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Métodos Terapéuticos y Terapias MTCI
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1.
Phytomedicine ; 69: 153202, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32169782

RESUMEN

BACKGROUND: 7-Hydroxycoumarin (7-HC), also known as umbelliferon, is commonly found in Chinese herbs (e.g. Eucommiae Cortex, Prunellae Spica, Radix Angelicae Biseratae). Previous laboratory studies have indicated that 7-HC has anti-inflammatory, anti-oxidative, and anti-tumor effects. Cisplatin is a widely used chemotherapeutic agent for cancer. Nephrotoxicity is one of the limiting side effects of cisplatin use. PURPOSE: This study aimed to evaluate the renoprotective effect of 7-HC in a cisplatin-induced acute kidney injury (AKI) mouse model. METHODS: AKI was induced in male C57BL/6 mice (aged 6-8 weeks) by a single intraperitoneal injection of cisplatin at 20 mg/kg. The mice received 7-HC at 30, 60, and 90 mg/kg intraperitoneally before or after cisplatin administration. Renal function, necroptosis, and cell proliferation were measured. Mechanisms underlying the reno-protective effect of 7-HC were explored in renal tubular epithelial cells treated with or without cisplatin. RESULTS: In-vivo experiments showed that 7-HC significantly improved the loss in kidney function induced by cisplatin, as indicated by lower levels of serum creatinine and blood urea nitrogen, in AKI mice. Consistent herewith, cisplatin-induced tubular damage was alleviated by 7-HC as shown by morphological (periodic acid-Schiff staining) and kidney injury marker (KIM-1) analyses. We found that 7-HC suppressed renal necroptosis via the RIPK1/RIPK3/MLKL pathway and accelerated renal repair as evidenced by the upregulation of cyclin D1 in cisplatin-induced nephropathy. In-vitro experiments showed that knockdown of Sox9 attenuated the suppressive effect of 7-HC on KIM-1 and reversed the stimulatory effect of 7-HC on cyclin D1 expression in cisplatin-treated HK-2 cells, indicating that 7-HC may protect against AKI via a Sox9-dependent mechanism. CONCLUSION: 7-HC inhibits cisplatin-induced AKI by suppressing RIPK1/RIPK3/MLKL-mediated necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation. 7-HC may serve as a preventive and therapeutic agent for AKI.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Cisplatino/efectos adversos , Riñón/efectos de los fármacos , Sustancias Protectoras/farmacología , Umbeliferonas/farmacología , Lesión Renal Aguda/tratamiento farmacológico , Animales , Antineoplásicos/efectos adversos , Línea Celular , Proliferación Celular/efectos de los fármacos , Humanos , Riñón/patología , Pruebas de Función Renal , Masculino , Ratones Endogámicos C57BL , Necroptosis/efectos de los fármacos , Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo
2.
Int Immunopharmacol ; 76: 105838, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31473406

RESUMEN

Hepatic fibrosis, a common pathological feature and leading cause of various chronic liver diseases, still lacks effective therapy. Hesperetin derivative (HD) is a derivative of Traditional Chinese Medicine monomer isolated from the fruit peel of Citrusaurantium L. (Rutaceae). In the present study, we revealed the anti-fibrotic effects of HD in CCl4-induced mouse hepatic fibrosis model and in TGF-ß1-activated LX-2 cells, in vivo and in vitro. Results showed that HD prevented CCl4-induced liver injury and histological damage. Consistently, HD inhibited the up-regulation of liver fibrogenesis markers α-SMA, Col1α1, Col3α1 and TIMP-1 in primary hepatic stellate cells (HSCs) and suppressed inflammatory responses in primary liver macrophages from hepatic fibrosis mice. Furthermore, HD promoted the apoptosis of activated HSCs, a key step in the onset of fibrosis regression. Mechanistically, the Hedgehog pathway was involved in HD-treated hepatic fibrosis, and HD specifically contributed to attenuate the aberrant expression of Glioma associated oncogene-1 (Gli-1). Interestingly, blockade of Gli-1 removed the inhibitory effect of HD on activated HSCs, indicating that Gli-1 may play a pivotal role in mediating the anti-fibrotic effect of HD in hepatic fibrosis. Collectively, our results suggest that HD may be a potential anti-fibrotic Traditional Chinese Medicine monomer for the treatment of hepatic fibrosis.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Hesperidina/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Tetracloruro de Carbono , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Citocinas/genética , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Hesperidina/farmacología , Humanos , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Sustancias Protectoras/farmacología , Factor de Crecimiento Transformador beta1/farmacología , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo
3.
Int Immunopharmacol ; 75: 105671, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31377590

RESUMEN

Liver fibrosis is the representative features of liver chronic inflammation and the characteristic of early cirrhosis. To date, effective therapy for liver fibrosis is lacking. Recently, Traditional Chinese Medicine (TCM) has attracted increasing attention due to its wide pharmacological effects and more uses in clinical. Wogonin, as one major active constituent of Scutellaria radix, has been reported it plays an important role in anti-inflammatory, anti-cancer, anti-viral, anti-angiogenesis, anti-oxidant and neuro-protective effects. However, the anti-fibrotic effect of wogonin is never covered in liver. In this study, we evaluated the protect effect of wogonin in liver fibrosis. Wogonin significantly attenuated liver fibrosis both in CCl4-induced mice and TGF-ß1 activated HSCs. Meanwhile, wogonin can enhances apoptosis of TGF-ß1 activated HSC-T6 cell from rat and LX-2 cell from human detected by flow cytometry. Additionally, wogonin can largely enhances cle-caspase3, cle-caspase9 expression and the ratio of Bax/Bcl-2 in T6 cells. Pro-apoptosis effect of wogonin in vivo was further verified in situ. In conclusion, wogonin can attenuate liver fibrosis via regulating the activation and apoptosis of hepatic stellate cells, and may be an effective drug to treat and prevent liver fibrosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Flavanonas/uso terapéutico , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Animales , Tetracloruro de Carbono , Línea Celular , Flavanonas/farmacología , Humanos , Masculino , Ratones Endogámicos C57BL , Ratas , Factor de Crecimiento Transformador beta1
4.
Front Pharmacol ; 10: 376, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31057404

RESUMEN

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid loss of renal function, which may further develop into chronic kidney damage (CKD) or even end-stage renal disease (ESRD). AKI is a global health problem associated with high morbidity and costly treatments, and there is no specific or effective strategy to treat AKI. In recent years, Traditional Chinese Medicine (TCM) has attracted more attention, with lines of evidence showing that application of TCM improved AKI, and the mechanisms of action for some TCMs have been well illustrated. However, reviews summarizing the progress in this field are still lacking. In this paper, we reviewed TCM preparations and TCM monomers in the treatment of AKI over the last 10 years, describing their renal protective effects and mechanisms of action, including alleviating inflammation, programmed cell death, necrosis, and reactive oxygen species. By focusing on the mechanisms of TCMs to improve renal function, we provide effective complementary evidence to promote the development of TCMs to treat AKI. Moreover, we also summarized TCMs with nephrotoxicity, which provides a more comprehensive understanding of TCMs in the treatment of AKI. This review may provide a theoretical basis for the clinical application of TCMs in the future.

5.
Int Immunopharmacol ; 50: 95-106, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28646664

RESUMEN

Alcoholic liver disease (ALD) is one of the predominant causes of liver-related morbidity and mortality worldwide. However, effective therapy for ALD is still lacking. Wogonin, a major flavonoid compound, is found in Scutellaria baicalensis Georgi. Accumulating studies have revealed that wogonin possesses anti-inflammatory and anti-tumour activities in various models. However, the hepatoprotective activity of wogonin in ALD is still obscure. In this study, we found that wogonin significantly attenuated inflammatory response in EtOH-fed mice, and reduced the expression of inflammatory cytokines such as TNF-α and IL-6 in EtOH-induced RAW264.7 cells. Furthermore, our findings showed that wogonin remarkably induced the expression of PPAR-γ in vivo and in vitro. Compared with the wogonin-treated group, blockade of PPAR-γ with inhibitor (T0070907) or PPAR-γ small interfering (si)-RNA were applied in RAW264.7 cells to evaluate the involvement of wogonin in alleviating EtOH-induced inflammation. Moreover, forced expression of PPAR-γ further suppressed the expression of TNF-α and IL-6 when treated with wogonin on EtOH-induced RAW264.7 cells. In addition, it was demonstrated that wogonin remarkably suppressed PPAR-γ-meditated phosphorylation and activation of NF-κB-P65. In conclusion, our results indicated that wogonin may serve as an effective modulator of PPAR-γ by down-regulating NF-κB pathway, thereby attenuated inflammatory response in ALD.


Asunto(s)
Antiinflamatorios/uso terapéutico , Flavanonas/uso terapéutico , Hepatopatías Alcohólicas/tratamiento farmacológico , PPAR gamma/metabolismo , Animales , Benzamidas/farmacología , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Humanos , Inmunomodulación , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Hepatopatías Alcohólicas/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR gamma/genética , Piridinas/farmacología , Células RAW 264.7 , ARN Interferente Pequeño/genética , Scutellaria baicalensis/inmunología , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
6.
Front Pharmacol ; 7: 479, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27999546

RESUMEN

Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment.

7.
Eur J Pharmacol ; 789: 134-143, 2016 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-27397431

RESUMEN

Renal fibrosis, a common feature and leading cause for End Stage Renal Disease, still lacks effective therapy. In the current study, we detected and compared the anti-fibrotic effects of wogonin and wogonoside, two major components of Scutellaria baicalensis Georgi, in TGF-ß1-treated tubular epithelial cells of human and murine origins. Results consistently showed that compared with wogonoside, wogonin inhibits TGF-ß1-induced upregulated mRNA and protein levels of collagen I and α-SMA with more efficiency, which was further confirmed by the immunofluorescence results that wogonin decreased the percentage of collagen I and α-SMA positive cells in TGF-ß1-treated tubular epithelial cells. Mechanistically, wogonin mainly decreased Smad3 phosphorylation, but had marginal effect on non-canonical TGF-ß signaling pathways, such as p38 and ERK MAP Kinase. Furthermore, in the cells deficient for TGF-ß signaling or downstream Smad3, results demonstrated that even high concentration of wogonin failed to further decrease the level of collagen I and α-SMA, indicating the essential role of TGF-ß/Smad3 signaling inhibition in the therapeutic action of wogonin in TGF-ß1-stimulated tubular epithelial cells. Collectively, our results indicated that wogonin may be utilized as a potential anti-fibrotic Traditional Chinese Medicine monomer in the treatment of renal fibrosis.


Asunto(s)
Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Flavanonas/farmacología , Glucósidos/farmacología , Túbulos Renales Proximales/patología , Proteína smad3/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Relación Dosis-Respuesta a Droga , Células Epiteliales/metabolismo , Fibrosis , Flavanonas/uso terapéutico , Glucósidos/uso terapéutico , Humanos , Ratones , Fosforilación/efectos de los fármacos , Ratas , Receptores de Factores de Crecimiento Transformadores beta/deficiencia , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteína smad3/deficiencia , Factor de Crecimiento Transformador beta1/farmacología
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