RESUMEN
BACKGROUND: Diabetes mellitus (DM) presents impediment to wound healing. While ultraviolet B (UVB) exposure showed therapeutic potential in various skin conditions, its capacity to mediate diabetic wound healing remains unclear. To investigate the efficacy of UVB on wound healing and its underlying basis. MATERIALS AND METHODS: Male C57BL/6 mice were subjected to the high-fat diet followed by streptozotocin administration to establish the diabetic model. Upon confirmation of diabetes, full-thickness wounds were inflicted and the treatment group received UVB radiation at 50 mJ/cm2 for 5 min every alternate day for 2 weeks. Wound healing rate was then assessed, accompanied by evaluations of blood glucose, lipid profiles, CD31 expression, and concentrations of ghrelin and leptin. Concurrently, in vitro studies were executed to evaluate the protective role of ghrelin on human umbilical vein endothelial cells (HUVEC) under high glucose (HG) conditions. RESULTS: Post UVB exposure, there was a marked acceleration in wound healing in DM mice without alterations in hyperglycemia and lipid profiles. Compared to non-UVB-exposed mice, the UVB group showed enhanced angiogenesis manifested by a surge in CD31 expression. This trend appeared to be in harmony with the elevated ghrelin levels. In vitro experiments indicated that ghrelin significantly enhanced the migratory pace and angiogenic properties of HUVEC under HG-induced stress, potentially mediated by an upregulation in vascular endothelial growth factor expression. CONCLUSION: UVB exposure bolstered wound healing in diabetic mice, plausibly mediated through augmented angiogenesis induced by ghrelin secretion. Such findings underscore the vast potential of UVB-induced ghrelin in therapeutic strategies targeting diabetic wound healing.
Asunto(s)
Diabetes Mellitus Experimental , Ghrelina , Células Endoteliales de la Vena Umbilical Humana , Ratones Endogámicos C57BL , Cicatrización de Heridas , Animales , Humanos , Masculino , Ratones , Glucemia/metabolismo , Ghrelina/metabolismo , Ghrelina/efectos de la radiación , Leptina/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Piel/efectos de la radiación , Piel/patología , Piel/metabolismo , Rayos Ultravioleta/efectos adversos , Terapia Ultravioleta/métodos , Cicatrización de Heridas/efectos de la radiaciónRESUMEN
Ursodeoxycholic acid (UDCA) is a type of hydrophilic bile acid extracted from animal bile with a wide range of biological functions. The present results demonstrated that UDCA could effectively inhibit the proliferation of two human melanoma cell line (M14 and A375) with time and concentrationdependence. Following exposure to various concentrations of UDCA, M14 cells exhibited typical morphological changes and weaker ability of colony forming. Flow cytometry analysis demonstrated that UDCA could induce a decrease of mitochondrial membrane potential and an increase in reactive oxygen species (ROS) levels in M14 cells. The cell cycle was arrested in the G2/M phase, which was confirmed by the decrease of cyclindependent kinase 1 and cyclinB1 at the protein level. However, when M14 cells were treated with UDCA and ZVADFMK (caspase inhibitor) synchronously, the apoptosis rate of the cells was reduced significantly. In addition, it was demonstrated that UDCA induced apoptosis of human melanoma M14 cells through the ROStriggered mitochondrialassociated pathway, which was indicated by the increased expression of cleavedcaspase3, cleavedcaspase9, apoptotic protease activating factor1, cleavedpoly (ADPribose) polymerase 1 and the elevation of B cell lymphoma2 (Bcl2) associated X protein/Bcl2 ratio associated with apoptosis. Therefore, UDCA may be a potential drug for the treatment of human melanoma.
Asunto(s)
Apoptosis/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Ácido Ursodesoxicólico/farmacología , Clorometilcetonas de Aminoácidos/farmacología , Inhibidores de Caspasas/farmacología , Caspasas/metabolismo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Melanoma/tratamiento farmacológico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Microscopía Electrónica de Transmisión , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
BACKGROUND: Aberrant expression of retinoic acid receptor α (RARα) was correlated with diverse carcinomas such as acute promyelocytic leukemia and colorectal carcinoma. Nevertheless, the function and mechanism of RARα in esophageal carcinoma (EC) remain unclear. AIM: To investigate the expression of RARα in EC and its effect in the tumorigenesis of EC. METHODS AND RESULTS: In immunohistochemistry study, RARα was overexpressed in human EC tissues, and its overexpression was closely related to the pathological differentiation, lymph node metastasis, and clinical stages in EC patients. Functionally, RARα knockdown suppressed the proliferation and metastasis of EC cells through downregulating the expression of PCNA, Ki67, MMP7, and MMP9, as well as enhanced drug susceptibility of EC cells to 5-fluorouracil and cisplatin. Mechanistically, RARα knockdown inhibited the activity of Wnt/ß-catenin pathway through reducing the phosphorylation level of GSK3ß at Ser-9 and inducing phosphorylation level at Tyr-216, which resulted in downregulation of its downstream targets such as MMP7, MMP9, and P-gP. CONCLUSIONS: Our results demonstrated that RARα knockdown suppressed the tumorigenicity of EC via Wnt/ß-catenin pathway. RARα might be a potential molecular target for EC clinical therapy.
Asunto(s)
Neoplasias Esofágicas , Regulación Neoplásica de la Expresión Génica , Receptor alfa de Ácido Retinoico/metabolismo , Vía de Señalización Wnt/fisiología , Carcinogénesis/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Femenino , Técnicas de Inactivación de Genes/métodos , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Ensayo de Tumor de Célula Madre/métodosRESUMEN
BACKGROUND: Crocodile oil and its products are used as ointments for burns and scalds in traditional medicines. A new ointment formulation - crocodile oil burn ointment (COBO) was developed to provide more efficient wound healing activity. The purpose of the study was to evaluate the burn healing efficacy of this new formulation by employing deep second-degree burns in a Wistar rat model. The analgesic and anti-inflammatory activities of COBO were also studied to provide some evidences for its further use. MATERIALS AND METHODS: The wound healing potential of this formulation was evaluated by employing a deep second-degree burn rat model and the efficiency was comparatively assessed against a reference ointment - (1% wt/wt) silver sulfadiazine (SSD). After 28 days, the animals were euthanized and the wounds were removed for transversal and longitudinal histological studies. Acetic acid-induced writhing in mice was used to evaluate the analgesic activity and its anti-inflammatory activity was observed in xylene -induced edema in mice. RESULTS: COBO enhanced the burn wound healing (20.5±1.3 d) as indicated by significant decrease in wound closure time compared with the burn control (25.0±2.16 d) (P<0.01). Hair follicles played an importance role in the physiological functions of the skin, and their growth in the wound could be revealed for the skin regeneration situation. Histological results showed that the hair follicles were well-distributed in the post-burn skin of COBO treatment group, and the amounts of total, active, primary and secondary hair follicles in post-burn 28-day skin of COBO treatment groups were more than those in burn control and SSD groups. On the other hand, the analgesic and anti-inflammatory activity of COBO were much better than those of control group, while they were very close to those of moist exposed burn ointment (MEBO). CONCLUSIONS: COBO accelerated wound closure, reduced inflammation, and had analgesic effects compared with SSD in deep second degree rat burn model. These findings suggest that COBO would be a potential therapy for treating human burns. Abbreviations: COBO, crocodile oil burn ointment; SSD, silver sulfadiazine; MEBO, moist exposed burn ointment; TCM, traditional Chinese medicine; CHM, Chinese herbal medicine; GC-MS, gas chromatography-mass spectrometry.
Asunto(s)
Analgésicos/administración & dosificación , Antiinflamatorios/administración & dosificación , Quemaduras/tratamiento farmacológico , Aceites/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , Caimanes y Cocodrilos , Animales , Quemaduras/fisiopatología , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones , Pomadas/administración & dosificación , Ratas , Ratas Wistar , Piel/efectos de los fármacos , Piel/lesiones , Resultado del TratamientoRESUMEN
Retinoic acid receptor γ (RARγ), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma. However, little is known about the regulatory mechanism of the RARγ expression in colorectal cancer (CRC) progression. In the present study, we found that RARγ was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in CRC specimens. Tissue microarrays showed that RARγ indicated vital clinical significance in CRC. RARγ knockdown neither affected CRC cell proliferation nor blocked the cell cycle of CRC cells. However, RARγ knockdown increased the sensitivity of CRC cells to chemotherapeutics through downregulation of multi-drug resistance 1(MDR1). Further studies suggested that RARγ knockdown resulted in downregulation of MDR1, in parallel with suppression of the Wnt/ß-catenin pathway. Moreover, a significantly positive association between RARγ and MDR1 was demonstrated in CRC tissue microarrays. Collectively, these results suggested that overexpression of RARγ contributed to the multidrug chemoresistance of CRC cells, at least in part due to upregulation of MDR1 via activation of the Wnt/ß-catenin pathway, indicating that RARγ might serve as a potential therapeutic target for chemoresistant CRC patients.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Técnicas de Silenciamiento del Gen , Oncogenes , Receptores de Ácido Retinoico/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Ácido Retinoico/genética , Regulación hacia Arriba/efectos de los fármacos , Vía de Señalización Wnt , Receptor de Ácido Retinoico gammaRESUMEN
Crocodile choline, an active compound isolated from Crocodylus siamensis, was found to exert potent anti-cancer activities against human gastric cancer cells in vitro and in vivo. Our study revealed that crocodile choline led to cell cycle arrest at the G2/M phase through attenuating the expressions of cyclins, Cyclin B1, and CDK-1. Furthermore, crocodile choline accelerated apoptosis through the mitochondrial apoptotic pathway with the decrease in mitochondrial membrane potential, the increase in reactive oxygen species production and Bax/Bcl-2 ratio, and the activation of caspase-3 along with the release of cytochrome c. In addition, this study, for the first time, shows that Notch pathway is remarkably deregulated by crocodile choline. The combination of crocodile choline and Notch1 short interfering RNA led to dramatically increased cytotoxicity than observed with either agent alone. Notch1 short interfering RNA sensitized and potentiated the capability of crocodile choline to suppress the cell progression and invasion of gastric cancer. Taken together, these data suggested that crocodile choline was a potent progression inhibitor of gastric cancer cells, which was correlated with mitochondrial apoptotic pathway and Notch pathway. Combining Notch1 inhibitors with crocodile choline might represent a novel approach for gastric cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Colina/administración & dosificación , Receptor Notch1/biosíntesis , Neoplasias Gástricas/tratamiento farmacológico , Caimanes y Cocodrilos/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína Quinasa CDC2 , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclina B1/biosíntesis , Quinasas Ciclina-Dependientes/biosíntesis , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mitocondrias/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Receptor Notch1/genética , Transducción de Señal/efectos de los fármacos , Proteína X Asociada a bcl-2/biosíntesisRESUMEN
Apoptosis, programmed cell death under physiological or pathological conditions, plays a critical role in the tissue homeostasis of eukaryotes. It is desirable to prevent the occurrence and metastasis of cancer through inducing apoptosis. Our previous study demonstrated that apoptosis could be induced by extract from crocodile in human cholangiocarcinoma. ESC-3, a novel cytotoxic compound isolated from the extract induced apoptosis in Mz-ChA-1 cells via the mitochondria-dependent pathway in a dose-dependent manner. In this study, ESC-3 significantly inhibited the proliferation of A2780 cells and arrested the cells at G2/M phase. After exposure to ESC-3, A2780 cells displayed typical morphological changes and the ability of colony-forming was remarkably inhibited. ESC-3 could significantly upregulate the expression of Bax proteins while Bcl-2 protein remained unchanged, resulting in the elevation of Bax/Bcl-2 ratio, which usually could induce apoptosis. The critical protein of Wnt signaling (ß-catenin) was significantly downregulated, whereas Hes1, the downstream protein of Notch signaling, was remarkably attenuated through upregulating the expression of P53. In addition, xenograft models demonstrated that ESC-3 effectively suppressed the growth of OvCa tumors (T/C=42%). Western blot analysis of PCNA and VEGF confirmed that ESC-3 could inhibit the growth and metastasis of OvCa tumors. In conclusion, apoptosis could be induced by ESC-3 through Wnt/ß-catenin and Notch signaling in vitro and in vivo, and might have therapeutic potential for the treatment of human OvCa.