Gut Microbes. 2021 Jan-Dec;13(1):1-29. doi: 10.1080/19490976.2021.1902705.

ABSTRACT

South Asian (SA) Canadian immigrants have a higher risk of developing certain immune-mediated inflammatory diseases compared to non-migrant SAs. We sought to investigate the effect of migration on the gut metagenome and to identify microbiological associations between migration and conditions that may influence the development of immune-mediated inflammatory diseases. Metagenomic analysis of 58 first-generation (GEN1) SA immigrants and 38 unrelated Canadian born children-of-immigrants (GEN2) determined that the time lived in Canada was associated with continued changes in gut microbial communities. Migration of GEN1 to Canada early in life results in a gut community with similarities to GEN2 SA Canadians and non-SA North Americans. Conversely, GEN1 immigrants who arrived recently to Canada exhibited pronounced differences from GEN2, while displaying microbial similarities to a non-migrating SA cohort. Multivariate analysis identified that community composition was primarily influenced by high abundance taxa. Prevotella copri dominated in GEN1 and non-migrant SAs. Clostridia and functionally related Bacteroidia spp. replaced P. copri dominance over generations in Canada. Mutually exclusive Dialister species occurred at differing relative abundances over time and generations in Canada. This shift in species composition is accompanied by a change in genes associated with carbohydrate utilization and short-chain fatty acid production. Total energy derived from carbohydrates compared to protein consumption was significantly higher for GEN1 recent immigrants, which may influence the functional requirements of the gut community. This study demonstrates the associations between migration and the gut microbiome, which may be further associated with the altered risk of immune-mediated inflammatory diseases observed for SA Canadians.

PMID:33794735 | DOI:10.1080/19490976.2021.1902705

OMICS. 2021 Apr 1. doi: 10.1089/omi.2021.0004. Online ahead of print.

ABSTRACT

Following the publication of the first human genome, OMICs research, including genomics, transcriptomics, proteomics, and metagenomics, has been on the rise. OMICs studies revealed the complex genetic diversity among human populations and challenged our understandings of genotype-phenotype correlations. Africa, being the cradle of the first modern humans, is distinguished by a large genetic diversity within its populations and rich ethnolinguistic history. However, the available human OMICs tools and databases are not representative of this diversity, therefore creating significant gaps in biomedical research. African scientists, students, and publics are among the key contributors to OMICs systems science. This expert review examines the pressing issues in human OMICs research, education, and development in Africa, as seen through a lens of computational biology, public health relevant technology innovation, critically-informed science governance, and how best to harness OMICs data to benefit health and societies in Africa and beyond. We underscore the disparities between North and Sub-Saharan Africa at different levels. A harmonized African ethnolinguistic classification would help address annotation challenges associated with population diversity. Finally, building on the existing strategic research initiatives, such as the H3Africa and H3ABioNet Consortia, we highly recommend addressing large-scale multidisciplinary research challenges, strengthening research collaborations and knowledge transfer, and enhancing the ability of African researchers to influence and shape national and international research, policy, and funding agendas. This article and analysis contribute to a deeper understanding of past and current challenges in the African OMICs innovation ecosystem, while also offering foresight on future innovation trajectories.

PMID:33794662 | DOI:10.1089/omi.2021.0004

J Proteome Res. 2021 Apr 2;20(4):1819-1820. doi: 10.1021/acs.jproteome.1c00182.

NO ABSTRACT

PMID:33794645 | DOI:10.1021/acs.jproteome.1c00182

Radiat Oncol J. 2021 Mar;39(1):48-60. doi: 10.3857/roj.2021.00045. Epub 2021 Mar 24.

ABSTRACT

PURPOSE: The integration of large-scale gene data and their functional analysis needs the effective application of various computational tools. Here we attempted to unravel the biological processes and cellular pathways in response to ionizing radiation using a systems biology approach.

MATERIALS AND METHODS: Analysis of gene ontology shows that 80, 42, 25, and 35 genes have roles in the biological process, molecular function, the cellular process, and immune system pathways, respectively. Therefore, our study emphasizes gene/protein network analysis on various differentially expressed genes (DEGs) to reveal the interactions between those proteins and their functional contribution upon radiation exposure.

RESULTS: A gene/protein interaction network was constructed, which comprises 79 interactors with 718 interactions and TP53, MAPK8, MAPK1, CASP3, MAPK14, ATM, NOTCH1, VEGFA, SIRT1, and PRKDC are the top 10 proteins in the network with high betweenness centrality values. Further, molecular complex detection was used to cluster these associated partners in the network, which produced three effective clusters based on the Molecular Complex Detection (MCODE) score. Interestingly, we found a high functional similarity from the associated genes/proteins in the network with known radiation response genes.

CONCLUSION: This network-based approach on DEGs of human lymphocytes upon response to ionizing radiation provides clues for an opportunity to improve therapeutic efficacy.

PMID:33794574 | DOI:10.3857/roj.2021.00045

J Nutr Biochem. 2021 Mar 29:108634. doi: 10.1016/j.jnutbio.2021.108634. Online ahead of print.

ABSTRACT

The high failure rate of the reductionist approach to discover effective and safe drugs to treat chronic inflammatory diseases has led scientists to seek alternative ways. Recently, targeting cell signaling pathways has been utilized as an innovative approach to discover drug leads from natural products. Cell signaling mechanisms have been identified playing key role in diverse diseases by inducing proliferation, cell survival and apoptosis. Phytochemicals are known to be able to modulate the cellular and molecular networks which are associated to chronic diseases including cancer-associated inflammation. In this review, the roles of dietary polyphenols (apigenin, kaempferol, quercetin, curcumin, genistein, isoliquiritigenin, resveratrol and gallic acid) in modulating multiple inflammation-associated cell signaling networks are deliberated. Scientific databases on suppressive effects of the polyphenols on chronic inflammation via modulation of the pathways especially in the recent five years are gathered and critically analyzed. The polyphenols are able to modulate several inflammation-associated cell signaling pathways, namely nuclear factor-kappa β (NF-κB), mitogen activated protein kinases (MAPKs), Wnt/β-catenin and phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) via selective actions on various components of the networks. The suppressive effects of the polyphenols on the multiple cell signaling pathways reveal their potential use in prevention and treatment of chronic inflammatory disorders. Understanding the mechanistic effects involved in modulation of the signaling pathways by the polyphenols is necessary for lead identification and development of future functional foods for prevention and treatment of chronic inflammatory diseases.

PMID:33794330 | DOI:10.1016/j.jnutbio.2021.108634

Biotechnol Adv. 2021 Mar 29:107739. doi: 10.1016/j.biotechadv.2021.107739. Online ahead of print.

ABSTRACT

With the development of modern high-throughput omic measurement platforms, it has become essential for biomedical studies to undertake an integrative (combined) approach to fully utilise these data to gain insights into biological systems. Data from various omics sources such as genetics, proteomics, and metabolomics can be integrated to unravel the intricate working of systems biology using machine learning-based predictive algorithms. Machine learning methods offer novel techniques to integrate and analyse the various omics data enabling the discovery of new biomarkers. These biomarkers have the potential to help in accurate disease prediction, patient stratification and delivering of precision medicine. This review paper explores different integrative machine learning methods which have been used to provide an in-depth understanding of biological systems during normal physiological functioning and in the presence of a disease. It provides insight and recommendations for interdisciplinary professionals who envisage employing machine learning skills in multi-omics studies.

PMID:33794304 | DOI:10.1016/j.biotechadv.2021.107739

Cell. 2021 Mar 23:S0092-8674(21)00241-5. doi: 10.1016/j.cell.2021.02.052. Online ahead of print.

ABSTRACT

Industrialization has impacted the human gut ecosystem, resulting in altered microbiome composition and diversity. Whether bacterial genomes may also adapt to the industrialization of their host populations remains largely unexplored. Here, we investigate the extent to which the rates and targets of horizontal gene transfer (HGT) vary across thousands of bacterial strains from 15 human populations spanning a range of industrialization. We show that HGTs have accumulated in the microbiome over recent host generations and that HGT occurs at high frequency within individuals. Comparison across human populations reveals that industrialized lifestyles are associated with higher HGT rates and that the functions of HGTs are related to the level of host industrialization. Our results suggest that gut bacteria continuously acquire new functionality based on host lifestyle and that high rates of HGT may be a recent development in human history linked to industrialization.

PMID:33794144 | DOI:10.1016/j.cell.2021.02.052

J Complement Integr Med. 2021 Apr 2. doi: 10.1515/jcim-2020-0265. Online ahead of print.

ABSTRACT

OBJECTIVES: Osteoarthritis (OA) is an inflammatory disorder of the joint characterized by pain and stiffness. Oxidative stress plays an important role in pathogenesis of OA. We aimed to evaluate the effects of avocado/soy unsaponifiables (ASU) compound on serum antioxidant and oxidative stress in patients with Osteoarthritis.

METHODS: A double-blind, randomized, placebo-controlled, cross-over trial was performed. Fourty patients with osteoarthritis were randomized to two different sequences: 1) DP: received ASU for three months followed by three months placebo, 2) PD: received placebo for the first three months followed by three months ASU. The oxidant statue was evaluated by measurement of serum malonldialdehyde (MDA). The total antioxidant capacity (TAC), reduced glutathione (GSH) and antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) were also assessed.

RESULTS: Mean serum of MDA level as a marker of oxidative stress significantly decreased in all patients after three months treatment with ASU (4.46 ± 0.11 nmol/L) compare with baseline and placebo levels (5 ± 0.15 and 5.82 ± 0.12 nmol/L respectively) (p<0.05). On the other hand, ASU resulted in positive changes in serum antioxidant levels (p<0.05). Mixed-effects model of variance analyses showed that ASU effect is regardless of the order of receiving medication (p>0.05).

CONCLUSIONS: These data showed that Avocado/Soy Unsaponifiable can be an effective supplement in treatment of osteoarthritis through the control of the balance between antioxidant and oxidant molecular markers.

PMID:33794080 | DOI:10.1515/jcim-2020-0265

Plant Physiol. 2020 Dec 18:kiaa074. doi: 10.1093/plphys/kiaa074. Online ahead of print.

NO ABSTRACT

PMID:33793888 | DOI:10.1093/plphys/kiaa074

Plant Cell. 2020 Dec 29:koaa038. doi: 10.1093/plcell/koaa038. Online ahead of print.

ABSTRACT

Twenty years ago, the Arabidopsis thaliana genome sequence was published. This was an important moment as it was the first sequenced plant genome and explicitly brought plant science into the genomics era. At the time, this was not only an outstanding technological achievement, but it was characterized by a superb global collaboration. The Arabidopsis genome was the seed for plant genomic research. Here, we review the development of numerous resources based on the genome that have enabled discoveries across plant species, which has enhanced our understanding of how plants function and interact with their environments.

PMID:33793861 | DOI:10.1093/plcell/koaa038

Plant Cell. 2021 Jan 25:koab004. doi: 10.1093/plcell/koab004. Online ahead of print.

ABSTRACT

Identifying protein-protein interactions (PPIs) is crucial for understanding biological processes. Many PPI tools are available, yet only some function within the context of a plant cell. Narrowing down even further, only a few tools allow complex multi-protein interactions to be visualized. Here, we present a conditional in vivo PPI tool for plant research that meets these criteria. Knocksideways in plants (KSP) is based on the ability of rapamycin to alter the localization of a bait protein and its interactors via the heterodimerization of FKBP and FRB domains. KSP is inherently free from many limitations of other PPI systems. This in vivo tool does not require spatial proximity of the bait and prey fluorophores and it is compatible with a broad range of fluorophores. KSP is also a conditional tool and therefore the visualization of the proteins in the absence of rapamycin acts as an internal control. We used KSP to confirm previously identified interactions in Nicotiana benthamiana leaf epidermal cells. Furthermore, the scripts that we generated allow the interactions to be quantified at high throughput. Finally, we demonstrate that KSP can easily be used to visualize complex multi-protein interactions. KSP is therefore a versatile tool with unique characteristics and applications that complements other plant PPI methods.

PMID:33793859 | DOI:10.1093/plcell/koab004

Plant Cell. 2021 Jan 25:koab005. doi: 10.1093/plcell/koab005. Online ahead of print.

ABSTRACT

Aluminum (Al) toxicity and inorganic phosphate (Pi) limitation are widespread chronic abiotic and mutually enhancing stresses that profoundly affect crop yield. Both stresses strongly inhibit root growth, resulting from a progressive exhaustion of the stem cell niche. Here, we report on a casein kinase 2 (CK2) inhibitor identified by its capability to maintain a functional root stem cell niche in Arabidopsis thaliana under Al toxic conditions. CK2 operates through phosphorylation of the cell cycle checkpoint activator SUPPRESSOR OF GAMMA RADIATION1 (SOG1), priming its activity under DNA-damaging conditions. In addition to yielding Al tolerance, CK2 and SOG1 inactivation prevents meristem exhaustion under Pi starvation, revealing the existence of a low Pi-induced cell cycle checkpoint that depends on the DNA damage activator ATAXIA-TELANGIECTASIA MUTATED (ATM). Overall, our data reveal an important physiological role for the plant DNA damage response pathway under agriculturally limiting growth conditions, opening new avenues to cope with Pi limitation.

PMID:33793856 | DOI:10.1093/plcell/koab005

Plant Cell. 2021 Feb 2:koab020. doi: 10.1093/plcell/koab020. Online ahead of print.

ABSTRACT

The 45S rRNA genes (rDNA) are amongst the largest repetitive elements in eukaryotic genomes. rDNA consists of tandem arrays of rRNA genes, many of which are transcriptionally silenced. Silent rDNA repeats may act as 'back-up' copies for ribosome biogenesis and have nuclear organization roles. Through Cas9-mediated genome editing in the Arabidopsis thaliana female gametophyte we reduced 45S rDNA copy number to a plateau of ∼10%. Two independent lines had rDNA copy numbers reduced by up to 90% at the T7 generation, named Low Copy Number (LCN) lines. Despite drastic reduction of rDNA copies, rRNA transcriptional rates and steady-state levels remained the same as wild type plants. Gene dosage compensation of rRNA transcript levels was associated with reduction of silencing histone marks at rDNA loci and altered Nucleolar Organiser Region 2 organization. While overall genome integrity of LCN lines appears unaffected, a chromosome segmental duplication occurred in one of the lines. Transcriptome analysis of LCN seedlings identified several shared dysregulated genes and pathways in both independent lines. Cas9 genome editing of rRNA repeats to generate LCN lines provides a powerful technique to elucidate rDNA dosage compensation mechanisms and impacts of low rDNA copy number on genome stability, development, and cellular processes.

PMID:33793816 | DOI:10.1093/plcell/koab020

PLoS One. 2021 Apr 1;16(4):e0249372. doi: 10.1371/journal.pone.0249372. eCollection 2021.

ABSTRACT

Computer simulations of mathematical models open up the possibility of assessing hypotheses generated by experiments on pathogen immune evasion in human whole-blood infection assays. We apply an interdisciplinary systems biology approach in which virtual infection models implemented for the dissection of specific immune mechanisms are combined with experimental studies to validate or falsify the respective hypotheses. Focusing on the assessment of mechanisms that enable pathogens to evade the immune response in the early time course of a whole-blood infection, the least-square error (LSE) as a measure for the quantitative agreement between the theoretical and experimental kinetics is combined with the Akaike information criterion (AIC) as a measure for the model quality depending on its complexity. In particular, we compare mathematical models with three different types of pathogen immune evasion as well as all their combinations: (i) spontaneous immune evasion, (ii) evasion mediated by immune cells, and (iii) pre-existence of an immune-evasive pathogen subpopulation. For example, by testing theoretical predictions in subsequent imaging experiments, we demonstrate that the simple hypothesis of having a subpopulation of pre-existing immune-evasive pathogens can be ruled out. Furthermore, in this study we extend our previous whole-blood infection assays for the two fungal pathogens Candida albicans and C. glabrata by the bacterial pathogen Staphylococcus aureus and calibrated the model predictions to the time-resolved experimental data for each pathogen. Our quantitative assessment generally reveals that models with a lower number of parameters are not only scored with better AIC values, but also exhibit lower values for the LSE. Furthermore, we describe in detail model-specific and pathogen-specific patterns in the kinetics of cell populations that may be measured in future experiments to distinguish and pinpoint the underlying immune mechanisms.

PMID:33793643 | DOI:10.1371/journal.pone.0249372

Circ Res. 2021 Apr 2;128(7):993-1020. doi: 10.1161/CIRCRESAHA.121.318063. Epub 2021 Apr 1.

ABSTRACT

A link between oxidative stress and hypertension has been firmly established in multiple animal models of hypertension but remains elusive in humans. While initial studies focused on inactivation of nitric oxide by superoxide, our understanding of relevant reactive oxygen species (superoxide, hydrogen peroxide, and peroxynitrite) and how they modify complex signaling pathways to promote hypertension has expanded significantly. In this review, we summarize recent advances in delineating the primary and secondary sources of reactive oxygen species (nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, endoplasmic reticulum, and mitochondria), the posttranslational oxidative modifications they induce on protein targets important for redox signaling, their interplay with endogenous antioxidant systems, and the role of inflammasome activation and endoplasmic reticular stress in the development of hypertension. We highlight how oxidative stress in different organ systems contributes to hypertension, describe new animal models that have clarified the importance of specific proteins, and discuss clinical studies that shed light on how these processes and pathways are altered in human hypertension. Finally, we focus on the promise of redox proteomics and systems biology to help us fully understand the relationship between ROS and hypertension and their potential for designing and evaluating novel antihypertensive therapies.

PMID:33793335 | DOI:10.1161/CIRCRESAHA.121.318063

J Proteome Res. 2021 Apr 1. doi: 10.1021/acs.jproteome.0c01037. Online ahead of print.

ABSTRACT

Decreased cellular NAD+ levels are causally linked to aging and aging-associated diseases. NAD+ precursors in oxidized form such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have gained much attention and been well studied for their ability to restore NAD+ levels in model organisms. Less is known about whether NAD+ precursors in reduced form can also efficiently increase the tissue and cellular NAD+ levels and have different effects on cellular processes than NMN or NR. In the present study, we developed a chemical method to produce dihydronicotinamide mononucleotide (NMNH), which is the reduced form of NMN. We demonstrated that NMNH was a better NAD+ enhancer than NMN both in vitro and in vivo, mediated by nicotinamide mononucleotide adenylyltransferase (NMNAT). Additionally, NMNH increased the reduced NAD (NADH) levels in cells and in mouse livers. Metabolomic analysis revealed that NMNH inhibited glycolysis and the TCA cycle. In vitro experiments demonstrated that NMNH induced cell cycle arrest and suppressed cell growth. Nevertheless, NMNH treatment did not cause an observable difference in mouse weight. Taken together, our work demonstrates that NMNH is a potent NAD+ enhancer and suppresses glycolysis, the TCA cycle, and cell growth.

PMID:33793246 | DOI:10.1021/acs.jproteome.0c01037

Pathog Dis. 2021 Apr 1:ftab022. doi: 10.1093/femspd/ftab022. Online ahead of print.

ABSTRACT

Tick-borne illnesses pose a serious concern to human and veterinary health and their prevalence is on the rise. The interactions between ticks and the pathogens they carry are largely undefined. However, the genus Anaplasma, a group of tick-borne bacteria, has been instrumental in uncovering novel paradigms in tick biology. The emergence of sophisticated technologies and the convergence of entomology with microbiology, immunology, metabolism, and systems biology has brought tick-Anaplasma interactions to the forefront of vector biology with broader implications for the infectious disease community. Here, we discuss the use of Anaplasma as an instrument for the elucidation of novel principles in arthropod-microbe interactions. We offer an outlook of the primary areas of study, outstanding questions, and future research directions.

PMID:33792663 | DOI:10.1093/femspd/ftab022

Adv Exp Med Biol. 2021;1280:97-113. doi: 10.1007/978-3-030-51652-9_7.

ABSTRACT

Most microbe-associated infectious diseases severely affect human health. However, clinical diagnosis of pathogenic diseases remains challenging due to the lack of specific and highly reliable methods. To better understand the diagnosis, pathogenesis, and treatment of these diseases, systems biology-driven metabolomics goes beyond the annotated phenotype and better targets the functions than conventional approaches. As a novel strategy for analysis of metabolomes in microbes, microbial metabolomics has been recently used to study many diseases, such as obesity, urinary tract infection (UTI), and hepatitis C. In this chapter, we attempt to introduce various microbial metabolomics methods to better interpret the microbial metabolism underlying a diversity of infectious diseases and inspire scientists to pay more attention to microbial metabolomics, enabling broadly and efficiently its translational applications to infectious diseases, from molecular diagnosis to therapeutic discovery.

PMID:33791977 | DOI:10.1007/978-3-030-51652-9_7

J Mol Neurosci. 2021 Mar 31. doi: 10.1007/s12031-021-01837-3. Online ahead of print.

ABSTRACT

Epilepsy-associated brain tumors (EATs) are usually slow-growing, with seizures as the primary and most dominant symptom. BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene mutations have been found in several subsets of EATs; the V600E mutation is currently believed to contribute to the intrinsic epileptogenicity and tumor growth. However, the relationship between BRAF V600E gene mutation and clinical characteristics in EAT patients is not clear. In this study, we aimed to systematically review the frequency of BRAF V600E gene mutation, as well as the relationship between BRAF V600E gene mutation and clinical characteristics, which may help with the diagnosis and treatment of EATs. Cochrane Library, PubMed, Embase, CNKI, WanFang Data, CQVIP, and SinoMed databases were searched up to October 2020 to identify peer-reviewed human studies on assessing the relationship between BRAF V600E gene mutations and clinical characteristics in EATs. The following data were calculated: the frequency of BRAF V600E mutation and clinical feature comparison between BRAF V600E mutations and wild type in EATs, such as gender, age of seizure onset, duration of epilepsy, location of tumors, and Engel outcome. A total of 12 articles were included in the analysis. Five hundred and nine patients with epilepsy-associated brain tumors were screened for the BRAF V600E gene mutation. Among them, 193 patients had the BRAF V600E mutation (34.06%, 95% CI = 0.25 to 0.43). The subgroup analyses of BRAF V600E mutation showed positive frequency of 44.76% (95% CI = 0.36 to 0.54) in ganglioglioma, 24.75% (95% CI = 0.14 to 0.37) in gysembryoplastic neuroepithelial tumor, 2.15% (95% CI = 0 to 0.19) in angiocentric glioma, and 50.16% (95% CI = 0.33 to 0.68) in pleomorphic xanthoastrocytoma. Compared with the overall frequency, the BRAF V600E positive frequency in ganglioglioma was significantly higher (P = 0.0283). We also found that BRAF V600E gene mutation was significantly associated with age at seizure onset (MD = -2.37; 95% CI = -4.33 to -0.41; P = 0.02). There was no statistical difference between BRAF V600E mutations and wild type in gender, duration of epilepsy, tumor site, and Engel outcome comparison. In conclusion, our updated and comprehensive meta-analysis based on a large number of clinical data demonstrated that BRAF V600E mutation is a specific biomarker and could be a pharmacological target for ganglioglioma patients and an exclusion diagnostic criterion for angiocentric glioma. This meta-analysis suggested the critical role of BRAF V600E mutation in the occurrence and development of EATs. Our findings help to elucidate the progression mechanisms in EATs and develop future therapeutic strategies for EATs.

PMID:33791912 | DOI:10.1007/s12031-021-01837-3

Front Cell Dev Biol. 2021 Mar 15;9:641404. doi: 10.3389/fcell.2021.641404. eCollection 2021.

ABSTRACT

Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; therefore, they can be an attractive target for pharmaceutical management of severe asthma. Wnt/β-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling. Here we explored the changes in Wnt signaling associated with asthma initiation and progression in epithelial and fibroblasts using a comprehensive approach based on in silico analysis and followed by in vitro validation. In summary, the in silico analysis showed that the bronchial epithelium of severe asthmatic patients showed a deranged balance between Wnt enhancer and Wnt inhibitors. A Th2-high phenotype is associated with upregulated Wnt-negative regulators, while inflammatory and neutrophilic severe asthmatics showed higher canonical Wnt signaling member enrichment. Most of these genes are regulators of healthy lung development early in life and, if disturbed, can make people susceptible to developing asthma early in life and prone to developing a severe phenotype. Most of the Wnt members are secreted, and their effect can be in an autocrine fashion on the bronchial epithelium, paracrine on nearby adjacent structural cells like fibroblasts and smooth muscles, or systemic in blood. Our results showed that canonical Wnt signaling is needed for the proper response of cells to proliferative stimuli, which puts cells under stress. Cells in response to this proliferative stress will activate the senescence mechanism, which is also dependent on Wnt signaling. Inhibition of Wnt signaling using FH535 inhibits both proliferation and senescence markers in bronchial fibroblasts compared to DMSO-treated cells. In fibroblasts from asthmatic patients, inhibition of Wnt signaling did not show that effect as the Wnt signaling is deranged besides other pathways that might be non-functional.

PMID:33791298 | PMC:PMC8006921 | DOI:10.3389/fcell.2021.641404