| 1. |
- Mohammadi, Elyas, et al.
(författare)
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Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:9, s. 1-24
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Forskningsöversikt (refereegranskat)abstract
- Simple Summary Drug repurposing is an accelerated route for drug development and a promising approach for finding medications for orphan and common diseases. Here, we compiled databases that comprise both computationally- or experimentally-derived data, and categorized them based on quiddity and origin of data, further focusing on those that present high throughput omic data or drug screens. These databases were then contextualized with genome-wide screening methods such as CRISPR/Cas9 and RNA interference, as well as state of art systems biology approaches that enable systematic characterizations of multi-omic data to find new indications for approved drugs or those that reached the latest phases of clinical trials. Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug-target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches.
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| 2. |
- Zhang, C., et al.
(författare)
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The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease
- 2020
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 16:4
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.
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| 3. |
- Bjerkeli, Pernilla J., et al.
(författare)
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Overuse of methylphenidate : an analysis of Swedish pharmacy dispensing data
- 2018
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Ingår i: Clinical Epidemiology. - : Dove Press. - 1179-1349. ; 10, s. 1657-1665
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To identify overuse of methylphenidate and to investigate patterns of overuse in relation to sociodemographic and clinical characteristics. Patients and methods: Swedish national, pharmacy dispensing data were analyzed for all 56,922 individuals aged 6-79 years, who filled a methylphenidate prescription between 2010 and 2011. Overuse was defined as having above 150% days covered by the dispensed amount during 365 days from the first prescription fill, assuming use at the maximum recommended daily dose. Results: In total, 4,304 individuals (7.6% of the methylphenidate users) were categorized as overusers. The risk of overuse increased with age (OR for 46-65 years vs 6-12 years 17.5, 95% CI 14.3-21.3), and was higher in men (OR 1.4, 95% CI 1.3-1.5) and individuals with low income (OR 1.1, 95% CI 1.0-1.2), as well as in individuals with an attention deficit hyperactivity disorder (ADHD) diagnosis (OR 1.4, 95% CI 1.3-1.6), health care visits (OR 1.3, 95% CI 1.2-1.4), previous ADHD medication use (OR 2.6, 95% CI 2.4-2.8), and previous diagnosis of mental and behavioral disorders due to psychoactive substance use (OR 2.1 95% CI 2.0-2.3). Conclusion: Among individuals using methylphenidate in Sweden, 7.6% receive amounts that are larger than what they should have a medical need for, assuming that they were using the maximum recommended daily dose 365 days per year. Notably, the prevalence of overuse was associated with previous diagnosis of alcohol and drug misuse. The prevalence was also positively associated with higher age and previous use of ADHD medication. These findings may point toward a link between exposure time and overuse. However, future studies with long-term data are needed to investigate this.
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| 4. |
- Borg, D., et al.
(författare)
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Tissue distribution of S-35-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure
- 2010
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 30:4, s. 558-565
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Tidskriftsartikel (refereegranskat)abstract
- Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to S-35-PFOS (12 5 mg/kg) we determined the distribution in dams fetuses (GD18 and GD20) and pups (postnatal day 1 PND1) employing whole-body autoradiography and liquid scintillation counting In dams levels were highest in liver and lungs After placental transfer S-35-PFOS was present on GD18 at 2-3 times higher levels in lungs liver and kidneys than in maternal blood In PND1 pups levels in lungs were significantly higher than in GD18 fetuses A heterogeneous distribution of S-35-PFOS was observed in brains of fetuses and pups with levels higher than in maternal brain This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.
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| 5. |
- Hendriks, Hester S., et al.
(författare)
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PCB-47, PBDE-47, and 6-OH-PBDE-47 Differentially Modulate Human GABA(A) and alpha(4)beta(2) Nicotinic Acetylcholine Receptors
- 2010
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 118:2, s. 635-642
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Tidskriftsartikel (refereegranskat)abstract
- Polychlorinated biphenyls (PCBs) and the structurally related polybrominated diphenyl ethers (PBDEs) are abundant persistent organic pollutants that exert several comparable neurotoxic effects. Importantly, hydroxylated metabolites of PCBs and PBDEs have an increased neurotoxic potency. Recently, we demonstrated that PCBs can act as (partial) agonist on GABA(A) neurotransmitter receptors, with PCB-47 being the most potent congener. It is, however, unknown whether PBDE-47 and its metabolite 6-OH-PBDE-47 exert similar effects and if these effects are limited to GABA(A) receptors only. We therefore investigated effects of PCB-47, PBDE-47, and 6-OH-PBDE-47 on the inhibitory GABA(A) and excitatory alpha(4)beta(2) nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Since human exposure is generally not limited to individual compounds, experiments with binary mixtures were also performed. The results demonstrate that PCB-47 and 6-OH-PBDE-47 act as full and partial agonist on the GABA(A) receptor. However, both congeners act as antagonist on the nACh receptor. PBDE-47 does not affect either type of receptor. Binary mixtures of PCB-47 and 6-OH-PBDE-47 induced an additive activation as well as potentiation of GABA(A) receptors, whereas this mixture resulted in an additive inhibition of nACh receptors. Binary mixtures of PBDE-47 and 6-OH-PBDE-47 yielded similar effects as 6-OH-PBDE-47 alone. These findings demonstrate that GABA(A) and nACh receptors are affected differently by PCB-47 and 6-OH-PBDE-47, with inhibitory GABA(A)-mediated signaling being potentiated and excitatory alpha(4)beta(2) nACh-mediated signaling being inhibited. Considering these opposite actions and the additive interaction of the congeners, these effects are likely to be augmented in vivo.
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| 6. |
- Högberg, Helena, 1975-
(författare)
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Developmental Neurotoxicity Testing Using In vitro Approaches
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is a great concern about children’s health as the developing brain in foetuses and children is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that the adult brain is well protected against chemicals by the blood brain barrier (BBB) and children have increased absorption rates and diminished ability to detoxify many exogenous compounds, in comparison to that of adults. Moreover, the development of the central nervous system (CNS) is a very complex process involving several different important events, e.g. proliferation, migration and differentiation of cells. These events are occurring within a strictly controlled time frame and therefore create different windows of vulnerability. Furthermore, the brain consists of numerous different cell types (neuronal, glial and endothelial cells) that have specific functions. The development of each cell type occurs within a specific time window and is therefore susceptible to environmental disturbances at different time periods. Evidence indicates that exposure to industrial chemicals, pesticides or drugs, contributes to the increasing incidence of neurodevelopment disorders. However, due to lack of studies only a few industrial chemicals have been identified as developmental neurotoxicants so far. The current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and US EPA 712-C-98-239) are based entirely on in vivo studies that are time consuming, complex, costly and not suitable for the testing of a high number of chemicals. Applying alternative approaches such as in silico, in vitro and non-mammalian models as a part of an integrated test strategy, could speed up the process of DNT evaluation and reduce and refine animal usage. Both in vitro and non-mammalian test systems offer the possibility of providing an early screening for a large number of chemicals, and could be particularly useful in characterising the compound-induced mechanism of toxicity of various developmental processes. This thesis has characterised two primary neuronal cultures (cerebellar granule cells (CGCs) and cortical neuronal cultures) and identified them as relevant models for DNT testing, since the key processes of brain development are present, such as cell proliferation, migration and neuronal/glial differentiation. Furthermore, two emerging technologies (gene expression and electrical activity) have been evaluated and were identified as promising tools for in vitro DNT assessment. In combination with other assays they could be included into a DNT intelligent testing strategy to speed up the process of DNT evaluation mainly by prioritising chemicals with DNT potential for further testing.
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| 7. |
- Al-Adwani, S, et al.
(författare)
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Studies on citrullinated LL-37: detection in human airways, antibacterial effects and biophysical properties
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 2376-
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Rehling, Daniel, et al.
(författare)
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Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity
- 2021
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 296
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Tidskriftsartikel (refereegranskat)abstract
- The enzyme NUDT15 efficiently hydrolyzes the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and preemptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants because of their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared with TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile, and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic.
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| 9. |
- Wastesson, Jonas W., et al.
(författare)
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Trends in Use of Paracetamol in the Nordic Countries
- 2018
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 123:3, s. 301-307
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol (acetaminophen) is one of the most commonly used analgesics in Europe; however, both the safety and efficacy of paracetamol have recently been questioned. Little is known about cross-national differences in the sales of paracetamol. Using national wholesale statistics and nationwide prescription drug registers, we investigated trends in total and prescribed use of paracetamol in the Nordic countries. The total sales of paracetamol (Anatomical Therapeutic Chemical (ATC) classification system code: N02BE01) measured as defined daily doses (DDD) per 1000 inhabitants/day, and the sales by prescription (users per 1000 inhabitants/year), increased in the Nordic countries from 2000 to 2015. The total sales were highest in Denmark throughout the period, with 65 DDD per 1000 inhabitants/day and lowest in Iceland with 30 DDD per 1000 inhabitants/day in 2015. The cross-national difference in total sales of paracetamol was smaller in 2015 than in 2000. The proportion of paracetamol (DDD per 1000 inhabitants/day) sold by prescription was also highest in Denmark (78%), compared with 75% in Finland, 69% in Sweden, 61% in Norway and 38% in Iceland. Paracetamol by prescription was more common at older ages and among women. Total and prescribed sales of paracetamol have increased in all five Nordic countries over time. Cross-national differences exist, with highest sales per capita in Denmark throughout the period.
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| 10. |
- Miller, Frank, et al.
(författare)
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A decision theoretical modeling for Phase III investments and drug licensing
- 2018
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Ingår i: Journal of Biopharmaceutical Statistics. - : Informa UK Limited. - 1054-3406 .- 1520-5711. ; 28:4, s. 698-721
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Tidskriftsartikel (refereegranskat)abstract
- For a new candidate drug to become an approved medicine, several decision points have to be passed. In this article, we focus on two of them: First, based on Phase II data, the commercial sponsor decides to invest (or not) in Phase III. Second, based on the outcome of Phase III, the regulator determines whether the drug should be granted market access. Assuming a population of candidate drugs with a distribution of true efficacy, we optimize the two stakeholders' decisions and study the interdependence between them. The regulator is assumed to seek to optimize the total public health benefit resulting from the efficacy of the drug and a safety penalty. In optimizing the regulatory rules, in terms of minimal required sample size and the Type I error in Phase III, we have to consider how these rules will modify the commercial optimization made by the sponsor. The results indicate that different Type I errors should be used depending on the rarity of the disease.
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