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Alopecia , Liquen Plano , Naltrexona , Humanos , Alopecia/tratamiento farmacológico , Alopecia/patología , Liquen Plano/tratamiento farmacológico , Liquen Plano/diagnóstico , Liquen Plano/patología , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Femenino , Administración Oral , Persona de Mediana Edad , Resultado del Tratamiento , Masculino , Adulto , Fibrosis/tratamiento farmacológico , Anciano , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéuticoRESUMEN
PURPOSE: This study aimed to investigate the inhibitory effect of chrysophanol on renal fibrosis and its molecular mechanism. METHODS: Initially, potential targets of chrysophanol were predicted through network pharmacology analysis, and a protein-protein interaction network of these targets was constructed using Venn diagrams and the STRING database. GO enrichment analysis predicted the biological process of chrysophanol in treating renal fibrosis. Subsequently, both in vivo and in vitro experiments were conducted using unilateral ureteral obstruction (UUO) induced CKD mouse model and HK-2 cell model, respectively. In the mouse model, different doses of chrysophanol were administered to assess its renal protective effects through biochemical indicators, histological examination, and immunofluorescence staining. In the cell model, the regulatory effect of chrysophanol on the Trx-1/JNK/Cx43 pathway was evaluated using western blotting and flow cytometry. RESULTS: Chrysophanol treatment significantly ameliorated renal dysfunction and histopathological damage in the UUO mouse model, accompanied by a reduction in serum oxidative stress markers. Furthermore, chrysophanol markedly upregulated the expression of Trx-1 in renal tissues and inhibited the activation of the JNK/Cx43 signaling pathway. At the cellular level, chrysophanol enhanced the activity of Trx-1 and downregulated the JNK/Cx43 signaling pathway, thereby inhibiting TGF-ß induced oxidative stress and cell apoptosis. CONCLUSION: This study demonstrated a significant inhibitory effect of chrysophanol on renal fibrosis, mediated by the activation of Trx-1 to inhibit the JNK/Cx43 pathway. These findings provide experimental support for the potential use of chrysophanol as a therapeutic agent for renal fibrosis.
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Antraquinonas , Modelos Animales de Enfermedad , Fibrosis , Riñón , Obstrucción Ureteral , Animales , Ratones , Fibrosis/tratamiento farmacológico , Masculino , Riñón/patología , Riñón/efectos de los fármacos , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Humanos , Estrés Oxidativo/efectos de los fármacos , Tiorredoxinas/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Transducción de Señal/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Línea Celular , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Sanqi oral solution (SQ) is a traditional Chinese patent medicine, widely used to treat chronic kidney diseases (CKD) in the clinic in China. Previous studies have confirmed its anti-renal fibrosis effect, but the specific pharmacological mechanism is still unclear. AIM OF THE STUDY: Focusing on energy metabolism in fibroblasts, the renoprotective mechanism of SQ was investigated in vitro and in vivo. METHODS: Firstly, the fingerprint of SQ was constructed and its elementary chemical composition was analyzed. In the 5/6Nx rats experiment, the efficacy of SQ on the kidney was evaluated by detecting serum and urine biochemical indexes and pathological staining of renal tissues. Lactic acid and pyruvic acid levels in serum and renal tissues were detected. PCNA protein expression in kidney tissue was detected by immunofluorescence assay and Western blot. Expression levels of HIF-1α, PKM2 and HK2 were determined by immunohistochemistry, Western blot or RT-qPCR assay. In addition, the effect of SQ intervention on cell proliferation and glycolysis was evaluated in TGF-ß1-induced NRK-49F cells, and the role of SQ exposure and HIF-1α/PKM2/glycolysis pathway were further investigated by silencing and overexpressing HIF-1α gene in NRK-49F cells. RESULTS: In 5/6 Nx rats, SQ effectively improved renal function and treated renal injury. It reduced the levels of lactic acid and pyruvic acid in kidney homogenates from CKD rats and decreased the expression levels of HIF-1α, PKM2, HK2, α-SMA, vimentin, collagen I and PCNA in kidney tissues. Similar results were observed in vitro. SQ inhibited NRK-49F cell proliferation, glycolysis and the expression levels of HIF-1α, PKM2 induced by TGF-ß1. Furthermore, we established NRK-49F cells transfected with siRNA or pDNA to silence or overexpress the HIF-1α gene. Overexpression of HIF-1α promoted cellular secretion of lactic acid and pyruvic acid in TGF-ß1-induced NRK-49F cells, however, this change was reversed by intervention with SQ or silencing the HIF-1α gene. Overexpression of HIF-1α can further induce increased PKM2 expression, while SQ intervention can reduce PKM2 expression. Moreover, PKM2 expression was also inhibited after silencing HIF-1α gene, and SQ was not effective even when given. CONCLUSION: The mechanism of action of SQ was explored from the perspective of energy metabolism, and it was found to regulate PKM2-activated glycolysis, inhibit fibroblast activation, and further ameliorate renal fibrosis in CKD by targeting HIF-1α.
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Fibroblastos , Fibrosis , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Riñón , Ratas Sprague-Dawley , Insuficiencia Renal Crónica , Proteínas de Unión a Hormona Tiroide , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Fibrosis/tratamiento farmacológico , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Masculino , Glucólisis/efectos de los fármacos , Ratas , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Medicamentos Herbarios Chinos/farmacología , Línea Celular , Piruvato Quinasa/metabolismo , Piruvato Quinasa/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Hormonas Tiroideas , Administración Oral , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Chlorogenic acid (CGA), a phenolic acid produced by the interaction of Caffeic acid and Quinic acid, is considered to be the main active ingredient in many heat-clearing and detoxifying Chinese medicines, such as honeysuckle, Houttuynia, Artemisia annua, Gardenia, etc. CGA has anti-inflammatory, antioxidant, anticancer, antibacterial and other properties. However, the effect and process of CGA in kidney fibrosis remain unknown. AIM OF THE STUDY: To investigate the therapeutic effects of CGA on alleviating kidney fibrosis and the underlying mechanisms. MATERIALS AND METHODS: C57BL/6 mouse kidney fibrosis model was established by unilateral uretera obstruction (UUO), followed by treatment with CGA (40, 80 mg/kg/d) for 10 days. The serum and kidney tissue were collected. Network pharmacology, molecular docking and transcriptomic analysis were conducted to explore the possible mechanisms. The HK-2 cells were cultured and treated with TGF-ß1(10 ng/mL) and CGA (50, 100 µM), to examine the role of TLR4/NF-ÒB signaling pathway in the therapeutic effect of CGA on kidney fibrosis. RESULTS: CGA significantly alleviated kidney injury, inflammation, oxidative stress and fibrosis in UUO models. CGA also effectively inhibited the expression of inflammatory factors and the process of oxidative stress both in vivo and in vitro fibrosis models. Further, transcriptomic analysis, molecular docking, and network pharmacology results indicated that the therapeutic effect of CGA on fibrosis was through the regulation of TLR4/NF-ÒB signaling pathway. CONCLUSION: CGA might provide benefits for the regulation of inflammatory response, oxidative stress and fibrogenesis by modulating TLR4/NF-ÒB signaling pathway on kidney fibrosis. Hence, CGA is an attractive agent for treating kidney fibrosis. The present study provided a basis for further research on the therapeutic strategies of kidney fibrosis.
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Ácido Clorogénico , Fibrosis , Inflamación , Riñón , Ratones Endogámicos C57BL , FN-kappa B , Estrés Oxidativo , Receptor Toll-Like 4 , Ácido Clorogénico/farmacología , Ácido Clorogénico/uso terapéutico , Animales , Receptor Toll-Like 4/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fibrosis/tratamiento farmacológico , FN-kappa B/metabolismo , Masculino , Ratones , Inflamación/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Humanos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Línea Celular , Transducción de Señal/efectos de los fármacos , Simulación del Acoplamiento Molecular , Obstrucción Ureteral/tratamiento farmacológico , Antiinflamatorios/farmacología , Modelos Animales de EnfermedadRESUMEN
Renal fibrosis lacks effective nephroprotective drugs in clinical settings due to poor accumulation of therapeutic agents in damaged kidneys, underscoring the urgent need for advanced renal-targeted delivery systems. Herein, we exploited the significantly increased expression of the leucine-rich α-2 glycoprotein 1 (LRG1) protein during renal fibrosis to develop a novel drug delivery system. Our engineered nanocarrier, DENNM, preferentially targets fibrotic kidneys via the decorated ET peptide's high affinity for LRG1. Once internalized by damaged renal cells, DENNM releases its encapsulated nintedanib, triggered by the active caspase-3 protease, disrupting the nanomedicine's structural integrity. The released nintedanib effectively reduces the level of expression of the extracellular matrix and impedes the progression of renal fibrosis by inhibiting the transforming growth factor-ß (TGF-ß)-Smad2/3 pathway. Our comprehensive in vitro and in vivo studies validate DENNM's antifibrotic efficacy, emphasizing LRG1's potential in renal targeted drug delivery and introducing an innovative approach to nanomedicine for treating renal fibrosis.
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Fibrosis , Indoles , Riñón , Fibrosis/tratamiento farmacológico , Animales , Indoles/química , Indoles/administración & dosificación , Indoles/farmacología , Humanos , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Ratones , Sistemas de Liberación de Medicamentos , Glicoproteínas , Factor de Crecimiento Transformador beta/metabolismo , Nanopartículas/química , Portadores de Fármacos/químicaRESUMEN
Cardiac fibrosis is characterized by the over-proliferation, over-transdifferentiation and over-deposition of extracellular matrix (ECM) of cardiac fibroblasts (CFs). Cardiac sympathetic activation is one of the leading causes of myocardial fibrosis. Meanwhile, cardiac fibrosis is often together with cardiac inflammation, which accelerates fibrosis by mediating inflammatory cytokines secretion. Recently, the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling pathway has been confirmed by its vital role during the progression of cardiac fibrosis. Thus, JAK/STAT3 signaling pathway is thought to be a potential therapeutic target for cardiac fibrosis. Baricitinib (BR), a novel JAK1/2 inhibitor, has been reported excellent effects of anti-fibrosis in multiple fibrotic diseases. However, little is known about whether and how BR ameliorates cardiac fibrosis caused by chronic sympathetic activation. Isoproterenol (ISO), a ß-Adrenergic receptor (ß-AR) nonselective agonist, was used to modulate chronic sympathetic activation in mice. As expected, our results proved that BR ameliorated ISO-induced cardiac dysfunction. Meanwhile, BR attenuated ISO-induced cardiac fibrosis and cardiac inflammation in mice. Moreover, BR also inhibited ISO-induced cardiac fibroblasts activation and macrophages pro-inflammatory secretion. As for mechanism studies, BR reduced ISO-induced cardiac fibroblasts by JAK2/STAT3 and PI3K/Akt signaling, while reduced ISO-induced macrophages pro-inflammatory secretion by JAK1/STAT3 and NF-κB signaling. In summary, BR alleviates cardiac fibrosis and inflammation caused by chronic sympathetic activation. The underlying mechanism involves BR-mediated suppression of JAK1/2/STAT3, PI3K/Akt and NF-κB signaling.
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Azetidinas , Fibroblastos , Fibrosis , Ratones Endogámicos C57BL , Purinas , Pirazoles , Sulfonamidas , Animales , Fibrosis/tratamiento farmacológico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Masculino , Fibroblastos/efectos de los fármacos , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ratones , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Miocardio/patología , Isoproterenol , Células Cultivadas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , FN-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo , Humanos , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-ß (TGF-ß) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-ß receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.
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Antifibróticos , Fibrosis , Humanos , Fibrosis/tratamiento farmacológico , Antifibróticos/uso terapéutico , Antifibróticos/farmacología , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Animales , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Inflammation plays a crucial role in progression of fibrosis. Epoxyeicosatrienoic acids (EET) have multiple protective effects in different diseases, but their ability to inhibit the development of LPS-induced fibrosis remains unknown. The potential therapeutic effects of 11,12-EET were studied in in vitro model of LPS-induced fibrosis. Mouse embryonic fibroblast cells NIH/3T3 were pre-incubated with 1 µM 11,12-EET and/or a structural analogue and selective EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid before exposing to LPS. The effect of EET was evaluated by the protein and mRNA expression of NF-κB, collagens I and III, and α-smooth muscle actin by Western blotting and quantitative reverse transcription PCR, respectively. LPS provoked inflammation and fibrosis-like changes accompanied by elevated expression of NF-κB and collagens in NIH/3T3 cells. We also studied the effects of 11,12-EET on the A2AR and PI3K/Akt signaling pathways in intact and LPS-treated NIH/3T3 cells. 11,12-EET prevented inflammation and fibrosis-like changes through up-regulation of A2AR and PI3K/Akt signaling pathways. Our findings demonstrate the potential antifibrotic effects of 11,12-EET, which can be natural antagonists of tissue fibrosis.
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Ácido 8,11,14-Eicosatrienoico , Fibrosis , Lipopolisacáridos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Ratones , Lipopolisacáridos/toxicidad , Transducción de Señal/efectos de los fármacos , Células 3T3 NIH , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Fibrosis/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacología , FN-kappa B/metabolismo , Actinas/metabolismo , Actinas/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patologíaRESUMEN
Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.
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Compuestos de Bencidrilo , Fibrosis , Glucósidos , Hiperuricemia , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Fibrosis/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/complicaciones , Humanos , Ratones , Masculino , Receptor Relacionado con Estrógeno ERRalfa , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones Endogámicos C57BL , Ácido Úrico/sangre , Receptores de Estrógenos/metabolismo , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Proteína 1 de Transporte de Anión Orgánico/genética , Línea Celular , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Modelos Animales de Enfermedad , FemeninoRESUMEN
Inflammation-induced choroidal neovascularization followed by the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial cells (RPEs) is a cause of neovascular age-related macular degeneration (nAMD). RPE-derived myofibroblasts overproduce extracellular matrix, leading to subretinal fibrosis. We already have demonstrated that benzylphenylurea (BPU) derivatives inhibit the function of cancer-associated fibroblasts. Here, we investigated the anti-myofibroblast effects of BPU derivatives and examined such BPU activity on subretinal fibrosis. A BPU derivative, BPU17, exhibits the most potent anti-myofibroblast activity among dozens of BPU derivatives and inhibits subretinal fibrosis in a mouse model of retinal degeneration. Investigations with primary cultured RPEs reveal that BPU17 suppresses cell motility and collagen synthesis in RPE-derived myofibroblasts. These effects depend on repressing the serum response factor (SRF)/CArG-box-dependent transcription. BPU17 inhibits the expression of SRF cofactor, cysteine and glycine-rich protein 2 (CRP2), which activates the SRF function. Proteomics analysis reveals that BPU17 binds to prohibitin 1 (PHB1) and inhibits the PHB1-PHB2 interaction, resulting in mild defects in mitochondrial function. This impairment causes a decrease in the expression of CRP2 and suppresses collagen synthesis. Our findings suggest that BPU17 is a promising agent against nAMD and the close relationship between PHB function and EMT.
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Fibrosis , Miofibroblastos , Prohibitinas , Proteínas Represoras , Animales , Proteínas Represoras/metabolismo , Humanos , Ratones , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Fibrosis/tratamiento farmacológico , Antifibróticos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Movimiento Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Degeneración Macular/patología , Células Cultivadas , Factor de Respuesta Sérica/metabolismo , Factor de Respuesta Sérica/antagonistas & inhibidoresRESUMEN
BACKGROUND: Fibrosis of the infrapatellar fat pad (IFP) is a feature of osteoarthritis and contributes substantially to the pain and dysfunction in patients' joints. However, the underlying mechanisms remain unclear. C-C motif chemokine ligand-2 (CCL2) plays a central role in tissue fibrosis. Thus, we aimed to investigate the role of CCL2 in the development of IFP fibrosis in a rat model of arthritis, hypothesizing that a CCL2 antagonist could mitigate fibrotic progression. METHODS: We induced arthritis in male Wistar rats using intra-articular injections of carrageenan. Furthermore, to evaluate the effects of a CCL2 antagonist on protein expression and collagen deposition in the IFP of the rats, we transferred an N-terminal-truncated CCL2 gene into a rat model via electroporation-mediated intramuscular injection. Macrophage infiltration and collagen deposition in the IFP were analyzed in vivo. Groups were compared using the Mann-Whitney U test and Student's t-test. RESULTS: We identified infiltrating macrophages as well as increases in CCL2 and TGF-ß levels as collagen deposition progressed. Gene transfer of the CCL2-antagonist before arthritis induction attenuated collagen deposition remarkably. CONCLUSIONS: We provide initial evidence that anti-CCL2 gene therapy can effectively suppress the development of IFP fibrosis in a rat model. Thus, targeting CCL2 holds promise as a therapeutic strategy for managing tissue fibrosis in osteoarthritis patients.
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Tejido Adiposo , Artritis Experimental , Quimiocina CCL2 , Fibrosis , Ratas Wistar , Animales , Masculino , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/metabolismo , Ratas , Fibrosis/tratamiento farmacológico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Experimental/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Tejido Adiposo/metabolismo , Modelos Animales de EnfermedadRESUMEN
Purpose: The purpose of this study was to evaluate the safety and efficacy of topical losartan in the therapeutic treatment of established corneal scaring fibrosis at 1 month after alkali burn in rabbits. Methods: Standardized alkali burns were performed in 1 eye of 24 rabbits with 0.75N NaOH for 15 seconds. Corneas were allowed to heal and develop scaring of the cornea for 1 month. Twelve eyes per group were treated with 50 µL of topical 0.8 mg/mL losartan in balanced salt solution (BSS), pH 7.0, and 12 eyes were treated with vehicle BSS 6 times per day. Six corneas were analyzed at 1 week or 1 month in each group. Standardized slit lamp photographs were obtained at the end point for each cornea and opacity was quantitated using ImageJ. Corneoscleral rims were cryofixed in optimum cutting temperature (OCT) solution and combined duplex immunohistochemistry for myofibroblast marker alpha-smooth muscle actin (α-SMA), mesenchymal cell marker vimentin, and TUNEL assay for apoptosis was performed on all corneas. Results: Topical losartan was effective in the treatment of established stromal fibrosis following alkali burn injury to the rabbit cornea. Stromal myofibroblast density was decreased and stromal cell apoptosis was increased (included both α-SMA-positive myofibroblasts and α-SMA-negative, vimentin-positive cells) at both 1 week and 1 month in the topical losartan-treated compared with vehicle-treated groups. Conclusions: Topical losartan is effective in the treatment of established stromal fibrosis in rabbits. Most myofibroblasts disappear from the stroma within the first month of losartan treatment. Longer treatment with topical losartan is needed to allow time for corneal fibroblast regeneration of the epithelial basement membrane (in coordination with epithelial cells) and the removal of disordered extracellular matrix produced by myofibroblasts.
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Quemaduras Químicas , Quemaduras Oculares , Fibrosis , Losartán , Animales , Conejos , Losartán/farmacología , Losartán/administración & dosificación , Losartán/uso terapéutico , Fibrosis/tratamiento farmacológico , Quemaduras Químicas/tratamiento farmacológico , Quemaduras Químicas/patología , Quemaduras Oculares/tratamiento farmacológico , Quemaduras Oculares/patología , Quemaduras Oculares/inducido químicamente , Modelos Animales de Enfermedad , Apoptosis/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Hidróxido de Sodio , Enfermedades de la Córnea/tratamiento farmacológico , Enfermedades de la Córnea/patología , Soluciones Oftálmicas/uso terapéutico , Soluciones Oftálmicas/administración & dosificación , Córnea/efectos de los fármacos , Córnea/patología , Etiquetado Corte-Fin in Situ , Miofibroblastos/efectos de los fármacos , Miofibroblastos/patología , Actinas/metabolismo , Masculino , Sustancia Propia/efectos de los fármacos , Sustancia Propia/patología , Sustancia Propia/metabolismo , Administración Tópica , Vimentina/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Jian-Pi-Yi-Shen (JPYS) formula is an effective herbal therapy against renal injury, and JPYS has been clinically applied to ameliorate chronic kidney disease (CKD) and CKD-associated anemia. Increasing evidence supports the link between renal fibrosis and anemia in CKD. JPYS possessed anti-fibrosis effects in experimental CKD. Nevertheless, research on the mechanisms of JPYS in ameliorating renal anemia (RA) through suppressing renal fibrosis remains to be clarified. AIM OF THE STUDY: Our study here was carried out to investigate the mechanisms of JPYS in protecting against RA. MATERIALS AND METHODS: An adenine-induced anemia model in rats with CKD at three different time points was established, and bio-samples taken from each group were analyzed. Biochemical analysis was employed to detect kidney function and hematological parameters. Masson staining was used to evaluate renal fibrosis of rats. Western blot and immunohistochemistry were utilized to evaluate the expressions of fibrotic markers, erythropoietin (EPO) and hypoxia inducible factor-2α (HIF-2α) in the kidneys of rats. Subsequently, transcriptomic analysis was conducted to disclose the possible mechanisms of JPYS in treating RA. Finally, the expression levels of key targets were analyzed and validated by using Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: JPYS treatment improved kidney function, suppressed renal fibrosis and enhanced hematological parameters in CKD rats. Moreover, JPYS treatment restored the increased expression levels of fibrotic markers and the declined EPO with time dependence. In parallel, data indicated JPYS treatment stimulated the translocation of HIF-2α into nucleus in the renal interstitium and thus promoted the expression of EPO. Transcriptomic profiling disclosed that activations of both nuclear factor kappa B (NF-κB) and transforming growth factor-ß (TGF-ß)/Smad pathways were closely associated with RA. Ultimately, experimental validation results presented that the increased expressions of target proteins from the above-mentioned two pathways in the kidneys were decreased significantly after JPYS treatment. CONCLUSION: Our findings suggest that JPYS may improve RA by alleviating renal fibrosis, and the mechanisms of which involve in inhibiting the NF-κB and TGF-ß/Smad pathways.
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Anemia , Medicamentos Herbarios Chinos , Eritropoyetina , Fibrosis , Riñón , Ratas Sprague-Dawley , Insuficiencia Renal Crónica , Animales , Insuficiencia Renal Crónica/tratamiento farmacológico , Fibrosis/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Anemia/tratamiento farmacológico , Anemia/etiología , Masculino , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Ratas , Modelos Animales de Enfermedad , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Adenina/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Recently, podocyte mitochondrial dysfunction and necroptosis have been shown to play critical roles in renal fibrosis (RF) in diabetic kidney disease (DKD); however, these conditions lack effective treatment. In China, the supplemented Gegen Qinlian Decoction Formula (SGQDF), which originates from the classical prescription Gegen Qinlian Decoction, has been widely used to treat patients with DKD. However, it remains unclear whether SGQDF alleviates podocyte injury-associated RF in patients with DKD. AIM OF STUDY: This study aimed to clarify the therapeutic effects of SGQDF compared with those of empagliflozin (EMPA) on podocyte mitochondrial fission and RF in DKD and its necroptosis-related mechanisms. MATERIALS AND METHODS: Modified DKD rat models were developed through a combination of uninephrectomy, streptozotocin administration through intraperitoneal injection, and exposure to a high-fat diet. Following RF formation, the DKD rat models received either a high dose of SGQDF (H-SGQDF), a low dose of SGQDF (L-SGQDF), EMPA, or vehicle for 4 weeks. In our in vitro study, we subjected cultured murine podocytes to a high-glucose environment and various treatments including Mdivi-1, adalimumab, and necrostatin-1, with or without H-SGQDF or EMPA. SGQDF target prediction and molecular docking verification were performed. For the in vivo study, we focused on examining changes in the parameters associated with renal injury, RF, and oxidative stress (OS)-induced injuries in podocytes. Both in vivo and in vitro studies included an analysis of changes in podocyte mitochondrial fission, TNF-α-induced podocyte necroptosis, and the RIPK1/RIPK3/MLKL signaling pathway activation. RESULTS: SGQDF improved renal injury markers, including body weight, blood glucose, serum creatinine, blood urea nitrogen, and urinary albumin, in a dose-dependent manner. The beneficial effects of H-SGQDF in vivo were greater than those of L-SGQDF alone in vivo. Interestingly, similar to EMPA, H-SGQDF ameliorated RF and reduced OS-induced podocyte injury in diabetic kidneys. Furthermore, TNF-α signaling was shown to be important in the network construction of "the SGQDF-component-target." Based on this, we also showed that the beneficial effects in vivo and in vitro of H-SGQDF were closely related to the improvement in mitochondrial dysfunction and the inhibition of TNF-α-induced necroptosis in podocytes. CONCLUSION: In the present study, we showed that H-SGQDF, similar to EMPA, attenuates podocyte mitochondrial fission and RF, and that the underlying therapeutic mechanisms are closely related to inhibiting the activation of the RIPK1/RIPK3/MLKL signaling axis in diabetic kidneys. Our findings provide new pharmacological evidence for the application of H-SGQDF in the RF treatment of DKD.
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Compuestos de Bencidrilo , Nefropatías Diabéticas , Medicamentos Herbarios Chinos , Fibrosis , Glucósidos , Dinámicas Mitocondriales , Necroptosis , Podocitos , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa , Animales , Glucósidos/farmacología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Compuestos de Bencidrilo/farmacología , Masculino , Podocitos/efectos de los fármacos , Podocitos/patología , Necroptosis/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Fibrosis/tratamiento farmacológico , Ratas , Medicamentos Herbarios Chinos/farmacología , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismoRESUMEN
BACKGROUD: Arsenic trioxide (ATO), the first-line drug in treating acute premyelogenous leukemia, has the profound side effect of inducing endothelial mesenchymal transition (EndMT) and causing cardiac fibrosis. Diosgenin (DIO), a pharmaceutical compound found in Paris polyphylla, exhibits promising potential in safeguarding cardiovascular health by mitigating EndMT. PURPOSE: This study aims to explore the role and mechanism of DIO in ATO-induced myocardial fibrosis to provide a novel therapeutic agent for ATO-induced cardiac fibrosis. METHODS: Wistar rats were given DIO by gavage and ATO by tail vein. Cardiac function and fibrosis were evaluated by echocardiography and Masson's trichrome staining in rats. Human aortic endothelial cells (HAECs) were utilized to analyze ATO-induced EndMT in vitro. The cytoskeleton of HAECs was visualized using F-actin staining to observe cell morphology, while Dil-Ac-LDL staining was employed to assess cell functionality. EndMT-related factors (CD31 and α-SMA), glucocorticoid receptor (GR) and interleukin-6 (IL-6) were detected by immunofluorescence and Western blot in vivo and in vitro. Furthermore, GR was knocked down by si-GR, and IL-6 was blocked by IL-6 neutralizing antibody to verify their role in the effect of DIO on ATO-induced EndMT in HAECs. RESULTS: DIO exhibited significant efficacy in ATO-induced damage to both cardiac diastolic and systolic function, along with mitigating cardiac fibrosis. Additionally, DIO alleviated the loss of cytoskeletal anisotropy and enhanced the uptake of Dil-Ac-LDL in HAECs. Furthermore, it reversed the ATO-induced downregulation of endothelial-specific markers CD31 and GR, while suppressing the upregulation of mesenchymal markers α-SMA and IL-6, both in vivo and in vitro. Notably, the protective effect of DIO was compromised upon knockdown of GR, which also led to a reversal of DIO-induced IL-6 downregulation. Furthermore, the neutralization of IL-6 with specific antibodies abolished the ATO-induced changes related to EndMT. CONCLUSION: In this study, we clarified the protective effect of DIO on ATO-induced myocardial fibrosis against EndMT via the GR/IL-6 axis for the first time and provided a potential therapeutic agent for preventing heart damage caused by ATO.
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Trióxido de Arsénico , Diosgenina , Células Endoteliales , Fibrosis , Ratas Wistar , Animales , Fibrosis/tratamiento farmacológico , Humanos , Masculino , Diosgenina/farmacología , Diosgenina/análogos & derivados , Células Endoteliales/efectos de los fármacos , Ratas , Interleucina-6/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Actinas/metabolismo , Miocardio/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Transición Endotelial-MesenquimatosaRESUMEN
BACKGROUND: Pirfenidone has demonstrated significant anti-inflammatory and antifibrotic effects in both animal models and some clinical trials. Its potential for antifibrotic activity positions it as a promising candidate for the treatment of various fibrotic diseases. Pirfenidone exerts several pleiotropic and anti-inflammatory effects through different molecular pathways, attenuating multiple inflammatory processes, including the secretion of pro-inflammatory cytokines, apoptosis, and fibroblast activation. OBJECTIVE: To present the current evidence of pirfenidone's effects on several fibrotic diseases, with a focus on its potential as a therapeutic option for managing chronic fibrotic conditions. FINDINGS: Pirfenidone has been extensively studied for idiopathic pulmonary fibrosis, showing a favorable impact and forming part of the current treatment regimen for this disease. Additionally, pirfenidone appears to have beneficial effects on similar fibrotic diseases such as interstitial lung disease, myocardial fibrosis, glomerulopathies, aberrant skin scarring, chronic liver disease, and other fibrotic disorders. CONCLUSION: Given the increasing incidence of chronic fibrotic conditions, pirfenidone emerges as a potential therapeutic option for these patients. However, further clinical trials are necessary to confirm its therapeutic efficacy in various fibrotic diseases. This review aims to highlight the current evidence of pirfenidone's effects in multiple fibrotic conditions.
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Fibrosis , Piridonas , Piridonas/uso terapéutico , Humanos , Animales , Fibrosis/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Antifibróticos/uso terapéuticoAsunto(s)
Alopecia , Dutasterida , Humanos , Alopecia/tratamiento farmacológico , Dutasterida/administración & dosificación , Dutasterida/uso terapéutico , Masculino , Femenino , Administración Oral , Persona de Mediana Edad , Inhibidores de 5-alfa-Reductasa/administración & dosificación , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Fibrosis/tratamiento farmacológico , Adulto , AncianoRESUMEN
Background: Qingchang Tongluo Decoction (QTF) is clinically used for the treatment of intestinal fibrosis in Crohn's Disease (CD). However, the role of QTF in CD-associated fibrosis and its potential pharmacological mechanism remains unclear. Purpose: The objective of this study was to elucidate the potential mechanism of QTF in treating CD-associated fibrosis, employing a combination of bioinformatics approaches - encompassing network pharmacology and molecular docking - complemented by experimental validation. Methods: To investigate the material basis and potential protective mechanism of QTF, a network pharmacology analysis was conducted. The core components and targets of QTF underwent molecular docking analysis to corroborate the findings obtained from network pharmacology. In vitro, a colon fibrotic model was established by stimulating IEC-6 cells with 10 ng/mL of transforming growth factor(TGF-ß1). In vivo, an intestinal fibrosis model was induced in BALB/c mice by TNBS. The role of QTF in inhibiting the TGF-ß1/Smad signaling pathway was investigated through RT-qPCR, Western blotting, immunohistochemistry staining, and immunofluorescence staining. Results: Network pharmacology analysis revealed that QTF could exert its protective effect. Bioinformatics analysis suggested that Flavone and Isoflavone might be the key components of the study. Additionally, AKT1, IL-6, TNF, and VEGFA were identified as potential therapeutic targets. Furthermore, experimental validation and molecular docking were employed to corroborate the results obtained from network pharmacology. RT-qPCR, Immunofluorescence, and Western blotting results demonstrated that QTF significantly improved colon function and inhibited pathological intestinal fibrosis in vivo and in vitro. Conclusion: Through the application of network pharmacology, molecular docking, and experimental validation, QTF could be confirmed to inhibit the proliferation of intestinal fibroblasts associated with CD and reduce the expression of Collagen I and VEGFA. This effect is achieved through the attenuation of ECM accumulation, primarily via the inhibition of the TGF-ß1/Smad signaling pathway.
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Enfermedad de Crohn , Medicamentos Herbarios Chinos , Fibrosis , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Farmacología en Red , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Animales , Fibrosis/tratamiento farmacológico , Ratones , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/patología , Enfermedad de Crohn/metabolismo , Ratas , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Modelos Animales de EnfermedadRESUMEN
Fibrosis leads to organ failure and death, which is the final stage of many chronic diseases. Triptolide (TPL) is a terpenoid extracted from the traditional Chinese medicine Tripterygium wilfordii Hook. F (TwHF). Triptolide and its derivatives (Omtriptolide, Minnelide, (5R)-5-hydroxytriptolide) have been proven to have a variety of pharmacological effects. This study comprehensively reviewed the antifibrotic mechanism of TPL and its derivatives, and discussed the application of advanced nanoparticles (NPs) drug delivery system in the treatment of fibrotic diseases by TPL. The results show that TPL can inhibit immune inflammatory response, relieve oxidative stress and endoplasmic reticulum stress (ERS), regulate collagen deposition and inhibit myofibroblast production to play an anti-fibrosis effect and reduce organ injury. A low dose of TPL has no obvious toxicity. Under pathological conditions, a toxic dose of TPL has a protective effect on organs. The emergence of TPL derivatives (especially Minnelide) and NPs drug delivery systems promotes the anti-fibrosis effect of TPL and reduces its toxicity, which may be the main direction of anti-fibrosis research in the future.
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Diterpenos , Compuestos Epoxi , Fibrosis , Fenantrenos , Diterpenos/farmacología , Diterpenos/química , Diterpenos/administración & dosificación , Fenantrenos/farmacología , Fenantrenos/química , Fenantrenos/administración & dosificación , Compuestos Epoxi/farmacología , Compuestos Epoxi/química , Compuestos Epoxi/administración & dosificación , Humanos , Fibrosis/tratamiento farmacológico , Animales , Antifibróticos/farmacología , Antifibróticos/químicaRESUMEN
Hypertension affects a large number of individuals globally and is a common cause of nephropathy, stroke, ischaemic heart disease and other vascular diseases. While many anti-hypertensive medications are used safely and effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, a xanthone molecule extracted from the pericarp of Garcinia mangostana L., has shown various beneficial effects such as anti-tumor, anti-hyperuricemia, and anti-inflammatory properties. However, the effects of α-Mangostin on hypertension remain unknown. In this study, we observed that α-Mangostin significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR), possibly through the down-regulation of angiotensin II (Ang II). We also identified early markers of hypertensive nephropathy, including urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG), which were reduced by α-Mangostin treatment. Mechanistic studies suggested that α-Mangostin may inhibit renal tubular epithelial-to-mesenchymal transformation (EMT) by down-regulating the TGF-ß signaling pathway, thus potentially offering a new therapeutic approach for hypertension and hypertensive nephropathy.