Role of MicroRNAs in Signaling Pathways Associated with the Pathogenesis of Idiopathic Pulmonary Fibrosis: A Focus on Epithelial-Mesenchymal Transition

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality and unclear etiology. Previous evidence supports that the origin of this disease is associated with epigenetic alterations, age, and environmental factors. IPF initiates with chronic epithelial lung injuries, followed by basal membrane destruction, which promotes the activation of myofibroblasts and excessive synthesis of extracellular matrix (ECM) proteins, as well as epithelial-mesenchymal transition (EMT). Due to miRNAs’ role as regulators of apoptosis, proliferation, differentiation, and cell-cell interaction processes, some studies have involved miRNAs in the biogenesis and progression of IPF. In this context, the analysis and discussion of the probable association of miRNAs with the signaling pathways involved in the development of IPF would improve our knowledge of the associated molecular mechanisms, thereby facilitating its evaluation as a therapeutic target for this severe lung disease. In this work, the most recent publications evaluating the role of miRNAs as regulators or activators of signal pathways associated with the pathogenesis of IPF were analyzed. The search in Pubmed was made using the following terms: “miRNAs and idiopathic pulmonary fibrosis (IPF)”; “miRNAs and IPF and signaling pathways (SP)”; and “miRNAs and IPF and SP and IPF pathogenesis”. Additionally, we focus mainly on those works where the signaling pathways involved with EMT, fibroblast differentiation, and synthesis of ECM components were assessed. Finally, the importance and significance of miRNAs as potential therapeutic or diagnostic tools for the treatment of IPF are discussed.     

p16-3MR: A Novel Model to Study Cellular Senescence in Cigarette Smoke-Induced Lung Injuries

Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16^INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12–14 months) and old (17–20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR reporter mouse model may be used as a novel tool for understanding the pathobiology of cellular senescence and other underlying mechanisms involved in COPD and fibrosis.     

Cellular Senescence and Inflammaging in the Skin Microenvironment

Cellular senescence and aging result in a reduced ability to manage persistent types of inflammation. Thus, the chronic low-level inflammation associated with aging phenotype is called “inflammaging”. Inflammaging is not only related with age-associated chronic systemic diseases such as cardiovascular disease and diabetes, but also skin aging. As the largest organ of the body, skin is continuously exposed to external stressors such as UV radiation, air particulate matter, and human microbiome. In this review article, we present mechanisms for accumulation of senescence cells in different compartments of the skin based on cell types, and their association with skin resident immune cells to describe changes in cutaneous immunity during the aging process.     

Adipose Tissue Plasticity in Response to Pathophysiological Cues: A Connecting Link between Obesity and Its Associated Comorbidities

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardiovascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells, low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orchestrated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new adipocytes appears to be the main instigator of the adipose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an altered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This “adipocentric view” extends the previous “expandability hypothesis”, which implies a reduced plasticity of the adipose organ at the nexus between unhealthy fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation, inflammation and cellular senescence as a novel triad orchestrating the conspiracy to adipose dysfunction. Finally, we discuss the scientific rationale for proposing adipose organ plasticity as a target to curb/prevent adiposity-linked cardio-metabolic complications.     

Cellular Senescence in Lung Fibrosis

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.     

mTOR Activity and Autophagy in Senescent Cells,a Complex Partnership

Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this “senescence-associated secretory phenotype (SASP)” accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy—a highly regulated catabolic process—is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.     

Extracellular Vesicles as New Players in Cellular Senescence

Cell senescence is associated with the secretion of many factors, the so-called “senescence-associated secretory phenotype”, which may alter tissue microenvironment, stimulating the organism to clean up senescent cells and replace them with newly divided ones. Therefore, although no longer dividing, these cells are still metabolically active and influence the surrounding tissue. Much attention has been recently focused not only on soluble factors released by senescent cells, but also on extracellular vesicles as conveyors of senescence signals outside the cell. Here, we give an overview of the role of extracellular vesicles in biological processes and signaling pathways related to senescence and aging.     

Therapeutic Approaches Targeting Proteostasis in Kidney Disease and Fibrosis

Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called “ER stress”. Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.     

The Ameliorative Effect of Dexamethasone on the Development of Autoimmune Lung Injury and Mediastinal Fat-Associated Lymphoid Clusters in an Autoimmune Disease Mouse Model

In our previous study, we revealed the ameliorative therapeutic effect of dexamethasone (Dex) for Lupus nephritis lesions in the MRL/MpJ-Fas ^lpr/lpr (Lpr) mouse model. The female Lpr mice developed a greater number of mediastinal fat-associated lymphoid clusters (MFALCs) and inflammatory lung lesions compared to the male mice. However, the effect of Dex, an immunosuppressive drug, on both lung lesions and the development of MFALCs in Lpr mice has not been identified yet. Therefore, in this study, we compared the development of lung lesions and MFALCs in female Lpr mice that received either saline (saline group “SG”) or dexamethasone (dexamethasone group “DG”) in drinking water as a daily dose along with weekly intraperitoneal injections for 10 weeks. Compared to the SG group, the DG group showed a significant reduction in the levels of serum anti-dsDNA antibodies, the size of MFALCs, the degree of lung injury, the area of high endothelial venules (HEVs), and the number of proliferating and immune cells in both MFALCs and the lungs. A significant positive correlation was observed between the size of MFALCs and the cellular aggregation in the lungs of Lpr mice. Therefore, this study confirmed the ameliorative effect of Dex on the development of lung injury and MFALCs via their regressive effect on both immune cells’ proliferative activity and the development of HEVs. Furthermore, the reprogramming of MFALCs by targeting immune cells and HEVs may provide a therapeutic strategy for autoimmune-disease-associated lung injury.     

The “Angiogenic Switch” and Functional Resources in Cyclic Sports Athletes

Regular physical activity in cyclic sports can influence the so-called “angiogenic switch”, which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the “angiogenic switch” problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the “angiogenic switch” is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the “angiogenic switch” as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance.     

Possible Crosstalk of the Immune Cells within the Lung and Mediastinal Fat-Associated Lymphoid Clusters in the Acute Inflammatory Lung Asthma-Like Mouse Model

Recently, we clarified the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of several respiratory diseases. However, their role has not yet been identified in the lung asthmatic condition. Hence, we compared the immune cells in lung and MFALCs of C57BL/6N mice on days 3 and 7 following intranasal instillation of either papain (papain group “PG”) or phosphate buffer saline (PBS) (vehicle group “VG”). The PG showed significantly prominent MFALCs, numerous goblet cells (GCs), and higher index ratios of different immune cells (macrophages, natural helper cells (NHC), B- and T-lymphocytes) within the MFALCs and lung than in the VG on both days 3 and 7. Interestingly, a tendency of decreased size of MFALCs and a significant reduction in the number of GCs and immune cells were observed within the MFALCs and lung in the PG on day 7 than on day 3. Furthermore, the quantitative parameters of these immune cells in MFALCs were significantly and positively correlated with the size of MFALCs and immune cells in the lung. This suggested that the possible crosstalk between immune cells within MFALCs and the lung could play a critical role in the progression and recovery of the acute inflammatory lung asthma.     

Cytokine Pathways and Investigational Target Therapies in Hidradenitis Suppurativa

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting areas with a high density of apocrine glands and characterized by subcutaneous nodules that may evolve into fistulas with pus secretion. Methods: The aim of this review is to investigate all current knowledge on cytokine regulation in the pathogenesis of HS. A systematic literature research using the words “cytokine”, “interleukin”, “pathway”, and “hidradenitis suppurativa” was performed in PubMed/Medline and Scopus/Embase databases. A search of the clinicaltrials.gov website for interventional recruiting and completed trials including the term “hidradenitis suppurativa” was also performed up to August 2020. We will discuss the pathogenetic role of various cytokines in HS and potential therapeutic targets for this debilitating disease. Results: The pathophysiology underlying this complex condition has not been clearly defined. An upregulation of various cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-17, IL-23, and other molecules seems to be related to this inflammatory condition. Various cells, such as lymphocytes T Helper 1 and 17 and keratinocytes seem to be involved in the genesis of this condition. Conclusions: Several future studies and clinical trials are necessary in order to have new knowledge about HS and to properly treat this complex condition.     

DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview

Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for “DAMPs” or “RAGE” or “S100B” and “traumatic brain injury” or “subarachnoid hemorrhage” or “stroke”. We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives     

Telomere Targeting Approaches in Cancer: Beyond Length Maintenance

Telomeres are crucial structures that preserve genome stability. Their progressive erosion over numerous DNA duplications determines the senescence of cells and organisms. As telomere length homeostasis is critical for cancer development, nowadays, telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere elongation, telomere dysfunction impinges on intracellular signaling pathways, in particular DNA damage signaling and repair, affecting cancer cell survival and proliferation. This review summarizes and discusses recent findings in anticancer drug development targeting different “telosome” components.     

Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review

Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords “nerve regeneration”, “stem cells”, “peripheral nerve injury”, “rat”, and “human” were used. Additionally, a “MeSH” research was performed in PubMed using the terms “stem cells” and “nerve regeneration”. The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.     

Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.     

Complex Analysis of Antioxidant Activity,Abscisic Acid Level,and Accumulation of Osmotica in Apple and Cherry In Vitro Cultures under Osmotic Stress

Plant response to osmotic stress is a complex issue and includes a wide range of physiological and biochemical processes. Extensive studies of known cultivars and their reaction to drought or salinity stress are very important for future breeding of new and tolerant cultivars. Our study focused on the antioxidant activity, accumulations of osmotica, and the content of abscisic acid in apple (cv. “Malinové holovouské”, “Fragrance”, “Rubinstep”, “Idared”, “Car Alexander”) and cherry (cv. “Regina”, “Napoleonova”, “Kaštánka”, “Sunburst”, “P-HL-C”) cultivated in vitro on media containing different levels of polyethylene glycol PEG-6000. Our results indicated that the studied genotypes responded differently to osmotic stress manifested as reduction in the leaf relative water content (RWC) and increment in the activities of antioxidant enzymes, proline, sugars, and abscisic acid content. Overall, cherry cultivars showed a smaller decrease in percentage RWC and enzymatic activities, but enhanced proline content compared to the apple plants cultivars. Cultivars “Rubinstep”, “Napoleonova”, and “Kaštánka” exhibited higher antioxidant capacity and accumulation of osmoprotectants like proline and sorbitol that can be associated with the drought-tolerance system.     

Genotypic Variation under Fe Deficiency Results in Rapid Changes in Protein Expressions and Genes Involved in Fe Metabolism and Antioxidant Mechanisms in Tomato Seedlings (Solanum lycopersicum L.)

To investigate Fe deficiency tolerance in tomato cultivars, quantification of proteins and genes involved in Fe metabolism and antioxidant mechanisms were performed in “Roggusanmaru” and “Super Doterang”. Fe deficiency (Moderate, low and –Fe) significantly decreased the biomass, total, and apoplastic Fe concentration of “Roggusanmaru”, while a slight variation was observed in “Super Doterang” cultivar. The quantity of important photosynthetic pigments such as total chlorophyll and carotenoid contents significantly decreased in “Roggusanmaru” than “Super Doterang” cultivar. The total protein profile in leaves and roots determines that “Super Doterang” exhibited an optimal tolerance to Fe deficiency compared to “Roggusanmaru” cultivar. A reduction in expression of PSI (photosystem I), PSII (photosystem II) super-complexes and related thylakoid protein contents were detected in “Roggusanmaru” than “Super Doterang” cultivar. Moreover, the relative gene expression of SlPSI and SlPSII were well maintained in “Super Doterang” than “Roggusanmaru” cultivar. The relative expression of genes involved in Fe-transport (SlIRT1 and SlIRT2) and Fe(III) chelates reductase oxidase (SlFRO1) were relatively reduced in “Roggusanmaru”, while increased in “Super Doterang” cultivar under Fe deficient conditions. The H⁺-ATPase relative gene expression (SlAHA1) in roots were maintained in “Super Doterang” compared to “Roggusanmaru”. Furthermore, the gene expressions involved in antioxidant defense mechanisms (SlSOD, SlAPX and SlCAT) in leaves and roots showed that these genes were highly increased in “Super Doterang”, whereas decreased in “Roggusanmaru” cultivar under Fe deficiency. The present study suggested that “Super Doterang” is better tomato cultivar than “Roggusanmaru” for calcareous soils.