflux transporter in the blood-brain barrier (BBB), protecting the brain from a wide range of substances. In this study, we investigated if BCRP function is affected by bisphenol A (BPA), a high production volume chemical used in common consumer products, as well as by bisphenol F (BPF) and bisphenol S (BPS), which are used to substitute BPA. We employed a transwell-based in vitro cell model of iPSC-derived brain microvascular endothelial cells, where BCRP function was assessed by measuring the intracellular accumulation of its substrate Hoechst 33342. Additionally, we used in silico modelling to predict if the bisphenols could directly interact with BCRP. Our results showed that BPA significantly inhibits the transport function of BCRP. Additionally, BPA was predicted to bind to the cavity that is targeted by known BCRP inhibitors. Taken together, our findings demonstrate that BPA inhibits BCRP function in vitro, probably by direct interaction with the transporter. This effect might contribute to BPA's known impact on neurodevelopment.
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| 14. |
- Rao, Komal Umashankar, et al.
(author)
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A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy
- 2021
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Journal article (peer-reviewed)abstract
- Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.
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| 15. |
- Björnsson, Bergthor, et al.
(author)
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Digital twins to personalize medicine
- 2020
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In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 12:1
-
Research review (peer-reviewed)abstract
- Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.
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| 16. |
- Khoomrung, Sakda, 1978, et al.
(author)
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Metabolic Profiling and Compound-Class Identification Reveal Alterations in Serum Triglyceride Levels in Mice Immunized with Human Vaccine Adjuvant Alum
- 2020
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3907 .- 1535-3893. ; 19:1, s. 269-278
-
Journal article (peer-reviewed)abstract
- Alum has been widely used as an adjuvant for human vaccines; however, the impact of Alum on host metabolism remains largely unknown. Herein, we applied mass spectrometry (MS) (liquid chromatography-MS)-based metabolic and lipid profiling to monitor the effects of the Alum adjuvant on mouse serum at 6, 24, 72, and 168 h post-vaccination. We propose a new strategy termed subclass identification and annotation for metabolomics for class-wise identification of untargeted metabolomics data generated from high-resolution MS. Using this approach, we identified and validated the levels of several lipids in mouse serum that were significantly altered following Alum administration. These lipids showed a biphasic response even 168 h after vaccination. The majority of the lipids were triglycerides (TAGs), where TAGs with long-chain unsaturated fatty acids (FAs) decreased at 24 h and TAGs with short-chain FAs decreased at 168 h. To our knowledge, this is the first report on the impact of human vaccine adjuvant Alum on the host metabolome, which may provide new insights into the mechanism of action of Alum. ©
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| 17. |
- Insulander Björk, Klara, 1982, et al.
(author)
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Experimental determination of concentration factors of Mn, Zn and I in the phytoplankton species Phaeodactylum Tricornutum
- 2023
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In: Journal of Environmental Radioactivity. - : Elsevier BV. - 0265-931X .- 1879-1700. ; 261
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Journal article (peer-reviewed)abstract
- Anthropogenic radionuclides released into the environment cause a radiation dose to wildlife and humans which must be quantified, both to assess the effect of normal releases, and to predict the consequences of a larger, unplanned release. To estimate the spread of the radioactive elements, the ecosystem around release points is modelled, and element uptake is usually quantified by concentration factors (CF), which relates the concentration of an element in an organism to the concentration of the same element in a medium under equilibrium conditions. In this work, we experimentally determine some phytoplankton CF that are needed for improved modelling of the marine ecosystems around nuclear facilities and release points. CFs that require better determination have been identified through literature search. Sensitivity studies, using the currently used ecosystem modelling software PREDO, show that for most studied groups, the dose committed by the respective radionuclides is almost proportional to the corresponding phytoplankton CFs. In the present work, CFs are determined through laboratory experiments with cultured phytoplankton and radionuclides of the concerned elements, assessing the element uptake by the phytoplankton through detection of the emitted radiation. The three CF assessed in this work were those for manganese, zinc and iodine in phytoplankton. Conservative estimates of these CF based on the present data are 40 000 L/kg for manganese, 50 000 L/kg for zinc and 180 L/kg for iodine with the phytoplankton masses referring to their dry weight.
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| 18. |
- Albofetileh, Mehdi, et al.
(author)
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Seaweed Proteins as a Source of Bioactive Peptides
- 2021
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In: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 27:11, s. 1342 -1352
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Research review (peer-reviewed)abstract
- Seaweeds have gained great attention as a vegetarian and sustainable marine source of protein which do not need irrigation, arable land and fertilization. Besides, seaweeds are considered as an untapped resource for discovering bioactive compounds with health benefits where bioactive peptides have shown outstanding potential. This review provides a detailed overview of available scientific knowledge on production methods, bioactivity and application of peptides from seaweed proteins. The emphasize is on the effects form seaweed varieties and peptide production condition on the bioactivity of the peptides and their potential health benefits. Bioactive properties of seaweed peptides including antioxidant, antihypertensive, antidiabetic, anti-inflammatory, anticancer activities and other potential health benefits have been discussed. It also covers current challenges and required future research and innovations for the successful application of seaweeds proteins as a sustainable source of bioactive peptides. Effects from seasonal variation of seaweed composition on the bioactivity of their peptides, difficulties in the extraction of proteins from seaweed complex structure, scalability and reproducibility of the developed methods for the production of bioactive peptides, the safety of the peptides are examples of highlighted challenges. Further studies on the bioavailability of the seaweed bioactive peptides and validation of the results in animal models and human trials are needed before their application as functional foods or pharmaceutical ingredients.
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| 19. |
- Asghar, Afshan, et al.
(author)
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"Ficus johannis Boiss. leaves ethanolic extract ameliorate streptozotocin-induced diabetes in rats by upregulating the expressions of GCK, GLUT4, and IGF and downregulating G6P"
- 2023
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In: Environmental Science and Pollution Research. - : Springer Nature. - 0944-1344 .- 1614-7499. ; 30:17, s. 49108-49124
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Journal article (peer-reviewed)abstract
- The leaves of Ficus johannis Boiss (F. johannis), commonly known as Fig tree, Anjir, and Teen, are used by the folk medicinal practitioners in Iran for controlling hyperglycemia in diabetic patients. This study investigated the pharmacological basis for antidiabetic effect of the ethanolic extract of F. johannis leaves using in vitro and in vivo experimental models. Qualitative screening of phytochemicals, estimation of total phenolic and flavonoid contents, and in vitro antioxidant and α-amylase inhibition assays were performed. Moreover, the High-performance liquid chromatography (HPLC) quantification, acute toxicity, glucose tolerance, and in vivo antidiabetic effect along with the evaluation of gene expressions involved in diabetes mellitus were carried out. Significant quantities of phenolic (71.208 ± 2.89 mgg−1 GAE) and flavonoid (26.38 ± 3.53 mgg−1 QE) were present. Inhibitory concentration (IC50) of the plant extract exhibited an excellent in vitro antioxidant (IC50 = 33.81 µg/mL) and α-amylase (IC50 = 12.18 µg/mL) inhibitory potential. The HPLC analysis confirmed the gallic acid (257.79 mgg−1) as main constituent of the extract followed by kaempferol (22.86 mgg−1), myricetin (0.16 mgg−1), and quercetin (3.22 mgg−1). Ethanolic extract displayed glucose tolerance in normo-glycemic rats. Streptozotocin-induced hyperglycemia declined dose dependently in the extract treated rats with improvement in lipid profile and liver and renal function biomarkers. The F. johannis-treated groups showed an increase in mRNA expressions of glucose transporter 4 (GLUT-4), glucokinase, insulin growth like factor 1 and peroxisomal proliferator activating receptor gamma in pancreas. However, the Glucose-6-phosphatase was downregulated. Present study suggests that the ethanolic extract of F. johannis leaves demonstrates a good anti-diabetic profile by improving insulin sensitivity, GLUT-4 translocation, and carbohydrate metabolism while inhibiting lipogenesis.
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| 20. |
- Becattini, Barbara, et al.
(author)
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Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect.
- 2024
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In: Cell reports. - 2211-1247. ; 43:5
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Journal article (peer-reviewed)abstract
- Insulin-PI3K signaling controls insulin secretion. Understanding this feedback mechanism is crucial for comprehending how insulin functions. However, the role of adipocyte insulin-PI3K signaling in controlling insulin secretion invivo remains unclear. Using adipocyte-specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we show that PI3Kα and PI3Kβ activities are functionally redundant in adipocyte insulin signaling. PI3Kβ-selective inhibitors have no effect on adipocyte AKT phosphorylation in control mice but blunt it in adipocytes of PI3KαAdQ mice, demonstrating adipocyte-selective pharmacological PI3K inhibition in the latter. Acute adipocyte-selective PI3K inhibition increases serum free fatty acid (FFA) and potently induces insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect operates in fasted mice with increasing FFA and decreasing glycemia, indicating that it is not primarily a control system for blood glucose. This feedback control system defines the rates of adipose tissue lipolysis and chiefly controls basal insulin secretion during fasting.
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