scholarly journals Control of Tissue Fibrosis by 5-Methoxytryptophan, an Innate Anti-Inflammatory Metabolite

2021 ◽  
Vol 12 ◽  
Author(s):  
Kenneth K Wu
Keyword(s):  
Tryptophan Hydroxylase ◽  
Stellate Cell ◽  
Normal Structure ◽  
Pulmonary Insufficiency ◽  
Tissue Fibrosis ◽  
Ecm Proteins ◽  
Vital Functions ◽  
Therapeutic Value ◽  
Tryptophan Catabolism ◽  
Inflammatory Macrophages

Tissue fibrosis causes debilitating human diseases such as liver cirrhosis, heart failure, chronic kidney disease and pulmonary insufficiency. It is a dynamic process orchestrated by specific subsets of monocyte-macrophages, fibroblasts, pericytes and hepatic stellate cells. Fibrosis is linked to tissue inflammation. Pro-inflammatory macrophages promote fibrosis by driving myofibroblast differentiation and macrophage myofibroblast transition. Myofibroblasts express α-smooth muscle cell actin (α-SMA) and secrete extracellular matrix (ECM) proteins notably collagen I and III. Deposition of ECM proteins at injury sites and interstitial tissues distorts normal structure and impairs vital functions. Despite advances in the mechanisms of fibrosis at cellular, molecular and genetic levels, prevention and treatment of fibrotic diseases remain poorly developed. Recent reports suggest that 5-methoxytryptophan (5-MTP) is effective in attenuating injury-induced liver, kidney, cardiac and pulmonary fibrosis. It inhibits macrophage activation and blocks fibroblast differentiation to myofibroblasts. Furthermore, it inhibits hepatic stellate cell differentiation into myofibroblasts. As 5-MTP is an endogenous molecule derived from tryptophan catabolism via tryptophan hydroxylase pathway, it is well-suited as a lead compound for developing new anti-fibrotic drugs. This article provides an overview of 5-MTP synthesis, and a critical review of its anti-fibrotic activities. Its mechanisms of actions and potential therapeutic value will be discussed.

scholarly journals Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2108
Author(s):  
Tania Aguado ◽  
Marta García ◽  
Adela García ◽  
Gemma Ferrer-Mayorga ◽  
Lucía Martínez-Santamaría ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Clinical Manifestations ◽  
Functional Screening ◽  
Dystrophic Epidermolysis Bullosa ◽  
Receptor Modulator ◽  
Ecm Proteins ◽  
Therapeutic Value ◽  
Recessive Dystrophic Epidermolysis Bullosa ◽  
Col7a1 Gene ◽  
Tgf Β1

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the COL7A1 gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event.

scholarly journals OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

2018 ◽  
Vol 47 (4) ◽  
pp. 1711-1720 ◽  
Author(s):  
Chunhua Wu ◽  
Shanhu Qiu ◽  
Xiangyun Zhu ◽  
Hao Lin ◽  
Ling Li
Keyword(s):  
Stellate Cell ◽  
Cell Activity ◽  
Organic Cation Transporter ◽  
Adenosine Monophosphate ◽  
Pharmacological Action ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Stellate Cell ◽  
Beneficial Effects ◽  
Regulatory Molecule ◽  
Ecm Proteins

Background/Aims: Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Methods: Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate–activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Results: Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Conclusions: Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity.

scholarly journals Metabolic Fingerprinting Uncovers the Distinction Between the Phenotypes of Tuberculosis Associated COPD and Smoking-Induced COPD

2021 ◽  
Vol 8 ◽  
Author(s):  
Da Jung Kim ◽  
Jee Youn Oh ◽  
Chin Kook Rhee ◽  
Seoung Ju Park ◽  
Jae Jeong Shim ◽  
...  
Keyword(s):  
Tryptophan Hydroxylase ◽  
Inflammatory Responses ◽  
Serum Levels ◽  
Chronic Obstructive ◽  
C Reactive Protein ◽  
Serum Samples ◽  
Cross Sectional ◽  
Reactive Protein ◽  
Metabolomic Profiling ◽  
Tryptophan Catabolism

Background: Although smoking is considered the main cause of chronic obstructive pulmonary disease (COPD), several other risk factors, including pulmonary tuberculosis (TB), contribute significantly to disease causation, particularly in developing countries. However, the underlying pathogenesis of TB-associated COPD (T-COPD) is unclear. Moreover, the need for prompt diagnosis and treatment of T-COPD to decrease the future burden of inflammation is underestimated. This study aimed to identify distinctive endogenous metabotypes of T-COPD, compared to smoking-associated COPD (S-COPD).Methods: Cross-sectional metabolomic analyses and clinical examinations of serum samples were performed for three groups of 168 male subjects: T-COPD (n = 59), S-COPD (n = 70), and healthy normal controls (n = 39). To retain a broad spectrum of metabolites, we performed technically distinct analyses (global metabolomic profiling using LC-QTOFMS and targeted analyses using LC-MS/MS).Results: Higher levels of IL-6 and C-reactive protein and St. George Respiratory Questionnaire scores were seen in the T-COPD group, compared to those in the S-COPD group. Global metabolomic profiling showed elevated metabolites, including arachidonic and eicosanoic acids, in the T-COPD group. Typical changes in tryptophan catabolism were observed through targeted profiling. Additionally, in the T-COPD group, kynurenine was elevated, and serotonin levels were reduced; therefore, indoleamine dioxygenase (IDO)/tryptophan hydroxylase (TPH) activities were dysregulated. Correlation analyses showed that changes in oxylipins were positively correlated with serum levels of IL-6 and C-reactive protein.Conclusion: Patients with TB-related COPD have enhanced inflammatory responses that may be linked to fatty acid pathways and tryptophan catabolism, which could be novel therapeutic targets for T-COPD.

scholarly journals Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale

2017 ◽  
Vol 10 ◽  
pp. 117864691771349 ◽  
Author(s):  
Hector Rodriguez Cetina Biefer ◽  
Anju Vasudevan ◽  
Abdallah Elkhal
Keyword(s):  
Immune Responses ◽  
Nicotinamide Adenine Dinucleotide ◽  
Tryptophan Hydroxylase ◽  
De Novo ◽  
Kynurenine Pathway ◽  
Nicotinamide Adenine ◽  
De Novo Synthesis ◽  
Major Pathway ◽  
Adaptive Immune ◽  
Tryptophan Catabolism

Increasing evidence underscores the interesting ability of tryptophan to regulate immune responses. However, the exact mechanisms of tryptophan’s immune regulation remain to be determined. Tryptophan catabolism via the kynurenine pathway is known to play an important role in tryptophan’s involvement in immune responses. Interestingly, quinolinic acid, which is a neurotoxic catabolite of the kynurenine pathway, is the major pathway for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that NAD+, a natural coenzyme found in all living cells, regulates immune responses and creates homeostasis via a novel signaling pathway. More importantly, the immunoregulatory properties of NAD+ are strongly related to the overexpression of tryptophan hydroxylase 1 (Tph1). This review provides recent knowledge of tryptophan and NAD+ and their specific and intriguing roles in the immune system. Furthermore, it focuses on the mechanisms by which tryptophan regulates NAD+ synthesis as well as innate and adaptive immune responses.

The Role of SRC in Strain- and Ligand- Dependent Phenotypic Modulation of Mouse Embryonic Fibroblasts

2011 ◽  
Author(s):  
M. K. Sewell-Loftin ◽  
W. David Merryman
Keyword(s):  
Type I Collagen ◽  
Heart Valve Disease ◽  
Contractile Element ◽  
Type I ◽  
Cellular Activation ◽  
Tissue Fibrosis ◽  
Mortality And Morbidity ◽  
Disease States ◽  
Ecm Proteins

Connective tissue fibrosis represents a significant portion of mortality and morbidity in our society. These diseases include many illnesses such as heart valve disease, atherosclerosis, macular degeneration, and cirrhosis, meaning that millions of lives are affected by these conditions each year. Fibrotic tissues form when quiescent fibroblasts activate becoming myofibroblasts, the phenotype of active tissue construction and fibrosis. During this process, the cells produce smooth muscle α-actin (αSMA), a contractile element considered to be the hallmark of cellular activation [1]. Following the production of αSMA, there is an increase in the synthesis of extracellular matrix (ECM) proteins, most notably type I collagen; this increase in ECM proteins causes the stiffening of the tissue characteristic of fibrotic disease. In non-disease states (such as wound healing or tissue development), the myofibroblasts will either deactivate, becoming fibroblasts again, or apoptose before tissue fibrosis occurs. However, when myofibroblasts persist, increased ECM protein deposition causes increased tissue stiffness and activates neighboring cells, causing the fibrosis to propagate. Currently there are no therapies to prevent or reverse fibrosis. Therefore a more thorough understanding of the dynamic mechanical environment and signaling pathways involved in the activation of fibroblasts is required to develop potential treatments.

scholarly journals Small extracellular vesicles derived from interferon-γ pre-conditioned mesenchymal stromal cells effectively treat liver fibrosis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Suguru Takeuchi ◽  
Atsunori Tsuchiya ◽  
Takahiro Iwasawa ◽  
Shunsuke Nojiri ◽  
Takayuki Watanabe ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Stellate Cell ◽  
Interferon Γ ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

AbstractMesenchymal stromal cells (MSCs) are used for ameliorating liver fibrosis and aiding liver regeneration after cirrhosis; Here, we analyzed the therapeutic potential of small extracellular vesicles (sEVs) derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs). γ-sEVs effectively induced anti-inflammatory macrophages with high motility and phagocytic abilities in vitro, while not preventing hepatic stellate cell (HSC; the major source of collagen fiber) activation in vitro. The proteome analysis of MSC-derived sEVs revealed anti-inflammatory macrophage inducible proteins (e.g., annexin-A1, lactotransferrin, and aminopeptidase N) upon IFN-γ stimulation. Furthermore, by enabling CX3CR1+ macrophage accumulation in the damaged area, γ-sEVs ameliorated inflammation and fibrosis in the cirrhosis mouse model more effectively than sEVs. Single cell RNA-Seq analysis revealed diverse effects, such as induction of anti-inflammatory macrophages and regulatory T cells, in the cirrhotic liver after γ-sEV administration. Overall, IFN-γ pre-conditioning altered sEVs resulted in efficient tissue repair indicating a new therapeutic strategy.

Fine Structure of the Malpighian Tubules of the Mosquito, Culex pipiens

1971 ◽  
Vol 29 ◽  
pp. 402-403
Author(s):  
Brendan Clifford
Keyword(s):  
Fine Structure ◽  
Culex Pipiens ◽  
Stellate Cell ◽  
Malpighian Tubule ◽  
Cell Types ◽  
Instar Larva ◽  
Malpighian Tubules ◽  
Calliphora Erythrocephala ◽  
Distinct Cell ◽  
Basal Plasma

An ultrastructural investigation of the Malpighian tubules of the fourth instar larva of Culex pipiens was undertaken as part of a continuing study of the fine structure of transport epithelia.Each of the five Malpighian tubules was found to be morphologically identical and regionally undifferentiated. Two distinct cell types, the primary and stellate, were found intermingled along the length of each tubule. The ultrastructure of the stellate cell was previously described in the Malpighian tubule of the blowfly, Calliphora erythrocephala by Berridge and Oschman.The basal plasma membrane of the primary cell is extremely irregular, giving rise to a complex interconnecting network of basal channels. The compartments of cytoplasm entrapped within this system of basal infoldings contain mitochondria, free ribosomes, and small amounts of rough endoplasmic reticulum. The mitochondria are distinctive in that the cristae run parallel to the long axis of the organelle.

The microtubule associated protein (MAP) tau forms a new class of triple-stranded left-hand helical fibrous protein polymer

1992 ◽  
Vol 50 (1) ◽  
pp. 540-541
Author(s):  
G. C. Ruben ◽  
K. Iqbal ◽  
I. Grundke-Iqbal ◽  
H. Wisniewski ◽  
T. L. Ciardelli ◽  
...  
Keyword(s):  
Axial Ratio ◽  
Normal Structure ◽  
Paired Helical Filaments ◽  
Left Hand ◽  
New Class ◽  
Protein Polymer ◽  
Fibrous Protein ◽  
Protein Map ◽  
Neurotransmitter Transport ◽  
Alzheimer Neurofibrillary Tangles

In neurons, the microtubule associated protein, tau, is found in the axons. Tau stabilizes the microtubules required for neurotransmitter transport to the axonal terminal. Since tau has been found in both Alzheimer neurofibrillary tangles (NFT) and in paired helical filaments (PHF), the study of tau's normal structure had to preceed TEM studies of NFT and PHF. The structure of tau was first studied by ultracentrifugation. This work suggested that it was a rod shaped molecule with an axial ratio of 20:1. More recently, paraciystals of phosphorylated and nonphosphoiylated tau have been reported. Phosphorylated tau was 90-95 nm in length and 3-6 nm in diameter where as nonphosphorylated tau was 69-75 nm in length. A shorter length of 30 nm was reported for undamaged tau indicating that it is an extremely flexible molecule. Tau was also studied in relation to microtubules, and its length was found to be 56.1±14.1 nm.

Healing gone wrong: convergence of hemostatic pathways and liver fibrosis?

2020 ◽  
Vol 134 (16) ◽  
pp. 2189-2201
Author(s):  
Jessica P.E. Davis ◽  
Stephen H. Caldwell
Keyword(s):  
Wound Healing ◽  
Liver Disease ◽  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Factor Xa ◽  
Clinical Trial Data ◽  
Chronic Liver ◽  
Healing Response ◽  
Wound Healing Response

Abstract Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis – the chronic nature of insult required and the liver’s unique ability to regenerate – give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

NCX-1000, an NO derivative of UDCA, refeases NO and protects against portal hypertension by inhibiting hepatic stellate cell contraction

2001 ◽  
Vol 120 (5) ◽  
pp. A379-A379
Author(s):  
S FIORUCCI ◽  
E ANTONELLI ◽  
O MORELLI ◽  
A MENCARELLI ◽  
B PALAZZETTI ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hepatic Stellate Cell ◽  
Stellate Cell ◽  
Cell Contraction
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