1.
Izsak, Julia, et al.
(författare)
Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function
2021
Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11
Tidskriftsartikel (refereegranskat) abstract
Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (<1 mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (>1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABAA-receptor antagonist. Patch–clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.
2.
Mohammadi, Elyas, et al.
(författare)
Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning
2020
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:9, s. 1-24
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.
3.
Altay, Özlem, et al.
(författare)
Current Status of COVID-19 Therapies and Drug Repositioning Applications
2020
Ingår i: Iscience. - : Elsevier BV. - 2589-0042. ; 23:7
Tidskriftsartikel (refereegranskat) abstract
The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2.
4.
Engdahl, Elin, et al.
(författare)
Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)
2021
Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:11
Tidskriftsartikel (refereegranskat) 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.
5.
Albofetileh, Mehdi, et al.
(författare)
Seaweed Proteins as a Source of Bioactive Peptides
2021
Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 27:11, s. 1342 -1352
Forskningsöversikt (refereegranskat) 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.
6.
Mitra, Sanhita, et al.
(författare)
Subcellular distribution of p53 by the p53-responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma.
2021
Ingår i: Cancer research. - 1538-7445. ; 81:6, s. 1457-1471
Tidskriftsartikel (refereegranskat) abstract
Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for high-risk neuroblastoma patients.
7.
Näslund, Jakob, et al.
(författare)
Expression of 22 serotonin-related genes in rat brain after sub-acute serotonin depletion or reuptake inhibition
2020
Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 32:3, s. 159-165
Tidskriftsartikel (refereegranskat) abstract
Objective: Although the assessment of expression of serotonin-related genes in experimental animals has become a common strategy to shed light on variations in brain serotonergic function, it remains largely unknown to what extent the manipulation of serotonin levels causes detectable changes in gene expression. We therefore chose to investigate how sub-acute depletion or elevation of brain serotonin influences the expression of a number of serotonin-related genes in six brain areas. Methods: Male Wistar rats were administered a serotonin synthesis inhibitor, para-chlorophenylalanine (p-CPA), or a serotonin reuptake inhibitor, paroxetine, for 3 days and then sacrificed. The expression of a number of serotonin-related genes in the raphe nuclei, hypothalamus, amygdala, striatum, hippocampus and prefrontal cortex was investigated using real-time quantitative PCR (rt-qPCR). Results: While most of the studied genes were uninfluenced by paroxetine treatment, we could observe a robust downregulation of tryptophan hydroxylase-2 in the brain region where the serotonergic cell bodies reside, that is, the raphe nuclei. p-CPA induced a significant increase in the expression of Htr1b and Htr2a in amygdala and of Htr2c in the striatum and a marked reduction in the expression of Htr6 in prefrontal cortex; it also enhanced the expression of the brain-derived neurotrophic factor (Bdnf) in raphe and hippocampus. Conclusion: With some notable exceptions, the expression of most of the studied genes is left unchanged by short-term modulation of extracellular levels of serotonin.
8.
Tripathi, Rekha, PhD student, 1985-
(författare)
Unlocking the Role Of Orphan Solute Carrier SLC38A10 In Brain Metabolism : The SLC38A10 transporter in nutrient and metabolic regulation
2021
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Membrane transporters are the primary gatekeepers of cells and regulate the transport of nutrients, metabolites, ions, water, and neurotransmitters into and across the human cells. The solute carrier transporters (SLCs) are the most prominent transporters, comprising 430 members divided into 65 subfamilies. SLCs are located on the plasma membrane and organelles such as mitochondria, vesicles, peroxisomes, endoplasmic reticulum, Golgi, and lysosomes. This thesis aimed to study SLCs of the SLC38 family under nutrient stress, focused particularly on the orphan SLC38A10 transporter.In Paper I, regulation of members of SLC38 family transporter, after amino acid starvation in mouse hypothalamic cells and primary cortex cells, was studied using microarrays and qPCR. We found several members of the SLC38 family that were strongly affected under amino acid starvation and showing a potential role in amino acid signaling in the brain. In Paper II, we performed a cellular and tissue localization and functional study of SLC38A10 transporter and revealed that SLC38A10 was expressed in both excitatory and inhibitory neurons in the mouse brain and has a unique subcellular localization in the ER and Golgi membrane. Furthermore, knockdown of the SLC38A10 gene resulted in reduced nascent protein synthesis in PC12 cells. Further, to unlock the biological function of the SLC38A10 transporter, in Paper III and Paper IV, we used SLC38A10 knockout mouse model.In Paper III, the goal was to uncover the role of SLC38A10 in acute glutamate and oxidative stress. Here, we found that a loss of SLC38A10 KO resulted in changes in the p53 levels and affected the mitochondrial function. Thus, this study established a possible role of SLC38A10 in cell survival, linked with p53, in mouse primary cortex cells. In Paper IV, we examined the role of SLC38A10 in amino acid metabolism and nutrient sensing in the mTOR signaling pathway. We performed complete amino acid starvation and refeed experiment on SLC38A10 knockout primary cortex cells. We concluded that SLC38A10 acts as a transceptor and regulates mTOR-dependent protein and lipid synthesis in brain cells, corroborating the findings from Paper II. To summarize, the present work has uncovered the function of SLC38A10 in the brain. It also provides knowledge of SLC38A10’s role in amino acid metabolism and signaling pathway(s). The findings of this thesis will enhance an understanding of SLC38A10 transporter and provide insight into future disease targeted drug studies focused on metabolic disorder and neurodegenerative disease.
9.
Yau, Estelle, et al.
(författare)
Global Sensitivity Analysis of the Rodgers and Rowland Model for Prediction of Tissue: Plasma Partitioning Coefficients: Assessment of the Key Physiological and Physicochemical Factors That Determine Small-Molecule Tissue Distribution
2020
Ingår i: AAPS Journal. - : Springer Nature. - 1550-7416. ; 22:2, s. 1-13
Tidskriftsartikel (refereegranskat) abstract
In physiologically based pharmacokinetic (PBPK) modelling, the large number of input parameters, limited amount of available data and the structural model complexity generally hinder simultaneous estimation of uncertain and/or unknown parameters. These parameters are generally subject to estimation. However, the approaches taken for parameter estimation vary widely. Global sensitivity analyses are proposed as a method to systematically determine the most influential parameters that can be subject to estimation. Herein, a global sensitivity analysis was conducted to identify the key drug and physiological parameters influencing drug disposition in PBPK models and to potentially reduce the PBPK model dimensionality. The impact of these parameters was evaluated on the tissue-to-unbound plasma partition coefficients (Kpus) predicted by the Rodgers and Rowland model using Latin hypercube sampling combined to partial rank correlation coefficients (PRCC). For most drug classes, PRCC showed that LogP and fraction unbound in plasma (fup) were generally the most influential parameters for Kpu predictions. For strong bases, blood:plasma partitioning was one of the most influential parameter. Uncertainty in tissue composition parameters had a large impact on Kpu and Vss predictions for all classes. Among tissue composition parameters, changes in Kpu outputs were especially attributed to changes in tissue acidic phospholipid concentrations and extracellular protein tissue:plasma ratio values. In conclusion, this work demonstrates that for parameter estimation involving PBPK models and dimensionality reduction purposes, less influential parameters might be assigned fixed values depending on the parameter space, while influential parameters could be subject to parameters estimation.
10.
Al-Adwani, S, et al.
(författare)
Studies on citrullinated LL-37: detection in human airways, antibacterial effects and biophysical properties
2020
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 2376-
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.
