Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.041
Filtrar
1.
Elife ; 112022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-35138248

RESUMO

Regional control of fibrosis after myocardial infarction is critical for maintaining structural integrity in the infarct while preventing collagen accumulation in non-infarcted areas. Cardiac fibroblasts modulate matrix turnover in response to biochemical and biomechanical cues, but the complex interactions between signaling pathways confound efforts to develop therapies for regional scar formation. We employed a logic-based ordinary differential equation model of fibroblast mechano-chemo signal transduction to predict matrix protein expression in response to canonical biochemical stimuli and mechanical tension. Functional analysis of mechano-chemo interactions showed extensive pathway crosstalk with tension amplifying, dampening, or reversing responses to biochemical stimuli. Comprehensive drug target screens identified 13 mechano-adaptive therapies that promote matrix accumulation in regions where it is needed and reduce matrix levels in regions where it is not needed. Our predictions suggest that mechano-chemo interactions likely mediate cell behavior across many tissues and demonstrate the utility of multi-pathway signaling networks in discovering therapies for context-specific disease states.


Assuntos
Fenômenos Biomecânicos/fisiologia , Fibroblastos , Mecanotransdução Celular/fisiologia , Infarto do Miocárdio/fisiopatologia , Animais , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/fisiologia , Fibrose/fisiopatologia , Humanos , Camundongos , Modelos Biológicos , Miocárdio/citologia , Transdução de Sinais/fisiologia
2.
Toxicol Lett ; 359: 10-21, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35114312

RESUMO

Organic anion transporters 1 (OAT1) and OAT3 are responsible for transporting adefovir (ADV) into renal tubular epithelial cells. Our previous research found that ADV accumulated in the renal interstitium and caused renal interstitial fibrosis when Oat1/3 were inhibited by OATs inhibitor probenecid for long-term. Mast cells (MCs) in the interstitial space are considered to be key drivers of renal fibrosis. The current work investigated the effect of ADV on MCs in vitro and during the development of interstitial fibrosis in rats. Results indicate that ADV triggers chymase release from cultured RBL-2H3 mast cells in a time-and concentration-dependent manner. Angiotensin II (Ang II) in renal interstitium is generated mainly by chymase, renin and other products released from MCs, and has a direct effect on fibrosis through the angiotensin receptor. The concentrations of Ang II and fibrosis was significantly increased after administration of ADV alone or with probenecid for 4 weeks. The MCs membrane stabilizer sodium cromoglycate (SCG) and the angiotensin receptor antagonist Valsartan (VAL) could ameliorate ADV-induced nephrotoxicity. Additionally, SCG or VAL could reduce the accumulation of ADV in the renal interstitium by upregulating the expression of Oat1/3 and multidrug resistance-associated protein 4. Therefore, ADV accumulation in the renal interstitium could promote the degranulation of interstitial MCs and drive the development of renal fibrosis. SCG or VAL could ameliorate ADV-associated fibrosis by decreasing degranulation of MCs and accelerating renal clearance of ADV.


Assuntos
Adenina/análogos & derivados , Adenina/toxicidade , Degranulação Celular/efeitos dos fármacos , Fibrose/induzido quimicamente , Nefropatias/induzido quimicamente , Mastócitos/efeitos dos fármacos , Organofosfonatos/toxicidade , Adenina/sangue , Animais , Modelos Animais de Doenças , Fibrose/fisiopatologia , Humanos , Nefropatias/fisiopatologia , Túbulos Renais/efeitos dos fármacos , Masculino , Organofosfonatos/sangue , Ratos
3.
Life Sci ; 295: 120377, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35131235

RESUMO

AIMS: We evaluated the role of intergenerational paternal exercise on fibrosis, inflammatory profile, and redox status in the adipose tissue of male rat offspring fed with high-fat diet (HFD) and explored to what extent programming affects the systemic metabolic profile. MAIN METHODS: Adult wistar rats were randomly divided into two groups: sedentary fathers and trained fathers (8 weeks of resistance training (RT), three times per week). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups (7 animals per group): offspring of sedentary fathers exposed to either a control diet (SFO-C) or a high-fat diet (SFO-HF); offspring of trained fathers exposed to a control diet (TFO-C) or a high-fat diet (TFO-HF). KEY FINDINGS: Paternal RT was effective in attenuating body weight gain, adipocyte size, collagen deposition, as well as downregulating genes (CTGF, VEGF, C/EBPα SREBP1, MCP-1, and NF-kB), pro-inflammatory cytokine levels (Tumor Necrosis Factor alpha and Interleukin-1-beta), matrix metalloproteinase -2 activity, and ROS production in the epididymal adipose tissue of offspring fed with HFD (TFO-HF vs. SFO-HF; P < 0.05). Moreover, paternal RT increased adiponectin and superoxide dismutase (SOD) activity in the tissue. These beneficial effects were accompanied by the increase of antioxidant enzymes (SOD and α-Klotho), while decreasing pro-oxidant agents (F2-isoprostanes, protein carbonyls levels), and metabolic markers (insulin and leptin, HOMA-ß, and HOMA-IR) in the offspring blood circulation. SIGNIFICANCE: Our findings reveal protective effects of intergenerational paternal RT on adipose tissue remodeling and metabolic health of offspring fed with HFD.


Assuntos
Tecido Adiposo/fisiologia , Fibrose/fisiopatologia , Herança Paterna/fisiologia , Animais , Peso Corporal , Citocinas/metabolismo , Dieta Hiperlipídica , Pai , Fibrose/prevenção & controle , Insulina/metabolismo , Interleucina-1beta/metabolismo , Masculino , Obesidade/metabolismo , Oxirredução , Exposição Paterna , Condicionamento Físico Animal/métodos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Treinamento de Força , Ganho de Peso
4.
Cells ; 11(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-35011717

RESUMO

Prior research has implicated the involvement of cell adhesion molecule N-cadherin in tissue fibrosis and remodeling. We hypothesize that anomalies in N-cadherin protein processing are involved in pathological fibrosis. Diseased tissues associated with fibrosis of the heart, lung, and liver were probed for the precursor form of N-cadherin, pro-N-cadherin (PNC), by immunohistochemistry and compared to healthy tissues. Myofibroblast cell lines were analyzed for cell surface pro-N-cadherin by flow cytometry and immunofluorescent microscopy. Soluble PNC products were immunoprecipitated from patient plasmas and an enzyme-linked immunoassay was developed for quantification. All fibrotic tissues examined show aberrant PNC localization. Cell surface PNC is expressed in myofibroblast cell lines isolated from cardiomyopathy and idiopathic pulmonary fibrosis but not on myofibroblasts isolated from healthy tissues. PNC is elevated in the plasma of patients with cardiomyopathy (p ≤ 0.0001), idiopathic pulmonary fibrosis (p ≤ 0.05), and nonalcoholic fatty liver disease with cirrhosis (p ≤ 0.05). Finally, we have humanized a murine antibody and demonstrate that it significantly inhibits migration of PNC expressing myofibroblasts. Collectively, the aberrant localization of PNC is observed in all fibrotic tissues examined in our study and our data suggest a role for cell surface PNC in the pathogenesis of fibrosis.


Assuntos
Caderinas/metabolismo , Fibrose/fisiopatologia , Proteólise/efeitos dos fármacos , Animais , Diferenciação Celular , Feminino , Humanos , Camundongos
5.
Adv Drug Deliv Rev ; 182: 114045, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34767865

RESUMO

The global prevalence of diabetes mellitus was estimated to be 463 million people in 2019 and is predicted to rise to 700 million by 2045. The associated financial and societal costs of this burgeoning epidemic demand an understanding of the pathology of this disease, and its complications, that will inform treatment to enable improved patient outcomes. Nearly two decades after the sequencing of the human genome, the significance of noncoding RNA expression is still being assessed. The family of functional noncoding RNAs known as microRNAs regulates the expression of most genes encoded by the human genome. Altered microRNA expression profiles have been observed both in diabetes and in diabetic complications. These transcripts therefore have significant potential and novelty as targets for therapy, therapeutic agents and biomarkers.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Portadores de Fármacos , MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Biomarcadores , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/fisiopatologia , Fibrose/tratamento farmacológico , Fibrose/fisiopatologia , Humanos , Hipoglicemiantes/farmacologia , Inflamação/metabolismo , MicroRNAs/administração & dosagem
6.
Hepatol Commun ; 6(1): 101-119, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34494384

RESUMO

No approved therapies are available for nonalcoholic steatohepatitis (NASH). Adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of cell metabolism; its activation has been suggested as a therapeutic approach to NASH. Here we aimed to fully characterize the potential for direct AMPK activation in preclinical models and to determine mechanisms that could contribute to efficacy for this disease. A novel small-molecule direct AMPK activator, PXL770, was used. Enzyme activity was measured with recombinant complexes. De novo lipogenesis (DNL) was quantitated in vivo and in mouse and human primary hepatocytes. Metabolic efficacy was assessed in ob/ob and high-fat diet-fed mice. Liver histology, biochemical measures, and immune cell profiling were assessed in diet-induced NASH mice. Direct effects on inflammation and fibrogenesis were assessed using primary mouse and human hepatic stellate cells, mouse adipose tissue explants, and human immune cells. PXL770 directly activated AMPK in vitro and reduced DNL in primary hepatocytes. In rodent models with metabolic syndrome, PXL770 improved glycemia, dyslipidemia, and insulin resistance. In mice with NASH, PXL770 reduced hepatic steatosis, ballooning, inflammation, and fibrogenesis. PXL770 exhibited direct inhibitory effects on pro-inflammatory cytokine production and activation of primary hepatic stellate cells. Conclusion: In rodent models, direct activation of AMPK is sufficient to produce improvements in all core components of NASH and to ameliorate related hyperglycemia, dyslipidemia, and systemic inflammation. Novel properties of direct AMPK activation were also unveiled: improved insulin resistance and direct suppression of inflammation and fibrogenesis. Given effects also documented in human cells (reduced DNL, suppression of inflammation and stellate cell activation), these studies support the potential for direct AMPK activation to effectively treat patients with NASH.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Fibrose/fisiopatologia , Hepatócitos/metabolismo , Humanos , Inflamação/fisiopatologia , Insulina/sangue , Lipogênese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Piridonas/farmacologia , Tetra-Hidronaftalenos/farmacologia
7.
Acta Ophthalmol ; 100(2): e521-e531, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34085771

RESUMO

PURPOSE: To assess the effect of clinical factors on the development and progression of atrophy and fibrosis in patients with neovascular age-related macular degeneration (nAMD) receiving long-term treatment in the real world. METHODS: An ambispective 36-month multicentre study, involving 359 nAMD patients from 17 Spanish hospitals treated according to the Spanish Vitreoretinal Society guidelines, was designed. The influence of demographic and clinical factors, including the presence and location of retinal fluid, on best-corrected visual acuity (BCVA) and progression to atrophy and/or fibrosis were analysed. RESULTS: After 36 months of follow-up and an average of 13.8 anti-VEGF intravitreal injections, the average BCVA gain was +1.5 letters, and atrophy and/or fibrosis were present in 54.8% of nAMD patients (OR = 8.54, 95% CI = 5.85-12.47, compared to baseline). Atrophy was associated with basal intraretinal fluid (IRF) (OR = 1.87, 95% CI = 1.09-3.20), whereas basal subretinal fluid (SRF) was associated with a lower rate of atrophy (OR = 0.40, 95% CI = 0.23-0.71) and its progression (OR = 0.44, 95% CI = 0.26-0.75), leading to a slow progression rate (OR = 0.34, 95% CI = 0.14-0.83). Fibrosis development and progression were related to IRF at any visit (p < 0.001). In contrast, 36-month SRF was related to a lower rate of fibrosis (OR = 0.49, 95% CI = 0.29-0.81) and its progression (OR = 0.50, 95% CI = 0.31-0.81). CONCLUSION: Atrophy and/or fibrosis were present in 1 of 2 nAMD patients treated for 3 years. Both, especially fibrosis, lead to vision loss. Subretinal fluid (SRF) was associated with good visual outcomes and lower rates of atrophy and fibrosis, whereas IRF yields worse visual results and a higher risk of atrophy and especially fibrosis in routine clinical practice.


Assuntos
Degeneração Macular/fisiopatologia , Líquido Sub-Retiniano/metabolismo , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese , Atrofia/fisiopatologia , Atrofia/prevenção & controle , Progressão da Doença , Feminino , Fibrose/fisiopatologia , Fibrose/prevenção & controle , Humanos , Injeções Intravítreas , Masculino , Estudos Prospectivos , Estudos Retrospectivos
8.
J Hepatol ; 76(1): 202-207, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34157322

RESUMO

There is a universal agreement that the occurrence of clinical complications, such as ascites, hepatic encephalopathy, gastrointestinal bleeding, and jaundice mark the transition from the compensated to the decompensated stage of cirrhosis. Decompensation is associated with a substantial worsening of patient prognosis and is therefore considered the most important stratification variable for the risk of death. However, this classification is an oversimplification, as it does not discriminate between the prognostic subgroups that characterise the course of decompensation, which depends on the type and number of decompensating events. A deeper insight into the clinical course of decompensated cirrhosis is provided by observational studies characterising acute decompensation (AD), which occurs mostly in patients who have already experienced decompensating events. Decompensation presents as AD in a portion of patients while in many others it presents as a slow development of ascites or mild grade 1 or 2 hepatic encephalopathy, or jaundice, not requiring hospitalisation. Thus, we propose that decompensation of cirrhosis occurs through 2 distinct pathways: a non-acute and an acute (which includes acute-on-chronic liver failure) pathway. Moreover, while non-acute decompensation is the most frequent pathway of the first decompensation, AD mostly represents further decompensation.


Assuntos
Deterioração Clínica , Fibrose/fisiopatologia , Ascite/etiologia , Ascite/fisiopatologia , Fibrose/complicações , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/fisiopatologia , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/fisiopatologia , Humanos , Índice de Gravidade de Doença
9.
Sci Rep ; 11(1): 23081, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34848763

RESUMO

Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.


Assuntos
Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Metaloproteinases da Matriz/fisiologia , Animais , Aterosclerose , Dieta Hiperlipídica , Progressão da Doença , Feminino , Fibrose/fisiopatologia , Ácidos Hidroxâmicos/farmacologia , Estimativa de Kaplan-Meier , Masculino , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Inibidor Tecidual de Metaloproteinase-1/genética
10.
J Diabetes Res ; 2021: 7618166, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869779

RESUMO

In this study, a diabetic kidney disease model was established by placing the test rats on a high-sugar/high-fat diet combined with streptozotocin induction. Histopathological examination (H&E, Masson, and PASM stain) showed pathological changes in the diabetic rat kidneys, in addition to fibrotic symptoms and collagen deposition. Immunohistochemistry and western blot analyses indicated that the diabetic condition significantly increased the expressions of fibrotic markers including collagen, α-SMA, and fibronectin. The levels of cholesterol, triglyceride, and low-density lipoprotein were also increased in diabetic kidney disease (DKD) rat blood, while the level of high-density lipoprotein was decreased. The results of Oil red O staining experiments indicated that the kidneys of diabetic rats exhibited appreciable fat deposition, with high contents of triglyceride and cholesterol. To inhibit fibrosis and reduce fat deposition, low molecular weight fucoidan (LMWF) may be used. Based on PCR and western blot analyses, LMWF can regulate the expression levels of important lipid metabolism regulators, thereby impeding the development of kidney fibrosis. Through the vitro model, it also be indicated that LMWF could inhibit fibrosis process through regulating lipid metabolism which induced by palmitic acid.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Fibrose/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Polissacarídeos/metabolismo , Animais , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , China , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Fibrose/metabolismo , Fibrose/fisiopatologia , Metabolismo dos Lipídeos/fisiologia , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/estatística & dados numéricos , Polissacarídeos/farmacocinética , Polissacarídeos/uso terapêutico , Ratos
11.
Aging Cell ; 20(12): e13512, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34761505

RESUMO

Inflammaging, characterized by an increase in low-grade chronic inflammation with age, is a hallmark of aging and is strongly associated with various age-related diseases, including chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we tested the hypothesis that age-associated increase in necroptosis contributes to chronic inflammation in aging liver. Phosphorylation of MLKL and MLKL oligomers, markers of necroptosis, as well as phosphorylation of RIPK3 and RIPK1 were significantly upregulated in the livers of old mice relative to young mice and this increase occurred in the later half of life (i.e., after 18 months of age). Markers of M1 macrophages, expression of pro-inflammatory cytokines (TNFα, IL6 and IL1ß), and markers of fibrosis were all significantly upregulated in the liver with age and the change in necroptosis paralleled the changes in inflammation and fibrosis. Hepatocytes and liver macrophages isolated from old mice showed elevated levels of necroptosis markers as well as increased expression of pro-inflammatory cytokines relative to young mice. Short-term treatment with the necroptosis inhibitor, necrostatin-1s (Nec-1s), reduced necroptosis, markers of M1 macrophages, fibrosis, and cell senescence as well as reducing the expression of pro-inflammatory cytokines in the livers of old mice. Thus, our data show for the first time that liver aging is associated with increased necroptosis and necroptosis contributes to chronic inflammation in the liver, which in turn appears to contribute to liver fibrosis and possibly CLD.


Assuntos
Fibrose/fisiopatologia , Inflamação/fisiopatologia , Fígado/patologia , Necroptose/genética , Envelhecimento , Doença Crônica
12.
Cell Mol Life Sci ; 78(24): 7917-7923, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34731251

RESUMO

Gremlin-1 is part of the TGF-ß superfamily and is a BMP antagonist that blocks BMP signalling to precisely control BMP gradients. Gremlin-1 is primarily involved in organogenesis and limb patterning however, has recently been described as being involved in fibrotic diseases. Initially described as a key factor involved in diabetic kidney fibrosis due to being induced by high glucose, it has now been described as being associated with lung, liver, eye, and skin fibrosis. This suggests that it is a key conserved molecule mediating fibrotic events irrespective of organ. It appears that Gremlin-1 may have effects mediated by BMP-dependent and independent pathways. The aim of this review is to evaluate the role of Gremlin-1 in fibrosis, its mechanisms and if this can be targeted therapeutically in fibrotic diseases, which currently have very limited treatment options and are highly prevalent.


Assuntos
Fibrose/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Cicatrização , Animais , Humanos
13.
Theranostics ; 11(20): 10114-10124, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34815807

RESUMO

Background: Extracellular vesicles (EV) mediate the therapeutic effects of stem cells but it is unclear whether this involves cardiac regeneration mediated by endogenous cardiomyocyte proliferation. Methods: Bi-transgenic MerCreMer/ZEG (n = 15/group) and Mosaic Analysis With Double Markers (MADM; n = 6/group) mouse models underwent permanent coronary artery ligation and received, 3 weeks later, 10 billion EV (from human iPS-derived cardiovascular progenitor cells [CPC]), or saline, injected percutaneously under echo guidance in the peri-infarcted myocardium. Endogenous cardiomyocyte proliferation was tracked by EdU labeling and biphoton microscopy. Other end points, including cardiac function (echocardiography and MRI), histology and transcriptomics were blindly assessed 4-6 weeks after injections. Results: There was no proliferation of cardiomyocytes in either transgenic mouse strains. Nevertheless, EV improved cardiac function in both models. In MerCreMer/ZEG mice, LVEF increased by 18.3 ± 0.2% between baseline and the end-study time point in EV-treated hearts which contrasted with a decrease by 2.3 ± 0.2% in the PBS group; MADM mice featured a similar pattern as intra-myocardial administration of EV improved LVEF by 13.3 ± 0.16% from baseline whereas it decreased by 14.4 ± 0.16% in the control PBS-injected group. This functional improvement was confirmed by MRI and associated with a reduction in infarct size, the decreased expression of several pro-fibrotic genes and an overexpression of the anti-fibrotic miRNA 133-a1 compared to controls. Experiments with an anti-miR133-a demonstrated that the cardio-reparative effects of EV were partly abrogated. Conclusions: EV-CPC do not trigger cardiomyocyte proliferation but still improve cardiac function by other mechanisms which may include the regulation of fibrosis.


Assuntos
Vesículas Extracelulares/metabolismo , Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Modelos Animais de Doenças , Vesículas Extracelulares/transplante , Fibrose/fisiopatologia , Regeneração Tecidual Guiada/métodos , Insuficiência Cardíaca/metabolismo , Testes de Função Cardíaca/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Camundongos , Camundongos Transgênicos , MicroRNAs/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos
14.
Elife ; 102021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34756162

RESUMO

Cellular senescence is a highly complex and programmed cellular state with diverse and, at times, conflicting physiological and pathological roles across the lifespan of an organism. Initially considered a cell culture artifact, senescence evolved from an age-related circumstance to an intricate cellular defense mechanism in response to stress, implicated in a wide spectrum of biological processes like tissue remodelling, injury and cancer. The development of new tools to study senescence in vivo paved the way to uncover its functional roles in various frameworks, which are sometimes hard to reconcile. Here, we review the functional impact of senescent cells on different organismal contexts. We provide updated insights on the role of senescent cells in tissue repair and regeneration, in which they essentially modulate the levels of fibrosis and inflammation, discussing how "time" seems to be the key maestro of their effects. Finally, we overview the current clinical research landscape to target senescent cells and contemplate its repercussions on this fast-evolving field.


Assuntos
Envelhecimento/fisiologia , Senescência Celular/fisiologia , Animais , Fibrose/fisiopatologia , Humanos , Inflamação , Regeneração/fisiologia
15.
Hum Genet ; 140(12): 1709-1731, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34652576

RESUMO

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.


Assuntos
Paralisia Facial/genética , Fibrose/genética , Mutação , Oftalmoplegia/genética , Doenças do Sistema Nervoso Periférico/genética , Tubulina (Proteína)/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Substituição de Aminoácidos , Arginina , Criança , Pré-Escolar , Paralisia Facial/diagnóstico , Paralisia Facial/fisiopatologia , Feminino , Fibrose/diagnóstico , Fibrose/fisiopatologia , Histidina , Humanos , Lactente , Masculino , Oftalmoplegia/diagnóstico , Oftalmoplegia/fisiopatologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Síndrome , Adulto Jovem
16.
Theranostics ; 11(19): 9331-9341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646373

RESUMO

Rationale: Fibrosis is a pathologic condition of abnormal accumulation of collagen fibrils. Collagen is a major extracellular matrix (ECM) protein synthesized and secreted by myofibroblasts, composing mainly (Gly-X-Y)n triplet repeats with >30% Gly residue. During fibrosis progression, myofibroblasts must upregulate glycine metabolism to meet the high demands of amino acids for collagen synthesis. Method: Expression of PKM2 in myofibroblasts was analyzed in cultured fibroblasts and fibrosis disease tissues. Functional roles of PKM2 and PKM2 activator in biosynthesis of serine → glycine and production of collagen from glycolysis intermediates were assayed in cultured activated LX-2 and human primary lung fibroblast cells. Mouse models of Liver, lung, and pancreas fibrosis were employed to analyze treatment effects of PKM2 activator in organ tissue fibrosis. Results: We report here that myofibroblast differentiation upregulates pyruvate kinase M2 (PKM2) and promotes dimerization of PKM2. Dimer PKM2 slows the flow rate of glycolysis and channels glycolytic intermediates to de novo glycine synthesis, which facilitates collagen synthesis and secretion in myofibroblasts. Our results show that PKM2 activator that converts PKM2 dimer to tetramer, inhibits fibrosis progression in mouse models of liver, lung, and pancreatic fibrosis. Furthermore, metabolism alteration by dimer PKM2 increases NADPH production, which consequently protects myofibroblasts from apoptosis. Conclusion: Our study uncovers a novel role of PKM2 in tissue/organ fibrosis, suggesting a possible strategy for treatment of fibrotic diseases using PKM2 activator.


Assuntos
Fibrose/metabolismo , Glicina/metabolismo , Piruvato Quinase/metabolismo , Animais , Apoptose , Diferenciação Celular , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose/fisiopatologia , Glicina/fisiologia , Glicólise/efeitos dos fármacos , Humanos , Fígado/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Miofibroblastos/fisiologia , Pâncreas/patologia , Piruvato Quinase/fisiologia , Transdução de Sinais
17.
Theranostics ; 11(18): 8624-8639, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522203

RESUMO

Rationale: The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear. This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy. Methods: In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, H9C2 cardiomyocytes and cardiac fibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS, or their combinations. Results: Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiac fibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. Conclusions: Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.


Assuntos
Angiotensina II/análogos & derivados , Cardiomiopatias Diabéticas/fisiopatologia , Proteína Forkhead Box O1/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Angiotensina II/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Glicemia , Linhagem Celular , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Fibrose/fisiopatologia , Proteína Forkhead Box O1/fisiologia , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Quinolonas/farmacologia , Transdução de Sinais , Estreptozocina/farmacologia , Disfunção Ventricular Esquerda
18.
Medicine (Baltimore) ; 100(35): e26774, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477116

RESUMO

ABSTRACT: Umbilical Vein Recanalization (UVR) may occur in patients with long-standing portal hypertension and liver cirrhosis. This study aimed to investigate the clinical significance of UVR.Medical records of a cohort of patients with cirrhosis (n = 247) who were hospitalized at the Digestive Medicine Center of the Second Affiliated Hospital of Nanchang University from January 2012 to October 2015 were accessed. The UVR diagnosis was made by ultrasound examination and was confirmed by computerized tomography scan.The UVR incidence was 20.2% (50/247) in the cohort. The size of UVR was 9.9 ±â€Š4.7 mm (range: 5-26.5 mm) in diameter. The UVR and non-UVR groups showed no difference in grades of hepatic encephalopathy (P = .496), Child-Pugh classification (P = .401), the incidence of moderately severe ascites (26% vs 26%, P = 1), the esophageal variceal bleeding rate (32% vs 39%, P = .402), or portal vein thrombosis (8% vs 12%, P = .580). However, the incidence of cavernous transformation of the portal vein was statistically different, that there was 0 case in the UVR group and 8 cases in the non-UVR group (P < .05).Our results suggested that UVR had little impact on the clinical manifestations of patients with liver cirrhosis, the significance of UVR as an intervention method requires further studies.


Assuntos
Cateterismo/estatística & dados numéricos , Fibrose/fisiopatologia , Veias Umbilicais , Adulto , Cateterismo/métodos , Feminino , Fibrose/classificação , Fibrose/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
19.
Phys Rev Lett ; 127(9): 098101, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34506203

RESUMO

Cardiac fibrosis is a well-known arrhythmogenic condition which can lead to sudden cardiac death. Physically, fibrosis can be viewed as a large number of small obstacles in an excitable medium, which may create nonlinear wave turbulence or reentry. The relation between the specific texture of fibrosis and the onset of reentry is of great theoretical and practical importance. Here, we present a conceptual framework which combines functional aspects of propagation manifested as conduction blocks, with reentry wavelength and geometrical clusters of fibrosis. We formulate them into the single concept of minimal functional cluster and through extensive simulations show that it characterizes the path of reexcitation accurately, and importantly its size distribution quantitatively predicts the reentry probability for different fibrosis densities and tissue excitabilities.


Assuntos
Sistema de Condução Cardíaco/fisiopatologia , Modelos Cardiovasculares , Miocárdio/patologia , Potenciais de Ação , Análise por Conglomerados , Fibrose/patologia , Fibrose/fisiopatologia , Humanos , Dinâmica não Linear
20.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502356

RESUMO

Previous studies have shown that glaucomatous Schlemm's canal endothelial cells (gSCECs) are stiffer and associated with reduced porosity and increased extracellular matrix (ECM) material compared to SCECs from healthy individuals. We hypothesised that Schlemm's canal (SC) cell stiffening was a function of fibrotic changes occurring at the inner wall of SC in glaucoma. This study was performed in primary cell cultures isolated from the SC lumen of human donor eyes. RNA and protein quantification of both fibrotic and endothelial cell markers was carried out on both healthy and gSCECs. Functional assays to assess cell density, size, migration, proliferation, and mitochondrial function of these cells were also carried out. Indeed, we found that gSCECs deviate from typical endothelial cell characteristics and exhibit a more fibrotic phenotype. For example, gSCECs expressed significantly higher protein levels of the fibrotic markers α-SMA, collagen I-α1, and fibronectin, as well as significantly increased protein expression of TGFß-2, the main driver of fibrosis, compared to healthy SCECs. Interestingly, we observed a significant increase in protein expression of endothelial marker VE-cadherin in gSCECs, compared to healthy SCECs. gSCECs also appeared to be significantly larger, and surprisingly proliferate and migrate at a significantly higher rate, as well as showing significantly reduced mitochondrial activity, compared to healthy SCECs.


Assuntos
Fibrose/fisiopatologia , Glaucoma/metabolismo , Glaucoma/fisiopatologia , Antígenos CD/metabolismo , Humor Aquoso/metabolismo , Caderinas/metabolismo , Contagem de Células , Movimento Celular , Proliferação de Células , Células Endoteliais/metabolismo , Endotélio , Matriz Extracelular , Olho/metabolismo , Humanos , Mitocôndrias , Porosidade , Cultura Primária de Células , Esclera , Malha Trabecular , Fator de Crescimento Transformador beta2/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...