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Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 22883

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Special Issue Editor

Dr. Georgina Hotter

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Guest Editor

Department of Experimental Pathology, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain. CIBER-BBN, Networking Center on Bioengineering, Biomaterials and Nanomedicine, Zaragoza, Spain
Interests: inflammation; macrophages; ischemia reperfusion; cytokines; regeneration; repair; kidney; acute renal failure; cell therapy

Special Issue Information

Dear Colleagues,

Damage and regeneration in abdominal organs produced as a consequence of tissue hypoxia/reoxygenation or ischemia/reperfusion between other pathological stimulus are part of a common response in which molecular signals and inflammatory cells have been recognized as critical stimulus to mediate injury and repair.

Tissue microenvironment, cytokines, leucocytes, and particularly macrophages are involved in both injury and repair mechanisms. Cell secreted factors and cell function are modified as a function of the microenvironment and can act in the aggravation of injury and/or in the repair mechanisms. The molecules, target cells, and regulatory mechanisms associated with ischemia or inflammatory signalling are emerging as promising therapeutic targets, able to promote organ repair and restore normal function.

In this Special Issue, expertise and original studies on all aspects of inflammation, inflammatory cells, cell therapy, and the molecular mechanisms involved in cell response to ischemia or inflammation in abdominal organs are welcomed.

Dr. Georgina Hotter
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cell therapy
inflammation
macrophages
ischemia/reperfusion
cytokines
regeneration
repair
kidney
pancreas
liver

Published Papers (7 papers)

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Research

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21 pages, 7662 KiB

Open AccessArticle

Renal Ischemia/Reperfusion Early Induces Myostatin and PCSK9 Expression in Rat Kidneys and HK-2 Cells

by Chiara Barisione, Daniela Verzola, Silvano Garibaldi, Pier Francesco Ferrari, Giacomo Garibotto, Pietro Ameri, Bianca Pane, Giovanni Spinella, Giovanni Pratesi and Domenico Palombo

Int. J. Mol. Sci. 2021, 22(18), 9884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189884 - 13 Sep 2021

Cited by 5 | Viewed by 2256

Abstract

During visceral interventions, the transient clampage of supraceliac aorta causes ischemia/reperfusion (I/R) in kidneys, sometime resulting in acute renal failure; preclinical studies identified redox imbalance as the main driver of I/R injury. However, in humans, the metabolic/inflammatory responses seem to prevail on oxidative stress. We investigated myostatin (Mstn) and proprotein convertase subtilisin/kexin type 9 (PCSK9), proatherogenic mediators, during renal I/R. Compared to sham-operated animals, the kidneys of rats who had experienced ischemia (30 min) had higher Mstn and PCSK9 expression after 4 h of reperfusion. After 24 h, they displayed tubular necrosis, increased nitrotyrosine positivity, and nuclear peroxisome proliferator-activated receptor gamma coactivator-1alpha relocation, markers of oxidative stress and mitochondria imbalance. Mstn immunopositivity was increased in tubuli, while PCSK9 immunosignal was depleted; systemically, PCSK9 was higher in plasma from I/R rats. In HK-2 cells, both ischemia and reperfusion enhanced reactive oxygen species production and mitochondrial dysfunction. H₂O₂ upregulated Mstn and PCSK9 mRNA after 1 and 3.5 h, respectively. Accordingly, ischemia early induced Mstn and PCSK9 mRNA; during reperfusion Mstn was augmented and PCSK9 decreased. Mstn treatment early increased PCSK9 expression (within 8 h), to diminish over time; finally, Mstn silencing restrained ischemia-induced PCSK9. Our study demonstrates that renal I/R enhances Mstn and PCSK9 expression and that Mstn induces PCSK9, suggesting them as therapeutic targets for vascular protection during visceral surgery. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs)

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16 pages, 2944 KiB

Open AccessArticle

Effectiveness Assessment of a Modified Preservation Solution Containing Thyrotropin or Follitropin Based on Biochemical Analysis in Perfundates and Homogenates of Isolated Porcine Kidneys after Static Cold Storage

by Aneta Ostróżka-Cieślik, Barbara Dolińska and Florian Ryszka

Int. J. Mol. Sci. 2021, 22(16), 8360; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168360 - 04 Aug 2021

Cited by 1 | Viewed by 2089

Abstract

In this paper, we assess the nephroprotective effects of thyrotropin and follitropin during ischaemia. The studies were performed in vitro in a model of isolated porcine kidneys stored in Biolasol (FZNP, Biochefa, Sosnowiec, Poland) and modified Biolasol (TSH: 1 µg/L; FSH 1 µg/L). We used the static cold storage method. The study was carried out based on 30 kidneys. The kidneys were placed in 500 mL of preservation solution chilled to 4 °C. The samples for biochemical tests were collected during the first kidney perfusion (after 2 h of storage) and during the second perfusion (after 48 h of storage). The results of ALT, AST, and LDH activities confirm the effectiveness of Biolasol + p-TSH in maintaining the structural integrity of renal cell membranes. Significantly reduced biochemical parameters of kidney function, i.e., creatinine and protein concentrations were also observed after 48 h storage. The protective effect of Biasol + p-TSH is most pronounced after 2 h of storage, suggesting a mild course of damage thereafter. A mild deterioration of renal function was observed after 48 h. The results of our analyses did not show any protective effect of Biolasol + p-FSH on the kidneys during ischaemia. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs)

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24 pages, 802 KiB

Open AccessArticle

Importance of Genetic Polymorphisms in MT1 and MT2 Genes in Metals Homeostasis and Their Relationship with the Risk of Acute Pancreatitis Occurrence in Smokers—Preliminary Findings

by Milena Ściskalska, Monika Ołdakowska and Halina Milnerowicz

Int. J. Mol. Sci. 2021, 22(11), 5725; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115725 - 27 May 2021

Cited by 2 | Viewed by 4358

Abstract

This study was aimed at evaluating the changes in metallothionein (MT) concentration in the blood of patients with acute pancreatitis (AP) and healthy subjects, taking into account the extracellular (plasma) and intracellular (erythrocyte lysate) compartments. The impact of single-nucleotide polymorphisms (SNPs) in the MT1A (rs11640851), MT1B (rs964372) and MT2A (rs10636) genes on MT concentration and their association with the concentration of metals (Cu, Zn, Cd) and ceruloplasmin as Cu-related proteins were analyzed. The concentration of a high-sensitivity C-reactive protein (hs-CRP) and IL-6 as markers of inflammation, and malonyldialdehyde (MDA), superoxide dismutase (SODs) activity and the value of total antioxidant capacity (TAC) as parameters describing the pro/antioxidative balance were also assessed. In the AP patient groups, an increased MT concentration in erythrocyte lysate compared to healthy subjects was shown, especially in individuals with the GG genotype for rs964372 in the MT1B gene. A Zn concentration was especially decreased in the blood of smoking AP patients with the AA genotype for SNP rs11640851 in the MT1A gene and the GC genotype for SNP rs10636 in MT2A, compared to non-smokers with AP, which was accompanied by an increase in the value of the Cu/Zn ratio. The exposure to tobacco smoke xenobiotics increased the risk of AP occurrence in subjects with the CC genotype for SNP rs11640851 in the MT1A gene by more than fourfold. The investigated polymorphisms, rs11640851 in the MT1A gene, rs964372 in the MT1B gene and rs10636 in the MT2A gene, seem to be an important factor in maintaining homeostasis in an organism under oxidative stress conditions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs)

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20 pages, 6422 KiB

Open AccessArticle

Both Specific Endothelial and Proximal Tubular Adam17 Deletion Protect against Diabetic Nephropathy

by Vanesa Palau, Bramasta Nugraha, David Benito, Julio Pascual, Maximilian Y. Emmert, Simon P. Hoerstrup, Marta Riera and Maria José Soler

Int. J. Mol. Sci. 2021, 22(11), 5520; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115520 - 24 May 2021

Cited by 9 | Viewed by 2733

Abstract

ADAM17 is a disintegrin and metalloproteinase capable of cleaving the ectodomains of a diverse variety of molecules including TNF-α, TGF-α, L-selectin, and ACE2. We have previously demonstrated that renal ADAM17 is upregulated in diabetic mice. The role of endothelial (eAdam17) and proximal tubular (tAdam17) Adam17 deletion in renal histology, modulation of the renin angiotensin system (RAS), renal inflammation, and fibrosis was studied in a mouse model of type 1 Diabetes Mellitus. Moreover, the effect of Adam17 deletion in an in vitro 3D cell culture from human proximal tubular cells under high glucose conditions was evaluated. eAdam17 deletion attenuates renal fibrosis and inflammation, whereas tAdam17 deletion decreases podocyte loss, attenuates the RAS, and decreases macrophage infiltration, α-SMA and collagen accumulation. The 3D in vitro cell culture reinforced the findings obtained in tAdam17KO mice with decreased fibrosis in the Adam17 knockout spheroids. In conclusion, Adam17 deletion either in the endothelial or the tubular cells mitigates kidney injury in the diabetic mice by targeting different pathways. The manipulation of Adam17 should be considered as a therapeutic strategy for treating DN. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs)

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15 pages, 3436 KiB

Open AccessArticle

IL-33 Is Involved in the Anti-Inflammatory Effects of Butyrate and Propionate on TNFα-Activated Endothelial Cells

by Meng Li, Betty C. A. M. van Esch, Paul A. J. Henricks, Johan Garssen and Gert Folkerts

Int. J. Mol. Sci. 2021, 22(5), 2447; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052447 - 28 Feb 2021

Cited by 8 | Viewed by 2084

Abstract

Short-chain fatty acids (e.g., butyrate and propionate) are able to diminish endothelial cell activation. The aim of this study was to investigate whether intracellular IL-33 mediates the effects of butyrate and propionate on TNFα-induced IL-8 production and vascular cell adhesion molecule-1 (VCAM-1) expression. In addition, it was investigated whether regulating NF-κB and MAPK signaling pathways are involved. Intracellular IL-33 was measured in human endothelial cells (HUVECs) pre-incubated for 24 h with butyrate (0.1 mM or 5 mM), propionate (0.3 mM or 10 mM), or trichostatin A (TSA, 0.5 μM) prior to TNFα (1 ng/mL) stimulation (24 h). The effects of butyrate, propionate, and TSA on TNFα-induced IL-8, vascular cell adhesion molecule-1 (VCAM-1), NF-κB, and MAPK signaling pathways in normal HUVECs and IL-33 siRNA (siIL-33)-transfected HUVECs were compared to study the role of IL-33 in the protective effects of butyrate and propionate. Endogenous IL-33 was highly expressed in the perinuclear in HUVECs, which was significantly reduced by TNFα stimulation. The TNFα-induced reduction in IL-33 was prevented by pre-incubation with butyrate or propionate. Butyrate (0.1 mM), propionate (0.3 mM), and TSA inhibited the IL-8 production and activation of NF-κB. Interestingly, this effect was not observed in siIL-33-transfected HUVECs. The effects of butyrate (5 mM), propionate (10 mM), and TSA (0.5 μM) on VCAM-1 expression and activation of MAPK signaling pathways were not affected by siIL-33 transfection. In conclusion, we showed that the inhibitory effects of butyrate and propionate on TNFα-induced IL-8 production were mediated by the HDACs/IL-33/NF-κB pathway, while their effects on VCAM-1 expression might be associated with the HDACs/MAPK signaling pathway, independently of IL-33. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs)

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Review

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20 pages, 2634 KiB

Open AccessReview

Molecular Mechanisms of Kidney Injury and Repair

by Sandra Rayego-Mateos, Laura Marquez-Expósito, Raquel Rodrigues-Diez, Ana B. Sanz, Roser Guiteras, Nuria Doladé, Irene Rubio-Soto, Anna Manonelles, Sergi Codina, Alberto Ortiz, Josep M. Cruzado, Marta Ruiz-Ortega and Anna Sola

Int. J. Mol. Sci. 2022, 23(3), 1542; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031542 - 28 Jan 2022

Cited by 28 | Viewed by 6137

Abstract

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms. Current therapeutic options slow CKD progression but fail to treat or accelerate recovery from AKI and are unable to promote kidney regeneration. Unraveling the cellular and molecular mechanisms involved in kidney injury and repair, including the failure of this process, may provide novel biomarkers and therapeutic tools. We now review the contribution of different molecular and cellular events to the AKI-to-CKD transition, focusing on the role of macrophages in kidney injury, the different forms of regulated cell death and necroinflammation, cellular senescence and the senescence-associated secretory phenotype (SAPS), polyploidization, and podocyte injury and activation of parietal epithelial cells. Next, we discuss key contributors to repair of kidney injury and opportunities for their therapeutic manipulation, with a focus on resident renal progenitor cells, stem cells and their reparative secretome, certain macrophage subphenotypes within the M2 phenotype and senescent cell clearance. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs)

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16 pages, 13191 KiB

Open AccessReview

Cell-Mediated Therapies to Facilitate Operational Tolerance in Liver Transplantation

by Samia D. Ellias, Ellen L. Larson, Timucin Taner and Scott L. Nyberg

Int. J. Mol. Sci. 2021, 22(8), 4016; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084016 - 13 Apr 2021

Cited by 7 | Viewed by 2411

Abstract

Cell therapies using immune cells or non-parenchymal cells of the liver have emerged as potential treatments to facilitate immunosuppression withdrawal and to induce operational tolerance in liver transplant (LT) recipients. Recent pre-clinical and clinical trials of cellular therapies including regulatory T cells, regulatory dendritic cells, and mesenchymal cells have shown promising results. Here we briefly summarize current concepts of cellular therapy for induction of operational tolerance in LT recipients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Damage and Regeneration in Disorders Associated with Abdominal Organs)

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