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1.
Molecules ; 26(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500586

RESUMO

Radiation-induced fibrosis (RIF) is a serious, yet incurable, complication of external beam radiation therapy for the treatment of cancer. Macrophages are key cellular actors in RIF because of their ability to produce reactive oxidants, such as reactive oxygen species (ROS) and inflammatory cytokines that, in turn, are the drivers of pro-fibrotic pathways. In a previous work, we showed that phagocytosis could be exploited to deliver the potent natural antioxidant astaxanthin specifically to macrophages. For this purpose, astaxanthin encapsulated into µm-sized protein particles could specifically target macrophages that can uptake the particles by phagocytosis. In these cells, astaxanthin microparticles significantly reduced intracellular ROS levels and the secretion of bioactive TGFß and increased cell survival after radiation treatments. Here we show that pentoxifylline, a drug currently used for the treatment of muscle pain resulting from peripheral artery disease, amplifies the effects of astaxanthin microparticles on J774A.1 macrophages. Combination treatments with pentoxifylline and encapsulated astaxanthin might reduce the risk of RIF in cancer patients.


Assuntos
Macrófagos/efeitos dos fármacos , Microplásticos/química , Pentoxifilina/química , Pentoxifilina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Células Cultivadas , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Humanos , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Tolerância a Radiação/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Xantofilas/química , Xantofilas/farmacologia
2.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34544860

RESUMO

Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell-rich environment in disease. Furthermore, we observed a subpopulation of IL-17A-producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKß inhibitor or anti-IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.


Assuntos
Bursite/fisiopatologia , Fibrose/patologia , Inflamação/patologia , Interleucina-17/imunologia , Linfócitos T/imunologia , Estudos de Casos e Controles , Células Cultivadas , Citocinas/metabolismo , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/imunologia , Fibrose/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais
3.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361060

RESUMO

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.


Assuntos
Sistema Nervoso Central/patologia , Fibrose/patologia , Miocárdio/patologia , Neurônios/patologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Sistema Nervoso Central/metabolismo , Feminino , Fibrose/metabolismo , Proteínas HMGA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Neurônios/metabolismo , Fenótipo , Fosforilação
4.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445567

RESUMO

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Fibrose/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Animais , Fibrose/metabolismo , Fibrose/patologia , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Receptores de Lisoesfingolipídeo
5.
Am J Physiol Renal Physiol ; 321(4): F431-F442, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34396791

RESUMO

The proximal tubule (PT) is highly vulnerable to acute injury, including ischemic insult and nephrotoxins, and chronic kidney injury. It has been established that PT injury is a primary cause of the development of chronic kidney disease, but the underlying molecular mechanism remains to be defined. Here, we tested whether PT cyclophilin D (CypD), a mitochondrial matrix protein, is a critical factor to cause kidney fibrosis progression. To define the role of CypD in kidney fibrosis, we used an established mouse model for kidney fibrosis: the unilateral ureteral obstruction (UUO) model in global and PT-specific CypD knockout (KO). Global CypD KO blunted kidney fibrosis progression with inhibition of myofibroblast activation and fibrosis. UUO-induced tubular atrophy was suppressed in kidneys of global CypD KO but not tubular dilation or apoptotic cell death. PT cell cycle arrest was highly increased in wild-type UUO kidneys but was markedly attenuated in global CypD KO UUO kidneys. The number of macrophages and neutrophils was less in UUO kidneys of global CypD KO than those of wild-type kidneys. Proinflammatory and profibrotic factors were all inhibited in global CypD KO. In line with those of global CypD KO, PT-specific CypD KO also blunted kidney fibrosis progression, along with less tubular atrophy, renal parenchymal loss, cell cycle arrest in PT, and inflammation, indicating a critical role for PT CypD in fibrogenesis. Collectively, our data demonstrate that CypD in the PT is a critical factor contributing to kidney fibrosis in UUO, providing a new paradigm for mitochondria-targeted therapeutics of fibrotic diseases.NEW & NOTEWORTHY It has been established that renal proximal tubule (PT) injury is a primary cause of the development of chronic kidney disease, but the underlying molecular mechanism remains to be defined. Here, we show that cyclophilin D, a mitochondrial matrix protein, in the PT causes kidney fibrogenesis in obstructive nephropathy. Our data suggest that targeting PT cyclophilin D could be beneficial to prevent fibrosis progression.


Assuntos
Ciclofilina D/metabolismo , Fibrose/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Regulação da Expressão Gênica , Nefropatias/etiologia , Ligadura , Masculino , Camundongos , Camundongos Knockout
6.
Am J Physiol Renal Physiol ; 321(4): F466-F479, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34423679

RESUMO

Intraurethral inoculation of mice with uropathogenic Escherichia coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of a mast cell stabilizer, cromolyn sodium, and the histamine 1 receptor antagonist cetirizine di-hydrochloride in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.NEW & NOTEWORTHY LUTS-associated benign prostatic hyperplasia is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model, suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.


Assuntos
Fibrose/patologia , Mastócitos/fisiologia , Miócitos de Músculo Liso/patologia , Doenças Prostáticas/patologia , Animais , Antialérgicos/uso terapêutico , Cetirizina/uso terapêutico , Cromolina Sódica/uso terapêutico , Escherichia coli , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/patologia , Fibrose/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , Próstata/metabolismo , Próstata/patologia , Doenças Prostáticas/metabolismo , Micção
7.
Adv Clin Chem ; 104: 233-297, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34462056

RESUMO

Epigenetics examines heritable changes in DNA and its associated proteins except mutations in gene sequence. Epigenetic regulation plays fundamental roles in kidney cell biology through the action of DNA methylation, chromatin modification via epigenetic regulators and non-coding RNA species. Kidney diseases, including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis are multistep processes associated with numerous molecular alterations even in individual kidney cells. Epigenetic alterations, including anomalous DNA methylation, aberrant histone alterations and changes of microRNA expression all contribute to kidney pathogenesis. These changes alter the genome-wide epigenetic signatures and disrupt essential pathways that protect renal cells from uncontrolled growth, apoptosis and development of other renal associated syndromes. Molecular changes impact cellular function within kidney cells and its microenvironment to drive and maintain disease phenotype. In this chapter, we briefly summarize epigenetic mechanisms in four kidney diseases including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis. We primarily focus on current knowledge about the genome-wide profiling of DNA methylation and histone modification, and epigenetic regulation on specific gene(s) in the pathophysiology of these diseases and the translational potential of identifying new biomarkers and treatment for prevention and therapy. Incorporating epigenomic testing into clinical research is essential to elucidate novel epigenetic biomarkers and develop precision medicine using emerging therapies.


Assuntos
Epigênese Genética/genética , Nefropatias/genética , Fibrose/genética , Fibrose/metabolismo , Humanos , Nefropatias/metabolismo
8.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299192

RESUMO

Transforming growth factor-ß (TGF-ß) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor microenvironment (TME) for accelerating invasion, metastasis, angiogenesis, and immunosuppression. Increasing evidence suggest a pleiotropic nature of TGF-ß signaling as a critical pathway for generating fibrotic TME, which contains numerous cancer-associated fibroblasts (CAFs), extracellular matrix proteins, and remodeling enzymes. Its pathogenic roles and working mechanisms in tumorigenesis are still largely unclear. Importantly, recent studies successfully demonstrated the clinical implications of fibrotic TME in cancer. This review systematically summarized the latest updates and discoveries of TGF-ß signaling in the fibrotic TME.


Assuntos
Fibroblastos Associados a Câncer/patologia , Fibrose/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibrose/metabolismo , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neovascularização Patológica/patologia , Transdução de Sinais , Microambiente Tumoral
9.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299270

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defined. Under the definition of HFpEF there is a wide spectrum of different myocardial structural alterations. Myocardial hypertrophy and fibrosis, coronary microvascular dysfunction, oxidative stress and inflammation are only some of the main pathological detectable processes. Furthermore, there is a lack of effective pharmacological targets to improve HFpEF patients' outcomes and risk factors control is the primary and unique approach to treat those patients. Myocardial tissue characterization, through invasive and non-invasive techniques, such as endomyocardial biopsy and cardiac magnetic resonance respectively, may represent the starting point to understand the genetic, molecular and pathophysiological mechanisms underlying this complex syndrome. The correlation between histopathological findings and imaging aspects may be the future challenge for the earlier and large-scale HFpEF diagnosis, in order to plan a specific and effective treatment able to modify the disease's natural course.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Miocárdio/patologia , Volume Sistólico/fisiologia , Ensaios Clínicos como Assunto , Fibrose/metabolismo , Fibrose/patologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Espectroscopia de Ressonância Magnética , Miocárdio/metabolismo
10.
Methods Mol Biol ; 2350: 313-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34331294

RESUMO

We describe a multiplexed imaging mass spectrometry approach especially suitable for fibrosis research. Fibrosis is a process characterized by excessive extracellular matrix (ECM) secretion. Buildup of ECM impairs tissue and organ function to promote further progression of disease. It is an ongoing analytical challenge to access ECM for diagnosis and therapeutic treatment of fibrosis. Recently, we reported the use of the enzyme collagenase type III to target the ECM proteome in thin histological tissue sections of fibrotic diseases including hepatocellular carcinoma, breast cancer, prostate cancer, lung cancer and aortic valve stenosis. Detection of collagenase type III peptides by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) allows localization of ECM peptide sequences to specific regions of fibrosis. We have further identified that the ECM proteome accessed by collagenase type III has on average 3.7 sites per protein that may be differentially N-glycosylated. N-glycosylation is a major posttranslational modification of the ECM proteome, influencing protein folding, secretion, and organization. Understanding both N-glycosylation signaling and regulation of ECM expression significantly informs on ECM signaling in fibrosis.


Assuntos
Biomarcadores , Matriz Extracelular/metabolismo , Histocitoquímica/métodos , Espectrometria de Massas/métodos , Polissacarídeos/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Glicosilação , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica/métodos , Peptídeos/metabolismo , Processamento de Proteína Pós-Traducional , Proteômica/métodos , Pesquisa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Fluxo de Trabalho
11.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202091

RESUMO

As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression or impairment may result in thrombosis, as in antiphospholipid syndrome, venous thromboembolism, or atherosclerosis. Within immune response cells, A2 orchestrates membrane repair, vesicle fusion, and cytoskeletal organization, thus playing a critical role in inflammatory response and tissue injury. Dysregulation of A2 is evident in multiple human disorders, and may contribute to the pathogenesis of various inflammatory disorders. The fibrinolytic system, moreover, is central to wound healing through its ability to remodel the provisional matrix and promote angiogenesis. A2 dysfunction may also promote tissue fibrogenesis and end-organ fibrosis.


Assuntos
Anexina A2/genética , Suscetibilidade a Doenças , Fibrinólise/genética , Fibrose/etiologia , Inflamação/etiologia , Animais , Anexina A2/metabolismo , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Biomarcadores , Fibrose/metabolismo , Hemostasia/genética , Humanos , Imunidade , Inflamação/metabolismo , Especificidade de Órgãos , Regeneração
12.
Am J Physiol Gastrointest Liver Physiol ; 321(3): G280-G297, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288735

RESUMO

Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs), contributing to tissue stiffening and luminal narrowing. Human nuclear receptor 4A 1 (NR4A1) was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function. Using the SAMP1/YitFc mouse, we tested whether two pharmacological agents known to enhance NR4A1 signaling, cytosporone B (Csn-B) or 6-mercaptopurine (6-MP), could reduce fibrosis. We also used the dextran sulfate sodium (DSS) model of colitis and assessed the magnitude of colonic fibrosis in mouse nuclear receptor 4A 1 (Nr4a1-/-) and their wild-type littermates (Nr4a1+/+). Lastly, intestinal myofibroblasts isolated from Nr4a1-/- and Nr4a1+/+ mice or primary human intestinal myofibroblasts were stimulated with transforming growth factor-ß1 (TGF-ß1), in the presence or absence of Csn-B or 6-MP, and proliferation and ECM gene expression assessed. Csn-B or 6-MP treatment significantly reduced ileal thickness, collagen, and overall ECM content in SAMP1/YitFc mice. This was associated with a reduction in proliferative markers within the mesenchymal compartment. Nr4a1-/- mice exposed to DSS exhibited increased colonic thickening and ECM content. Nr4a1-/- myofibroblasts displayed enhanced TGF-ß1-induced proliferation. Furthermore, Csn-B or 6-MP treatment was antiproliferative in Nr4a1+/+ but not Nr4a1-/- cells. Lastly, activating NR4A1 in human myofibroblasts reduced TGF-ß1-induced collagen deposition and fibrosis-related gene expression. Our data suggest that NR4A1 can attenuate fibrotic processes in intestinal myofibroblasts and could provide a valuable clinical target to treat inflammation-associated intestinal fibrosis.NEW & NOTEWORTHY Fibrosis and increased muscle thickening contribute to stricture formation and intestinal obstruction, a complication that occurs in 30%-50% of patients with CD within 10 yr of disease onset. More than 50% of those who undergo surgery to remove the obstructed bowel will experience stricture recurrence. To date, there are no drug-based approaches approved to treat intestinal strictures. In the current submission, we identify NR4A1 as a novel target to treat inflammation-associated intestinal fibrosis.


Assuntos
Fibrose/metabolismo , Inflamação/metabolismo , Miofibroblastos/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Animais , Células Cultivadas , Humanos , Intestinos/patologia , Camundongos , Transdução de Sinais/fisiologia
13.
Biomed Res Int ; 2021: 5521564, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212030

RESUMO

Background: Cardiovascular disease (CVD) contributes critically to the mortality, morbidity, and economic problem of illness globally. Exercise is a share of everyone's life. Some evidence-based studies have frequently shown a progressive correlation between physical activity and good health. Objective: The effects of daily exercise on cardiomyocyte size, collagen content (fibrosis), and releasing mast cells (MCs') tryptase of the model of myocardial infarction (MI) were assessed. Methods: 40 rats were coincidentally spread into sham+inertia (control), sham+exercise, infarction+inertia, and infarction+exercise groups. An experimental model of acute MI was induced in infarction groups. One week after surgery, exercising groups were allowed to an aerobic exercise program for six weeks. At the endpoint of the study, all examinations were performed. Results: We found lesser fibrosis in sham+exercise and infarction+exercise groups compared to sham+inertia and infarction+inertia groups, respectively (p = 0.023, p = 0.001). Also, infarction groups were significantly lower than sham groups (p < 0.05) and the infarction+exercise group was significantly lower than the infarction+inertia group (p < 0.05). The effect of exercise on MCs while increased MC density and degranulation occur at the site of fibrosis, we demonstrated that exercise decreases both total MC density and degranulation in both sham and infarction groups (p < 0.05). Immunohistochemistry examinations were significantly higher expression of MCs' tryptase in infarction groups than sham groups (p < 0.05, p < 0.0001). Conclusion: Exercise improves fibrosis and cardiac function in both healthy and MI rats by inhibiting released MCs' tryptase.


Assuntos
Mastócitos/metabolismo , Mastócitos/fisiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Condicionamento Físico Animal/fisiologia , Regeneração/fisiologia , Triptases/metabolismo , Animais , Ecocardiografia/métodos , Terapia por Exercício/métodos , Fibrose/metabolismo , Fibrose/fisiopatologia , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Ratos , Ratos Wistar , Função Ventricular Esquerda/fisiologia
14.
Immunity ; 54(7): 1374-1376, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34260885

RESUMO

In a recent issue of Nature, Hoeffel et al. describe a novel pathway of sterile tissue repair utilizing a mouse model of sunburn. This wound healing pathway is coordinated by sensory neuron-derived TAFA4 that induces IL-10 production from Tim4+ dermal macrophages to prevent sustained inflammation and the emergence of tissue fibrosis.


Assuntos
Células Receptoras Sensoriais/patologia , Queimadura Solar/patologia , Cicatrização/fisiologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose/metabolismo , Fibrose/patologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Transdução de Sinais/fisiologia , Pele/metabolismo , Pele/patologia , Queimadura Solar/metabolismo
15.
Toxicol Appl Pharmacol ; 427: 115654, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34310909

RESUMO

Diabetic cardiomyopathy (DCM) is a serious diabetic complication that lacks effective preventive or therapeutic approaches. Wild-type and Klf15 knockout (Klf15-KO) mice were fed with either high fat diet (HFD, 60% kcal from fat) or normal diet (ND, 10% kcal from fat) for 3 months and then injected with streptozotocin or vehicle, to induce type 2 diabetes (T2D). All T2D and age-matched control mice were treated with or without SDF-1ß at 5 mg/kg body-weight twice a week and also continually received HFD or ND for 3 months. At the end of 6-month study, after cardiac functions were measured, mice were euthanized to collect heart tissue. For in vitro mechanistic study, H9c2 cells were exposed to palmitate to mimic in vivo condition of T2D. SDF-1ß prevented T2D-induced cardiac dysfunction and fibrosis and T2D-down-regulated KLF15 expression in wild-type diabetic heart tissue. However, the preventive effects of SDF-1ß on both KLF15 expression and fibrosis was abolished, with partial cardiac protection in Klf15-KO/T2D mice. These results demonstrate partial KLF15-dependence for SDF-1ß's cardiac fibrotic protection from T2D, but not on SDF-1ß's protective effects on T2D-induced cardiac dysfunction. Further study showed that SDF-1ß inhibited palmitate-induced cardiomyocyte fibrosis through its receptor CXCR7-mediated activation of p38ß MAPK signaling pathway.


Assuntos
Quimiocina CXCL12/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Fatores de Transcrição Kruppel-Like/deficiência , Animais , Linhagem Celular , Quimiocina CXCL12/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ratos
16.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299227

RESUMO

Our previous study showed that in adult mice, conditional Nedd4-2-deficiency in club and alveolar epithelial type II (AE2) cells results in impaired mucociliary clearance, accumulation of Muc5b and progressive, terminal pulmonary fibrosis within 16 weeks. In the present study, we investigated ultrastructural alterations of the alveolar epithelium in relation to interstitial remodeling in alveolar septa as a function of disease progression. Two, eight and twelve weeks after induction of Nedd4-2 knockout, lungs were fixed and subjected to design-based stereological investigation at the light and electron microscopic level. Quantitative data did not show any abnormalities until 8 weeks compared to controls. At 12 weeks, however, volume of septal wall tissue increased while volume of acinar airspace and alveolar surface area significantly decreased. Volume and surface area of alveolar epithelial type I cells were reduced, which could not be compensated by a corresponding increase of AE2 cells. The volume of collagen fibrils in septal walls increased and was linked with an increase in blood-gas barrier thickness. A high correlation between parameters reflecting interstitial remodeling and abnormal AE2 cell ultrastructure could be established. Taken together, abnormal regeneration of the alveolar epithelium is correlated with interstitial septal wall remodeling.


Assuntos
Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/ultraestrutura , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Remodelação das Vias Aéreas/fisiologia , Células Epiteliais Alveolares/fisiologia , Animais , Células Epiteliais/metabolismo , Feminino , Fibrose/metabolismo , Fibrose/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Ubiquitina-Proteína Ligases Nedd4/genética , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Surfactantes Pulmonares , Mucosa Respiratória/metabolismo
17.
J Med Chem ; 64(13): 9537-9549, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142552

RESUMO

Hepatic fibrosis commonly exists in chronic liver disease and would eventually develop to cirrhosis and liver cancer with high fatality. Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug target because of its highest binding affinity among phosphodiesterases (PDEs) with cyclic guanosine monophosphate. However, no published study has reported PDE9 inhibitors as potential agents against hepatic fibrosis yet. Herein, structural modification from a starting hit LL01 led to lead 4a, which exhibited an IC50 value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with 4a revealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of 4a exerted a significant antifibrotic effect in bile duct-ligation-induced rats with hepatic fibrosis and transforming growth factor-ß-induced fibrogenesis. This therapeutic effect was indeed achieved by selectively inhibiting PDE9 rather than other PDE isoforms, identifying PDE9 inhibitors as potential agents against hepatic fibrosis.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Descoberta de Drogas , Fibrose/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Ductos Biliares/metabolismo , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose/metabolismo , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Relação Estrutura-Atividade
18.
Chembiochem ; 22(15): 2516-2520, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34132013

RESUMO

The outbreak of SARS-CoV-2 has been an extraordinary event that constituted a global health emergency. As the novel coronavirus is continuing to spread over the world, the need for therapeutic agents to control this pandemic is increasing. αV ß6 Integrin may be an intriguing target not only for the inhibition of SARS-CoV-2 entry, but also for the diagnosis/treatment of COVID-19 related fibrosis, an emerging type of fibrotic disease which will probably affect a significant part of the recovered patients. In this short article, the possible role of this integrin for fighting COVID-19 is discussed on the basis of recently published evidence, showing how its underestimated involvement may be interesting for the development of novel pharmacological tools.


Assuntos
COVID-19/virologia , Fibrose/virologia , Cadeias beta de Integrinas/metabolismo , SARS-CoV-2/isolamento & purificação , COVID-19/metabolismo , COVID-19/patologia , Fibrose/metabolismo , Fibrose/patologia , Humanos
19.
ACS Chem Biol ; 16(6): 945-972, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34102834

RESUMO

Iron is an essential mineral that serves as a prosthetic group for a variety of proteins involved in vital cellular processes. The iron economy within humans is highly conserved in that there is no proper iron excretion pathway. Therefore, iron homeostasis is highly evolved to coordinate iron acquisition, storage, transport, and recycling efficiently. A disturbance in this state can result in excess iron burden in which an ensuing iron-mediated generation of reactive oxygen species imparts widespread oxidative damage to proteins, lipids, and DNA. On the contrary, problems in iron deficiency either due to genetic or nutritional causes can lead to a number of iron deficiency disorders. Iron chelation strategies have been in the works since the early 1900s, and they still remain the most viable therapeutic approach to mitigate the toxic side effects of excess iron. Intense investigations on improving the efficacy of chelation strategies while being well tolerated and accepted by patients have been a particular focus for many researchers over the past 30 years. Moreover, recent advances in our understanding on the role of iron in the pathogenesis of different diseases (both in iron overload and iron deficiency conditions) motivate the need to develop new therapeutics. We summarized recent investigations into the role of iron in health and disease conditions, iron chelation, and iron delivery strategies. Information regarding small molecule as well as macromolecular approaches and how they are employed within different disease pathogenesis such as primary and secondary iron overload diseases, cancer, diabetes, neurodegenerative diseases, infections, and in iron deficiency is provided.


Assuntos
Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Ferro/deficiência , Ferro/metabolismo , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Humanos , Ferro/análise , Ferro/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo
20.
FASEB J ; 35(7): e21497, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34152015

RESUMO

Despite the increasing understanding of the pathophysiology of hepatic fibrosis, the therapies to combat it remain inadequate. Fluorofenidone (AKF-PD) is a novel pyridone agent able to ameliorate hepatic fibrosis in an experimental hepatic fibrosis model induced by dimethylnitrosamine. However, the underlying mechanism remains to be further elucidated. In light of the critical role of the NF-κB pathway in inflammation and hepatic fibrosis, together with the preliminary finding that AKF-PD decreases the release of proinflammatory cytokines in the endotoxemia and unilateral ureteral occlusion model, the aim of this study was to explore whether AKF-PD exerts an antifibrotic effect in hepatic fibrosis by inhibiting inflammation and suppressing the activation of the NF-κB pathway in vivo and in vitro. To test this possibility, the effect of AKF-PD on hepatic fibrosis models induced by both carbon tetrachloride (CCL4 ) and porcine serum (PS) was investigated. Our results showed that AKF-PD treatment ameliorated hepatic injury and fibrosis in both models. Furthermore, the administration of AKF-PD induced a robust anti-inflammatory reaction revealed by the downregulation of the proinflammatory cytokines as well as the suppression of the infiltration of inflammatory cells in the fibrotic liver. The analysis of the mechanism of action demonstrated that the attenuation of the production of proinflammatory cytokines and chemokines mediated by AKF-PD in vivo and in vitro were accompanied by the suppression in the activation of the NF-κB signaling pathway. In conclusion, AKF-PD might be considered as an antifibrotic agent attenuating hepatic inflammation and fibrosis potentially through the suppression of the NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Hepatopatias/prevenção & controle , NF-kappa B/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Piridonas/farmacologia , Animais , Células Cultivadas , Fibrose/metabolismo , Fibrose/patologia , Inflamação/metabolismo , Inflamação/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Ratos , Ratos Sprague-Dawley
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