Publications by authors named "Ruchi Bansal"

77 Publications

Metal tolerance in plants: Molecular and physicochemical interface determines the "not so heavy effect" of heavy metals.

Chemosphere 2021 Aug 20;287(Pt 1):131957. Epub 2021 Aug 20.

Centre for Environment Science and Climate Resilient Agriculture, ICAR-Indian Agricultural Research Institute, New Delhi, 110 012, India. Electronic address:

An increase in technological interventions and ruthless urbanization in the name of development has deteriorated our environment over time and caused the buildup of heavy metals (HMs) in the soil and water resources. These heavy metals are gaining increased access into our food chain through the plant and/or animal-based products, to adversely impact human health. The issue of how to restrict the entry of HMs or modulate their response in event of their ingress into the plant system is worrisome. The current knowledge on the interactive-regulatory role and contribution of different physical, biophysical, biochemical, physiological, and molecular factors that determine the heavy metal availability-uptake-partitioning dynamics in the soil-plant-environment needs to be updated. The present review critically analyses the interactive overlaps between different adaptation and tolerance strategies that may be causally related to their cellular localization, conjugation and homeostasis, a relative affinity for the transporters, rhizosphere modifications, activation of efflux pumps and vacuolar sequestration that singly or collectively determine a plant's response to HM stress. Recently postulated role of gaseous pollutants such as SO and other secondary metabolites in heavy metal tolerance, which may be regulated at the whole plant and/or tissue/cell is discussed to delineate and work towards a "not so heavy" response of plants to heavy metals present in the contaminated soils.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131957DOI Listing
August 2021

Growth and Antioxidant Responses in Iron-Biofortified Lentil under Cadmium Stress.

Toxics 2021 Jul 31;9(8). Epub 2021 Jul 31.

The UWA Institute of Agriculture, The University of Western Australia, Perth, WA 6001, Australia.

Cadmium (Cd) is a hazardous heavy metal, toxic to our ecosystem even at low concentrations. Cd stress negatively affects plant growth and development by triggering oxidative stress. Limited information is available on the role of iron (Fe) in ameliorating Cd stress tolerance in legumes. This study assessed the effect of Cd stress in two lentil ( Medik.) varieties differing in seed Fe concentration (L4717 (Fe-biofortified) and JL3) under controlled conditions. Six biochemical traits, five growth parameters, and Cd uptake were recorded at the seedling stage (21 days after sowing) in the studied genotypes grown under controlled conditions at two levels (100 μM and 200 μM) of cadmium chloride (CdCl). The studied traits revealed significant genotype, treatment, and genotype × treatment interactions. Cd-induced oxidative damage led to the accumulation of hydrogen peroxide (HO) and malondialdehyde in both genotypes. JL3 accumulated 77.1% more HO and 75% more lipid peroxidation products than L4717 at the high Cd level. Antioxidant enzyme activities increased in response to Cd stress, with significant genotype, treatment, and genotype × treatment interactions ( < 0.01). L4717 had remarkably higher catalase (40.5%), peroxidase (43.9%), superoxide dismutase (31.7%), and glutathione reductase (47.3%) activities than JL3 under high Cd conditions. In addition, L4717 sustained better growth in terms of fresh weight and dry weight than JL3 under stress. JL3 exhibited high Cd uptake (14.87 mg g fresh weight) compared to L4717 (7.32 mg g fresh weight). The study concluded that the Fe-biofortified lentil genotype L4717 exhibited Cd tolerance by inciting an efficient antioxidative response to Cd toxicity. Further studies are required to elucidate the possibility of seed Fe content as a surrogacy trait for Cd tolerance.
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http://dx.doi.org/10.3390/toxics9080182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402566PMC
July 2021

A Review of Oxidative Stress Products and Related Genes in Early Alzheimer's Disease.

J Alzheimers Dis 2021 Aug 17. Epub 2021 Aug 17.

Department of Applied Stem Cell Technologies, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.

Oxidative stress is associated with the progression of Alzheimer's disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type 1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients.
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http://dx.doi.org/10.3233/JAD-210497DOI Listing
August 2021

cGAS-STING effectively restricts murine norovirus infection but antagonizes the antiviral action of N-terminus of RIG-I in mouse macrophages.

Gut Microbes 2021 Jan-Dec;13(1):1959839

Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.

Although cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling has been well recognized in defending DNA viruses, the role of cGAS-STING signaling in regulating infection of RNA viruses remains largely elusive. Noroviruses, as single-stranded RNA viruses, are the main causative agents of acute viral gastroenteritis worldwide. This study comprehensively investigated the role of cGAS-STING in response to murine norovirus (MNV) infection. We found that STING agonists potently inhibited MNV replication in mouse macrophages partially requiring the JAK/STAT pathway that induced transcription of interferon (IFN)-stimulated genes (ISGs). Loss- and gain-function assays revealed that both cGAS and STING were necessary for host defense against MNV propagation. Knocking out cGAS or STING in mouse macrophages led to defects in induction of antiviral ISGs upon MNV infection. Overexpression of cGAS and STING moderately increased ISG transcription but potently inhibited MNV replication in human HEK293T cells ectopically expressing the viral receptor CD300lf. This inhibitory effect was not affected by JAK inhibitor treatment or expression of different MNV viral proteins. Interestingly, STING but not cGAS interacted with mouse RIG-I, and attenuated its N-terminus-mediated anti-MNV effects. Our results implicate an essential role for mouse cGAS and STING in regulating innate immune response and defending MNV infection. This further strengthens the evidence of cGAS-STING signaling in response to RNA virus infection.
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http://dx.doi.org/10.1080/19490976.2021.1959839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344765PMC
August 2021

Genome-wide association mapping reveals key genomic regions for physiological and yield-related traits under salinity stress in wheat (Triticum aestivum L.).

Genomics 2021 Sep 19;113(5):3198-3215. Epub 2021 Jul 19.

ICAR-National Bureau of Plant Genetic Resources, Pusa Campus, New Delhi 110012, India.

A genome-wide association study (GWAS) was conducted using six different multi-locus GWAS models and 35K SNP array to demarcate genomic regions underlying reproductive stage salinity tolerance. Marker-trait association analysis was performed for salt tolerance indices (STI) of 11 morpho-physiological traits, and the actual concentrations of Na and K, and the Na/K ratio in flag leaf. A total of 293 significantly associated quantitative trait nucleotides (QTNs) for 14 morpho-physiological traits were identified. Of these 293 QTNs, 12 major QTNs with R ≥ 10.0% were detected in three or more GWAS models. Novel major QTNs were identified for plant height, number of effective tillers, biomass, grain yield, thousand grain weight, Na and K content, and the Na/K ratio in flag leaf. Moreover, 48 candidate genes were identified from the associated genomic regions. The QTNs identified in this study could potentially be targeted for improving salinity tolerance in wheat.
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http://dx.doi.org/10.1016/j.ygeno.2021.07.014DOI Listing
September 2021

Genetic Dissection of Seedling Root System Architectural Traits in a Diverse Panel of Hexaploid Wheat through Multi-Locus Genome-Wide Association Mapping for Improving Drought Tolerance.

Int J Mol Sci 2021 Jul 2;22(13). Epub 2021 Jul 2.

Department of Agronomy, Kansas State University, Manhattan, KS 66506, USA.

Cultivars with efficient root systems play a major role in enhancing resource use efficiency, particularly water absorption, and thus in drought tolerance. In this study, a diverse wheat association panel of 136 wheat accessions including mini core subset was genotyped using Axiom 35k Breeders' Array to identify genomic regions associated with seedling stage root architecture and shoot traits using multi-locus genome-wide association studies (ML-GWAS). The association panel revealed a wide variation of 1.5- to 50-fold and were grouped into six clusters based on 15 traits. Six different ML-GWAS models revealed 456 significant quantitative trait nucleotides (QTNs) for various traits with phenotypic variance in the range of 0.12-38.60%. Of these, 87 QTNs were repeatedly detected by two or more models and were considered reliable genomic regions for the respective traits. Among these QTNs, eleven were associated with average diameter and nine each for second order lateral root number (SOLRN), root volume (RV) and root length density (RLD). A total of eleven genomic regions were pleiotropic and each controlled two or three traits. Some important candidate genes such as Formin homology 1, Ubiquitin-like domain superfamily and ATP-dependent 6-phosphofructokinase were identified from the associated genomic regions. The genomic regions/genes identified in this study could potentially be targeted for improving root traits and drought tolerance in wheat.
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http://dx.doi.org/10.3390/ijms22137188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268147PMC
July 2021

An N-terminal fusion allele to study melanin concentrating hormone receptor 1.

Genesis 2021 Aug 14;59(7-8):e23438. Epub 2021 Jun 14.

Department of Neuroscience and Center for Smell and Taste, University of Florida, Gainesville, Florida, USA.

Cilia on neurons play critical roles in both the development and function of the central nervous system (CNS). While it remains challenging to elucidate the precise roles for neuronal cilia, it is clear that a subset of G-protein-coupled receptors (GPCRs) preferentially localize to the cilia membrane. Further, ciliary GPCR signaling has been implicated in regulating a variety of behaviors. Melanin concentrating hormone receptor 1 (MCHR1), is a GPCR expressed centrally in rodents known to be enriched in cilia. Here we have used MCHR1 as a model ciliary GPCR to develop a strategy to fluorescently tag receptors expressed from the endogenous locus in vivo. Using CRISPR/Cas9, we inserted the coding sequence of the fluorescent protein mCherry into the N-terminus of Mchr1. Analysis of the fusion protein ( MCHR1) revealed its localization to neuronal cilia in the CNS, across multiple developmental time points and in various regions of the adult brain. Our approach simultaneously produced fortuitous in/dels altering the Mchr1 start codon resulting in a new MCHR1 knockout line. Functional studies using electrophysiology show a significant alteration of synaptic strength in MCHR1 knockout mice. A reduction in strength is also detected in mice homozygous for the mCherry insertion, suggesting that while the strategy is useful for monitoring the receptor, activity could be altered. However, both lines should aid in studies of MCHR1 function and contribute to our understanding of MCHR1 signaling in the brain. Additionally, this approach could be expanded to aid in the study of other ciliary GPCRs.
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http://dx.doi.org/10.1002/dvg.23438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376785PMC
August 2021

Versatile role of silicon in cereals: Health benefits, uptake mechanism, and evolution.

Plant Physiol Biochem 2021 Aug 28;165:173-186. Epub 2021 Apr 28.

National Agri-Food Biotechnology Institute (NABI) Mohali, Punjab, India. Electronic address:

Silicon (Si) is an omnipresent and second most abundant element in the soil lithosphere after oxygen. Silicon being a beneficial element imparts several benefits to the plants and animals. In many plant species, including the cereals the uptake of Si from the soil even exceeds the uptake of essential nutrients. Cereals are the monocots which are known to accumulate a high amount of Si, and reaping maximum benefits associated with it. Cereals contribute a high amount of Si to the human diet compared to other food crops. In the present review, we have summarized distribution of the dietary Si in cereals and its role in the animal and human health. The Si derived benefits in cereals, specifically with respect to biotic and abiotic stress tolerance has been described. We have also discussed the molecular mechanism involved in the Si uptake in cereals, evolution of the Si transport mechanism and genetic variation in the Si concentration among different cultivars of the same species. Various genetic mutants deficient in the Si uptake have been developed and many QTLs governing the Si accumulation have been identified in cereals. The existing knowledge about the Si biology and available resources needs to be explored to understand and improve the Si accumulation in crop plants to achieve sustainability in agriculture.
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http://dx.doi.org/10.1016/j.plaphy.2021.03.060DOI Listing
August 2021

Artificial Intelligence Approaches to Assessing Primary Cilia.

J Vis Exp 2021 05 1(171). Epub 2021 May 1.

Department of Biology, Indiana University-Purdue University Indianapolis; Stark Neurosciences Research Institute, Indiana University; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine;

Cilia are microtubule based cellular appendages that function as signaling centers for a diversity of signaling pathways in many mammalian cell types. Cilia length is highly conserved, tightly regulated, and varies between different cell types and tissues and has been implicated in directly impacting their signaling capacity. For example, cilia have been shown to alter their lengths in response to activation of ciliary G protein-coupled receptors. However, accurately and reproducibly measuring the lengths of numerous cilia is a time-consuming and labor-intensive procedure. Current approaches are also error and bias prone. Artificial intelligence (Ai) programs can be utilized to overcome many of these challenges due to capabilities that permit assimilation, manipulation, and optimization of extensive data sets. Here, we demonstrate that an Ai module can be trained to recognize cilia in images from both in vivo and in vitro samples. After using the trained Ai to identify cilia, we are able to design and rapidly utilize applications that analyze hundreds of cilia in a single sample for length, fluorescence intensity and co-localization. This unbiased approach increased our confidence and rigor when comparing samples from different primary neuronal preps in vitro as well as across different brain regions within an animal and between animals. Moreover, this technique can be used to reliably analyze cilia dynamics from any cell type and tissue in a high-throughput manner across multiple samples and treatment groups. Ultimately, Ai-based approaches will likely become standard as most fields move toward less biased and more reproducible approaches for image acquisition and analysis.
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http://dx.doi.org/10.3791/62521DOI Listing
May 2021

Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis.

J Control Release 2021 04 15;332:594-607. Epub 2021 Mar 15.

Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7522 NB Enschede, the Netherlands. Electronic address:

Liver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl)-induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl-induced early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating liver fibrosis.
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http://dx.doi.org/10.1016/j.jconrel.2021.03.016DOI Listing
April 2021

High Mobility Group Box 1 Release by Cholangiocytes Governs Biliary Atresia Pathogenesis and Correlates With Increases in Afflicted Infants.

Hepatology 2021 Aug;74(2):864-878

Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Background And Aims: Biliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai hepatoportoenterostomy (HPE) restores biliary drainage in a subset of patients, but most patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling that of human BA. High-mobility group box 1 (HMGB1) is an important member of the danger-associated molecular patterns capable of mediating inflammation during infection-associated responses. In this study, we investigated the role of HMGB1 in BA pathogenesis.

Approach And Results: In cholangiocytes, RRV induced the expression and release of HMGB1 through the p38 mitogen-activated protein kinase signaling pathway, and inhibition of p38 blocked HMGB1 release. Treatment of cholangiocytes with ethyl pyruvate suppressed the release of HMGB1. Administration of glycyrrhizin in vivo decreased symptoms and increased survival in the murine model of BA. HMGB1 levels were measured in serum obtained from infants with BA enrolled in the PROBE and START studies conducted by the Childhood Liver Disease Research Network. High HMGB1 levels were found in a subset of patients at the time of HPE. These patients had higher bilirubin levels 3 months post-HPE and a lower survival of their native liver at 2 years.

Conclusions: These results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1.
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http://dx.doi.org/10.1002/hep.31745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349381PMC
August 2021

Lyophilization stabilizes clinical-stage core-crosslinked polymeric micelles to overcome cold chain supply challenges.

Biotechnol J 2021 Jun 11;16(6):e2000212. Epub 2021 Feb 11.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

Background: CriPec technology enables the generation of drug-entrapped biodegradable core-crosslinked polymeric micelles (CCPM) with high drug loading capacity, tailorable size, and drug release kinetics. Docetaxel (DTX)-entrapped CCPM, also referred to as CPC634, have demonstrated favorable pharmacokinetics, tolerability, and enhanced tumor uptake in patients. Clinical efficacy evaluation is ongoing. CPC634 is currently stored (shelf life > 5 years) and shipped as a frozen aqueous dispersion at temperatures below -60°C, in order to prevent premature release of DTX and hydrolysis of the core-crosslinks. Consequently, like other aqueous nanomedicine formulations, CPC634 relies on cold chain supply, which is unfavorable for commercialization. Lyophilization can help to bypass this issue.

Methods And Results: Freeze-drying methodology for CCPM was developed by employing CPC634 as a model formulation, and sucrose and trehalose as cryoprotectants. We studied the residual moisture content and reconstitution behavior of the CPC634 freeze-dried cake, as well as the size, polydispersity index, morphology, drug retention, and release kinetics of reconstituted CPC634. Subsequently, the freeze-drying methodology was validated in an industrial setting, yielding a CPC634 freeze-dried cake with a moisture content of less than 0.1 wt%. It was found that trehalose-cryoprotected CPC634 could be rapidly reconstituted in less than 5 min at room temperature. Critical quality attributes such as size, morphology, drug retention, and release kinetics of trehalose-cryoprotected freeze-dried CPC634 upon reconstitution were identical to those of non-freeze-dried CPC634.

Conclusion: Our findings provide proof-of-concept for the lyophilization of drug-containing CCPM and our methodology is readily translatable to large-scale manufacturing for future commercialization.
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http://dx.doi.org/10.1002/biot.202000212DOI Listing
June 2021

Evolutionary Understanding of Metacaspase Genes in Cultivated and Wild Species and Its Role in Disease Resistance Mechanism in Rice.

Genes (Basel) 2020 11 26;11(12). Epub 2020 Nov 26.

National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab 140306, India.

Metacaspases (MCs), a class of cysteine-dependent proteases found in plants, fungi, and protozoa, are predominately involved in programmed cell death processes. In this study, we identified metacaspase genes in cultivated and wild rice species. Characterization of metacaspase genes identified both in cultivated subspecies of , , and and in nine wild rice species was performed. Extensive computational analysis was conducted to understand gene structures, phylogenetic relationships, -regulatory elements, expression patterns, and haplotypic variations. Further, the haplotyping study of metacaspase genes was conducted using the whole-genome resequencing data publicly available for 4726 diverse genotype and in-house resequencing data generated for north-east Indian rice lines. Sequence variations observed among wild and cultivated rice species for metacaspase genes were used to understand the duplication and neofunctionalization events. The expression profiles of metacaspase genes were analyzed using RNA-seq transcriptome profiling in rice during different developmental stages and stress conditions. Real-time quantitative PCR analysis of candidate metacaspase genes in rice cultivars Pusa Basmati-1 in response to infection indicated a significant role in the disease resistance mechanism. The information provided here will help to understand the evolution of metacaspases and their role under stress conditions in rice.
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http://dx.doi.org/10.3390/genes11121412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760854PMC
November 2020

Unexplored nutritive potential of tomato to combat global malnutrition.

Crit Rev Food Sci Nutr 2020 Oct 22:1-32. Epub 2020 Oct 22.

National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.

Tomato, a widely consumed vegetable crop, offers a real potential to combat human nutritional deficiencies. Tomatoes are rich in micronutrients and other bioactive compounds (including vitamins, carotenoids, and minerals) that are known to be essential or beneficial for human health. This review highlights the current state of the art in the molecular understanding of the nutritional aspects, conventional and molecular breeding efforts, and biofortification studies undertaken to improve the nutritional content and quality of tomato. Transcriptomics and metabolomics studies, which offer a deeper understanding of the molecular regulation of the tomato's nutrients, are discussed. The potential uses of the wastes from the tomato processing industry (i.e., the peels and seed extracts) that are particularly rich in oils and proteins are also discussed. Recent advancements with CRISPR/Cas mediated gene-editing technology provide enormous opportunities to enhance the nutritional content of agricultural produces, including tomatoes. In this regard, genome editing efforts with respect to biofortification in the tomato plant are also discussed. The recent technological advancements and knowledge gaps described herein aim to help explore the unexplored nutritional potential of the tomato.
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http://dx.doi.org/10.1080/10408398.2020.1832954DOI Listing
October 2020

Fibroblast growth factor 2 conjugated superparamagnetic iron oxide nanoparticles (FGF2-SPIONs) ameliorate hepatic stellate cells activation in vitro and acute liver injury in vivo.

J Control Release 2020 12 24;328:640-652. Epub 2020 Sep 24.

Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands. Electronic address:

Liver diseases are the growing health problem with no clinically approved therapy available. Activated hepatic stellate cells (HSCs) are the key driver cells responsible for extracellular matrix deposition, the hallmark of liver fibrosis. Fibroblast growth factor 2 (FGF2) has shown to possess anti-fibrotic effects in fibrotic diseases including liver fibosis, and promote tissue regeneration. Among the fibroblast growth factor receptors (FGFRs), FGF2 interact primarily with FGFR1, highly overexpressed on activated HSCs, and inhibit HSCs activation. However, FGF2 poses several limitations including poor systemic half-life and stability owing to enzymatic degradation. The aim of this study is to improve the stability and half-life of FGF2 thereby improving the therapuetic efficacy of FGF2 for the treatment of liver fibrosis. We found that FGFR1-3 mRNA levels were overexpressed in cirrhotic human livers, while FGFR1c, 2c, 3c, 4 and FGF2 mRNA levels were overexpressed in TGFβ-activated HSCs (LX2 cells) and FGFR1 protein expression was highly increased in TGFβ-activated HSCs. Treatment with FGF2 inhibited TGFβ-induced HSCs activation, migration and contraction in vitro. FGF2 was conjugated to superparamagnetic iron-oxide nanoparticles (SPIONs) using carbodiimide chemistry, and the resulting FGF2-SPIONs were confirmed by dynamic light scattering (DLS), zeta potential, dot-blot analysis and Prussian Blue iron-staining. In vitro, treatment with FGF2-SPIONs evidenced increased therapeutic effects (attenuated TGFβ-induced HSCs activation, migration and contraction) of FGF2 in TGFβ-activated HSCs and ameliorated early liver fibrogenesis in vivo in acute carbon tetrachloride (CCl)-induced liver injury mouse model. In contrast, free FGF2 showed no significant effects in vivo. Altogether, this study presents a promising therapeutic approach using FGF2-SPIONs for the treatment of liver fibrosis.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.041DOI Listing
December 2020

Immune Organs and Immune Cells on a Chip: An Overview of Biomedical Applications.

Micromachines (Basel) 2020 Sep 12;11(9). Epub 2020 Sep 12.

Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02139, USA.

Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune system's function and behavior in vivo. However, these conventional models do not fully emulate the complexity of the human immune system or the human in vivo microenvironment. Consequently, many promising preclinical findings have not been reproduced in human clinical trials. Organ-on-a-chip platforms can provide a solution to bridge this gap by offering human micro-(patho)physiological systems in which the immune system can be studied. This review provides an overview of the existing immune-organs-on-a-chip platforms, with a special emphasis on interorgan communication. In addition, future challenges to develop a comprehensive immune system-on-chip model are discussed.
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http://dx.doi.org/10.3390/mi11090849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570325PMC
September 2020

Editorial: Macrophages in Liver Disease.

Front Immunol 2020 4;11:1754. Epub 2020 Aug 4.

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany.

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http://dx.doi.org/10.3389/fimmu.2020.01754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417358PMC
April 2021

The hepatic lipidome: From basic science to clinical translation.

Adv Drug Deliv Rev 2020 30;159:180-197. Epub 2020 Jun 30.

Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede 7500 AE, the Netherlands. Electronic address:

The liver is the key organ involved in lipid metabolism and transport. Excessive lipid accumulation due to dysregulated lipid metabolism predisposes the liver to steatosis, cirrhosis, and hepatocellular carcinoma. Lipids are generally compartmentalized in specialized organelles called lipid droplets that enable cells to store and release lipids in a regulated manner. However, during flux-in and flux-out of droplets, lipids are converted into toxic species leading to lipid-mediated liver damage. Lipids are categorized into 'toxic' or 'healthy' lipids that are involved in liver disease pathogenesis or resolution, respectively. Lipidomic analysis have revealed unique lipid signature that correlates with the disease progression therefore being used for disease diagnosis. In this comprehensive review, we provide an overview on hepatic lipid homeostasis, lipid compartmentalization mechanisms and lipidomic profiles in different liver diseases. We further discuss promising therapeutics targeting the hepatic lipidome including pro-resolving lipids, liposomes, and small-molecule inhibitors for the treatment of liver diseases.
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http://dx.doi.org/10.1016/j.addr.2020.06.027DOI Listing
August 2021

Drought tolerance in L. genotypes associated with enhanced antioxidative protection and declined lipid peroxidation.

3 Biotech 2020 Jun 2;10(6):281. Epub 2020 Jun 2.

ICAR-National Bureau of Plant Genetic Resources, Pusa Campus, New Delhi, 110 012 India.

Drought is one of the major constraints in wheat production and causes a huge loss at grain-filling stage. In this study we highlighted the response of different wheat genotypes under drought stress at the grain-filling stage. Field experiments were conducted to evaluate 72 wheat ( L.) genotypes under two water regimes: irrigated and drought condition. Four wheat genotypes, two each of drought tolerant (IC36761A, IC128335) and drought-susceptible category (IC335732 and IC138852) were selected on the basis of agronomic traits and drought susceptibility index (DSI), to understand their morphological, biochemical and molecular basis of drought stress tolerance. Among agronomic traits, productive tillers followed by biomass had high percent reduction under drought stress, thus drought stress had a great impact. Antioxidant activity (AO), total phenolic and proline content were found to be significantly higher in IC128335 genotype. Differential expression pattern of transcription factors of ten genes revealed that transcription factor qTaWRKY2 followed by qTaDREB, qTaEXPB23 and qTaAPEX might be utilized for developing wheat varieties resistant to drought stress. Understanding the role of TFs would be helpful to decipher the molecular mechanism involved in drought stress. Identified genotypes (IC128335 and IC36761A) may be useful as parental material for future breeding program to generate new drought-tolerant varieties.
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http://dx.doi.org/10.1007/s13205-020-02264-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266904PMC
June 2020

Apoptosis-inducing peptide loaded in PLGA nanoparticles induces anti-tumor effects in vivo.

Int J Pharm 2020 Jul 10;585:119535. Epub 2020 Jun 10.

Targeted Therapeutics and Nanomedicine, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands. Electronic address:

Induction of apoptosis in tumor cells specifically within the complex tumor microenvironment is highly desirable to kill them efficiently and to enhance the effects of chemotherapy. Second mitochondria-derived activator of caspase (Smac) is a key pro-apoptotic pathway which can be activated with a Smac mimetic peptide. However, in vivo application of peptides is hampered by several limitations such as poor pharmacokinetics, rapid elimination, enzymatic degradation, and insufficient intracellular delivery. In this study, we developed a nanosystem to deliver a Smac peptide to tumor by passive targeting. We first synthesized a chimeric peptide that consists of the 8-mer Smac peptide and a 14-mer cell penetrating peptide (CPP) and then encapsulated the Smac-CPP into polymeric nanoparticles (Smac-CPP-NPs). In vitro, Smac-CPP-NPs were rapidly internalized by 4T1 mammary tumor cells and subsequently released Smac-CPP into the cells, as shown with fluorescence microscopy. Furthermore, Smac-CPP-NPs induced apoptosis in tumor cells, as confirmed with cell viability and caspase 3/7 assays. Interestingly, combination of Smac-CPP-NPs with doxorubicin (dox), a clinically used cytostatic drug, showed combined effects in vitro in 4T1 cells. The effect was significantly better than that of SMAC-CPP-NPs alone as well as empty nanoparticles and dox. In vivo, co-treatment with Smac-CPP-NPs and free dox reduced the tumor growth to 85%. Furthermore, the combination of Smac-CPP-NPs and free dox showed reduced proliferating tumor cells (Ki-67 staining) and increased apoptotic cells (cleaved caspase-3 staining) in tumors. In conclusion, the present study demonstrates that the intracellular delivery of Smac-mimetic peptide using nanoparticle system can be an interesting strategy to attenuate the tumor growth and to potentiate the therapeutic efficacy of chemotherapy in vivo.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119535DOI Listing
July 2020

Cilia signaling and obesity.

Semin Cell Dev Biol 2021 02 25;110:43-50. Epub 2020 May 25.

Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address:

An emerging number of rare genetic disorders termed ciliopathies are associated with pediatric obesity. It is becoming clear that the mechanisms associated with cilia dysfunction and obesity in these syndromes are complex. In addition to ciliopathic syndromic forms of obesity, several cilia-associated signaling gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis including their roles in centrally mediated food intake as well as in peripheral tissues, many questions remain. Here, we briefly discuss the syndromic ciliopathies and monoallelic cilia signaling gene mutations associated with obesity. We also describe potential ways cilia may be involved in common obesity. We discuss how neuronal cilia impact food intake potentially through leptin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We highlight several recent studies that have implicated the potential for cilia in peripheral tissues such as adipose and the pancreas to contribute to metabolic dysfunction. Then we discuss the potential for cilia to impact energy homeostasis through their roles in both development and adult tissue homeostasis. The studies discussed in this review highlight how a comprehensive understanding of the requirement of cilia for the regulation of diverse biological functions will contribute to our understanding of common forms of obesity.
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http://dx.doi.org/10.1016/j.semcdb.2020.05.006DOI Listing
February 2021

Tomographic Ultrasound and LED-Based Photoacoustic System for Preclinical Imaging.

Sensors (Basel) 2020 May 14;20(10). Epub 2020 May 14.

Biomedical Photonics Imaging (BMPI), Technical Medical Center, University of Twente, 7522 NH Enschede, The Netherlands.

Small animals are widely used as disease models in medical research. Noninvasive imaging modalities with functional capability play an important role in studying the disease state and treatment progress. Photoacoustics, being a noninvasive and functional modality, has the potential for small-animal imaging. However, the conventional photoacoustic tomographic systems use pulsed lasers, making it expensive, bulky, and require long acquisition time. In this work, we propose the use of photoacoustic and ultrasound tomographic imaging with LEDs as the light source and acoustic detection using a linear transducer array. We have demonstrated full-view tomographic imaging of a euthanized mouse and a potential application in liver fibrosis research.
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http://dx.doi.org/10.3390/s20102793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294432PMC
May 2020

Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases.

Cells 2020 05 13;9(5). Epub 2020 May 13.

Translational Liver Research, Department of Medical Cell BioPhysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, 7522 NB Enschede, The Netherlands.

Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.
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http://dx.doi.org/10.3390/cells9051212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290342PMC
May 2020

Role of spleen tyrosine kinase in liver diseases.

World J Gastroenterol 2020 Mar;26(10):1005-1019

Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Enschede 7500, the Netherlands.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses. SYK mediate diverse cellular responses an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways, ITAMs-independent and ITAMs-semi-dependent signalling pathways. In liver, SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells), and found to be positively correlated with the disease severity. The implication of SYK pathway has been reported in different liver diseases including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target. This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.
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http://dx.doi.org/10.3748/wjg.v26.i10.1005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081001PMC
March 2020

Innate Immunity and Pathogenesis of Biliary Atresia.

Front Immunol 2020 25;11:329. Epub 2020 Feb 25.

Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.

Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.
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http://dx.doi.org/10.3389/fimmu.2020.00329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052372PMC
March 2021

Pharmacological inhibition of STAT3 pathway ameliorates acute liver injury in vivo via inactivation of inflammatory macrophages and hepatic stellate cells.

FASEB Bioadv 2020 Feb 3;2(2):77-89. Epub 2020 Jan 3.

Department of Biomaterials Science and Technology Technical Medical Centre Faculty of Science and Technology University of Twente Enschede The Netherlands.

Liver diseases represent a major health problem worldwide, in particular, acute liver injury is associated with high mortality and morbidity. Inflammatory macrophages and hepatic stellate cells (HSCs) are known to be involved in the pathogenesis of acute liver injury. In this study, we have investigated the implication of STAT3 inhibition in acute liver injury/early fibrogenesis. In fibrotic human livers, we found STAT3 mRNA expression was significantly upregulated and correlated with collagen I expression. In vitro, STAT3 signaling pathway was found to be activated in TGFβ-activated HSCs and inflammatory macrophages. STAT3 inhibitor, WP1066 significantly inhibited TGFβ-induced collagen I, vimentin and α-SMA expression, and contractility in human HSCs. In LPS- and IFNγ-induced pro-inflammatory macrophages, WP1066 strongly attenuated nitric-oxide release and expression of major inflammatory markers such as TNF-α, iNOS, CCL2, IL-1β, IL-6, and CCR2. In vivo in CCl-induced acute liver injury mouse model, WP1066 significantly reduced collagen expression, HSCs activation, and intrahepatic inflammation. Finally, in LPS-induced human hepatic 3D spheroid model, WP1066 inhibited LPS-induced fibrotic and inflammatory parameters. In conclusion, our results demonstrate that the therapeutic inhibition of STAT3 pathway using WP1066 targeting HSCs and inflammatory macrophages suggests a potential pharmacological approach for the treatment of acute liver injury.
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http://dx.doi.org/10.1096/fba.2019-00070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003653PMC
February 2020

Battling IL-17, the troublemaker in alcohol-induced hepatocellular carcinoma.

Authors:
Ruchi Bansal

J Hepatol 2020 05 28;72(5):809-812. Epub 2020 Feb 28.

Translational Liver Research, Department of Medical Cell BioPhysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.02.011DOI Listing
May 2020

Bioengineered 3D Models to Recapitulate Tissue Fibrosis.

Trends Biotechnol 2020 06 15;38(6):623-636. Epub 2020 Jan 15.

Department of Biomechanical Engineering, Technical Medical Centre, Faculty of Engineering Technology, University of Twente, Enschede, The Netherlands. Electronic address:

Fibrosis, characterized by progressive tissue stiffening resulting in organ failure, is a growing health problem affecting millions of people worldwide. Currently, therapeutic options for tissue fibrosis are severely limited and organ transplantation is the only effective treatment for the end-stage fibrotic diseases with inherent limitations. Recent advancements in engineered 3D in vitro human disease mimic models, recapitulating the tissue pathophysiology, have provided unique state-of-the-art platforms for: (i) understanding the biological mechanisms involved in the disease pathogenesis; and (ii) high-throughput and reproducible drug screening. This review focuses on the recent multidisciplinary developments made towards advanced 3D biomimetic fibrotic tissue (liver, kidney, and lung) models that combine highly precision manufacturing techniques with high cellular functionality and biophysical (mechanical) properties.
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http://dx.doi.org/10.1016/j.tibtech.2019.12.010DOI Listing
June 2020

FGF2 engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in 3D heterospheroidal model of pancreatic tumor.

Nanotheranostics 2020 1;4(1):26-39. Epub 2020 Jan 1.

Targeted Therapeutics, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and technology, University of Twente, Enschede, The Netherlands.

Pancreatic ductal adenocarcinoma (PDAC), characterized with abundant tumor stroma, is a highly malignant tumor with poor prognosis. The tumor stroma largely consists of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), and is known to promote tumor growth and progression as well as acts as a barrier to chemotherapy. Inhibition of tumor stroma is highly crucial to induce the effect of chemotherapy. In this study, we delivered fibroblast growth factor 2 (FGF2) to human pancreatic stellate cells (hPSCs), the precursors of CAFs, using superparamagnetic iron oxide nanoparticles (SPIONs). FGF2 was covalently conjugated to functionalized PEGylated dextran-coated SPIONs. FGF2-SPIONs significantly reduced TGF-β induced hPSCs differentiation (α-SMA and collagen-1 expression) by inhibiting pSmad2/3 signaling and inducing ERK1/2 activity, as shown with western blot analysis. Then, we established a stroma-rich self-assembling 3D heterospheroid model by co-culturing PANC-1 and hPSCs in 3D environment. We found that FGF2-SPIONs treatment alone inhibited the tumor stroma-induced spheroid growth. In addition, they also potentiated the effect of gemcitabine, as shown by measuring the spheroid size and ATP content. These effects were attributed to the reduced expression of the hPSC activation and differentiation marker, α-SMA. Furthermore, to demonstrate an application of SPIONs, we applied an external magnetic field to spheroids while incubated with FGF2-SPIONs. This resulted in an enhanced effect of gemcitabine in our 3D model. In conclusion, this study presents a novel approach to target FGF2 to tumor stroma using SPIONs and thereby enhancing the effect of gemcitabine as demonstrated in the complex 3D tumor spheroid model.
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http://dx.doi.org/10.7150/ntno.38092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940204PMC
April 2021

Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases.

Front Immunol 2019 3;10:2852. Epub 2019 Dec 3.

Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede, Netherlands.

Hepatic macrophages play a central role in maintaining homeostasis in the liver, as well as in the initiation and progression of liver diseases. Hepatic macrophages are mainly derived from resident hepatic macrophages called Kupffer cells or circulating bone marrow-derived monocytes. Kupffer cells are self-renewing and typically non-migrating macrophages in the liver and are stationed in the liver sinusoids in contrast to macrophages originating from circulating monocytes. Kupffer cells regulate liver homeostasis by mediating immunity against non-pathogenic blood-borne molecules, while participating in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes present in the vasculature. Monocyte-derived macrophages infiltrate into the liver tissue when metabolic or toxic damage instigates and are likely dispensable for replenishing the macrophage population in homeostasis. In recent years, different populations of hepatic macrophages have been identified with distinct phenotypes with discrete functions, far beyond the central dogma of M1 and M2 macrophages. Hepatic macrophages play a central role in the pathogenesis of acute and chronic liver failure, liver fibrosis, non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and hepatocellular carcinoma, as well as in disease resolution. The understanding of the role of hepatic macrophages in liver diseases provides opportunities for the development of targeted therapeutics for respective malignancies. This review will summarize the current knowledge of the hepatic macrophages, their origin, functions, their critical role in maintaining homeostasis and in the progression or resolution of liver diseases. Furthermore, we will provide a comprehensive overview of the therapeutic targeting strategies against hepatic macrophages developed for the treatment of liver diseases.
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http://dx.doi.org/10.3389/fimmu.2019.02852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901832PMC
November 2020
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