The Role of Macrophages in Kidney Fibrosis

The phenotypic heterogeneity and functional diversity of macrophages confer on them complexed roles in the development and progression of kidney diseases. After kidney injury, bone marrow-derived monocytes are rapidly recruited to the glomerulus and tubulointerstitium. They are activated and differentiated on site into pro-inflammatory M1 macrophages, which initiate Th1-type adaptive immune responses and damage normal tissues. In contrast, anti-inflammatory M2 macrophages induce Th2-type immune responses, secrete large amounts of TGF-β and anti-inflammatory cytokines, transform into αSMA+ myofibroblasts in injured kidney, inhibit immune responses, and promote wound healing and tissue fibrosis. Previous studies on the role of macrophages in kidney fibrosis were mainly focused on inflammation-associated injury and injury repair. Apart from macrophage-secreted profibrotic cytokines, such as TGF-β, evidence for a direct contribution of macrophages to kidney fibrosis is lacking. However, under inflammatory conditions, Wnt ligands are derived mainly from macrophages and Wnt signaling is central in the network of multiple profibrotic pathways. Largely underinvestigated are the direct contribution of macrophages to profibrotic signaling pathways, macrophage phenotypic heterogeneity and functional diversity in relation to kidney fibrosis, and on their cross-talk with other cells in profibrotic signaling networks that cause fibrosis. Here we aim to provide an overview on the roles of macrophage phenotypic and functional diversity in their contribution to pro-fibrotic signaling pathways, and on the therapeutic potential of targeting macrophages for the treatment of kidney fibrosis.

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Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180723104340 ◽

2019 ◽

Vol 14 (3) ◽

pp. 219-225 ◽

Cited By ~ 6

Author(s):

Cong Tang ◽

Guodong Zhu

Keyword(s):

Cancer Therapy ◽

Tyrosine Kinase ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Cell Receptor ◽

Transmembrane Receptors ◽

Biological Responses ◽

Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

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N-Acetylcysteine (NAC): Impacts on Human Health

Antioxidants ◽

10.3390/antiox10060967 ◽

2021 ◽

Vol 10 (6) ◽

pp. 967

Author(s):

Micaely Cristina dos Santos Tenório ◽

Nayara Gomes Graciliano ◽

Fabiana Andréa Moura ◽

Alane Cabral Menezes de Oliveira ◽

Marília Oliveira Fonseca Goulart

Keyword(s):

Human Health ◽

Therapeutic Potential ◽

Experimental Studies ◽

Primary Role ◽

Necrosis Factor Alpha ◽

Biochemical Basis ◽

Tnf Α ◽

Factor Alpha ◽

Anti Inflammatory

N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance. As an anti-inflammatory compound, NAC can reduce levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB). Despite NAC’s relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Thus, the purpose of this chapter is to provide an overview of the medicinal effects and applications of NAC to human health based on current therapeutic evidence.

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Hydrogen sulfide-mediated cardioprotection: mechanisms and therapeutic potential

Clinical Science ◽

10.1042/cs20100462 ◽

2010 ◽

Vol 120 (6) ◽

pp. 219-229 ◽

Cited By ~ 104

Author(s):

Madhav Lavu ◽

Shashi Bhushan ◽

David J. Lefer

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Hydrogen Sulfide ◽

Therapeutic Potential ◽

Blood Pressure Regulation ◽

Pressure Regulation ◽

Signalling Molecule ◽

Anti Inflammatory ◽

Antioxidant Effects

H2S (hydrogen sulfide), viewed with dread for more than 300 years, is rapidly becoming a ubiquitously present and physiologically relevant signalling molecule. Knowledge of the production and metabolism of H2S has spurred interest in delineating its functions both in physiology and pathophysiology of disease. Although its role in blood pressure regulation and interaction with NO is controversial, H2S, through its anti-apoptotic, anti-inflammatory and antioxidant effects, has demonstrated significant cardioprotection. As a result, a number of sulfide-donor drugs, including garlic-derived polysulfides, are currently being designed and investigated for the treatment of cardiovascular conditions, specifically myocardial ischaemic disease. However, huge gaps remain in our knowledge about this gasotransmitter. Only by additional studies will we understand more about the role of this intriguing molecule in the treatment of cardiovascular disease.

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The Role of the CX3CL1-CX3CR1 Axis in Renal Disease

AJP Renal Physiology ◽

10.1152/ajprenal.00059.2021 ◽

2021 ◽

Author(s):

Diana Hamdan ◽

Lisa A. Robinson

Keyword(s):

Therapeutic Potential ◽

Kidney Diseases ◽

Transmembrane Protein ◽

Soluble Form ◽

Protective Effects ◽

Chronic Kidney Diseases ◽

The Family ◽

Soluble Species ◽

And Function

Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines are key drivers of this process. CX3CL1 (fractalkine) is one of two unique chemokines synthesized as a transmembrane protein which undergoes proteolytic cleavage to generate a soluble species. Through interacting with its cognate receptor, CX3CR1, CX3CL1 was originally shown to act as a conventional chemoattractant in the soluble form, and as an adhesion molecule in the transmembrane form. Since then, other functions of CX3CL1 beyond leukocyte recruitment have been described, including cell survival, immunosurveillance, and cell-mediated cytotoxicity. This review summarizes diverse roles of CX3CL1 in kidney disease and potential uses as a therapeutic target and novel biomarker. As the CX3CL1-CX3CR1 axis has been shown to contribute to both detrimental and protective effects in various kidney diseases, a thorough understanding of how the expression and function of CX3CL1 are regulated is needed to unlock its therapeutic potential.

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Fate alteration of bone marrow-derived macrophages ameliorates kidney fibrosis in murine model of unilateral ureteral obstruction

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy381 ◽

2018 ◽

Vol 34 (10) ◽

pp. 1657-1668 ◽

Cited By ~ 4

Author(s):

Ying Yang ◽

Xiaojian Feng ◽

Xinyan Liu ◽

Ying Wang ◽

Min Hu ◽

...

Keyword(s):

Bone Marrow ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Kidney Diseases ◽

Unilateral Ureteral Obstruction ◽

Immunofluorescent Staining ◽

Enzyme Linked Immunosorbent Assay ◽

Pathological Feature ◽

Kidney Fibrosis ◽

Anti Inflammatory

AbstractBackgroundRenal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-β-induced macrophage–myofibroblast transition (MMT) in renal fibrosis.MethodsTGF-β signaling was redirected by inhibition of β-catenin/T-cell factor (TCF) to increase β-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay.ResultsInhibition of β-catenin/TCF by ICG-001 combined with TGF-β1 treatment increased β-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model.ConclusionsOur results demonstrate that diversion of β-catenin from TCF to Foxo1-mediated transcription not only inhibits the β-catenin/TCF-mediated fibrotic effect of TGF-β, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-β to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.

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The complex functions of microRNA-150 in allergy, autoimmunity and immune tolerance

AIMS Allergy and Immunology ◽

10.3934/allergy.2021016 ◽

2021 ◽

Vol 5 (4) ◽

pp. 195-221

Author(s):

Katarzyna Nazimek ◽

Keyword(s):

Immune Responses ◽

Immune Tolerance ◽

Therapeutic Potential ◽

Current Knowledge ◽

Signaling Cascades ◽

Cell Functions ◽

Regulatory Circuits ◽

Complex Functions ◽

Genetic Level

<abstract> <p>At present, special efforts are being made to develop the strategies allowing for activation of long-lasting antigen-specific immune tolerance in therapy of allergic and autoimmune diseases. Some of these therapeutic approaches are aimed at modulating cell functions at genetic level by using miRNA-based and miRNA-targeting treatments. Simultaneously, the crucial role of extracellular vesicles as natural miRNA conveyors is highlighted for induction of antigen-specific immune tolerance, especially that they appear to be easily manipulatable for therapeutic applications. Among other immune-related miRNAs, miR-150 is getting special attention as it is differently expressed by immune cells at various stages of their maturation and differentiation. In addition, miR-150 is involved in different signaling cascades orchestrating humoral and cell-mediated mechanisms of both innate and adaptive immune responses. Therefore, miR-150 is considered a master regulator of immunity in mammals. Currently, physiological miR-150-dependent regulatory circuits and causes of their malfunctioning that underlie the pathogenesis of allergic and autoimmune disorders are being unraveled. Thus, present review summarizes the current knowledge of the role of miR-150 in the pathogenesis and complications of these diseases. Furthermore, the involvement of miR-150 in regulation of immune responses to allergens and self-antigens and in induction of antigen-specific immune tolerance is discussed with the special emphasis on the therapeutic potential of this miRNA.</p> </abstract>

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Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential

Metabolites ◽

10.3390/metabo12010058 ◽

2022 ◽

Vol 12 (1) ◽

pp. 58

Author(s):

Xiaoqin Zhang ◽

Xiaogang Li

Keyword(s):

Kidney Disease ◽

Signaling Pathways ◽

Metabolic Pathways ◽

Molecular Mechanisms ◽

Unsaturated Fatty Acids ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Intracellular Iron ◽

Metabolic Signaling ◽

Iron Regulatory Proteins

Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. Ferroptosis has distinct biological and morphology characteristics, such as shrunken mitochondria when compared to other known regulated cell deaths. The regulation of ferroptosis includes different molecular mechanisms and multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling pathways, which are involved in the amino acid metabolism and the activation of GPX4; iron metabolic signaling pathways, which are involved in the regulation of iron import/export and the storage/release of intracellular iron through iron-regulatory proteins (IRPs), and lipid metabolic signaling pathways, which are involved in the metabolism of unsaturated fatty acids in cell membranes. Ferroptosis plays an essential role in the pathology of various kidneys diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), autosomal dominant polycystic kidney disease (ADPKD), and renal cell carcinoma (RCC). Targeting ferroptosis with its inducers/initiators and inhibitors can modulate the progression of kidney diseases in animal models. In this review, we discuss the characteristics of ferroptosis and the ferroptosis-based mechanisms, highlighting the potential role of the main ferroptosis-associated metabolic pathways in the treatment and prevention of various kidney diseases.

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The Role of Phytodiversity in Riparian Alder Forests in Supporting the Provision of Ecosystem Services

Acta Regionalia et Environmentalica ◽

10.1515/aree-2016-0010 ◽

2016 ◽

Vol 13 (2) ◽

pp. 47-51

Author(s):

Patrícia Mariničová ◽

Pavol Eliáš

Keyword(s):

Ecosystem Services ◽

Species Diversity ◽

Medicinal Plants ◽

Functional Groups ◽

Functional Diversity ◽

Woody Plants ◽

Forest Ecosystems ◽

Therapeutic Potential ◽

Human Society

Abstract Nature, ecosystems and biodiversity provide human society with many benefits known as ecosystem services. Functional diversity is an important aspect of biodiversity. In this paper, we applied inductive approach to the identification, mapping and evaluation of ecosystem services of the Aegopodio-Alnetum glutinosae community in Tribeč Mts. The results from 2015 show that the alder floodplain forest represents one of the most productive forest ecosystems with seasonal maximum production of 59.03 g m−2, species diversity of N0 = 40 and functional diversity of FD = 10. The forage potential of this community is medium, the melliferous potential is high and the therapeutic potential was estimated as extremely rich in medicinal plants. From the functional groups for providing ecosystem services, woody plants and hemicryptophytes play the most significant role.

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Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies

Current Medicinal Chemistry ◽

10.2174/0929867328666210707194543 ◽

2021 ◽

Vol 28 ◽

Author(s):

Adeleh Sahebnasagh ◽

Fatemeh Saghafi ◽

Sina Negintaji ◽

Tingyan Hu ◽

Mojtaba Shabani-Boroujeni ◽

...

Keyword(s):

Nitric Oxide ◽

Immune Responses ◽

Therapeutic Potential ◽

Relevant Literature ◽

Cochrane Library ◽

Signaling Molecule ◽

No Donors ◽

The Cochrane Library ◽

Oxide Synthase

: In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low / moderate levels may favor tumorigenesis while higher levels would exert anti-tumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this “double-edged sword” in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression, and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.

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The Role of Simvastatin in the Therapeutic Approach of Rheumatoid Arthritis

Autoimmune Diseases ◽

10.1155/2013/326258 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Lucia Cojocaru ◽

Andrei Constantin Rusali ◽

Cristina Şuţa ◽

Anca Mihaela Rădulescu ◽

Maria Şuţa ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cardiovascular Disease ◽

Active Rheumatoid Arthritis ◽

Therapeutic Potential ◽

Efficacy And Safety ◽

Good Safety Profile ◽

Study Support ◽

Anti Inflammatory ◽

Inflammatory Effect

The pleiotropic effects of statins, especially the anti-inflammatory and immunomodulatory ones, indicate that their therapeutic potential might extend beyond cholesterol lowering and cardiovascular disease to other inflammatory disorders such as rheumatoid arthritis. Therefore, we undertook a prospective cohort study to evaluate the efficacy and safety of simvastatin used for inflammation control in patients with rheumatoid arthritis. One hundred patients with active rheumatoid arthritis divided into two equal groups (the study one who received 20 mg/day of simvastatin in addition to prior DMARDs and the control one) were followed up over six months during three study visits. The results of the study support the fact that simvastatin at a dose of 20 mg/day has a low anti-inflammatory effect in patients with rheumatoid arthritis with a good safety profile.

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