RESUMEN
Targeted synergistic therapy has broad prospects in tumor treatments. Here, a multi-functional nanodrug GDYO-CDDP/DOX@DSPE-PEG-MTX (GCDM) based on three traditional anticancer drugs (doxorubicin (DOX), cisplatin (CDDP) and methotrexate (MTX)) modified graphdiyne oxide (GDYO) is described, for diagnosis and targeted cancer photo-chemo synergetic therapy. In this system, for the first time, these three traditional anti-cancer drugs have played new roles and can reduce multidrug resistance through synergistic anti-tumor effects. Cisplatin can be hybridized with GDYO to form a multifunctional and well-dispersed three-dimensional framework, which can not only be used as nano-drug carriers to achieve high drug loading rates (40.3%), but also exhibit excellent photothermal conversion efficiency (47%) and good photodynamic effects under NIR irradiation. Doxorubicin (DOX) is loaded onto GDYO-CDDP through π-π stacking, which is used as an anticancer drug and as a fluorescent probe for nanodrug detection. Methotrexate (MTX) can be applied in tumor targeting and play a role in synergistic chemotherapy with DOX and CDDP. The synthesized multi-functional nanodrug GCDM has good biocompatibility, active targeting, long-term retention, sustained drug release, excellent fluorescence imaging capabilities, and remarkable photo-chemo synergistic therapeutic effects.
Asunto(s)
Grafito , Nanopartículas , Neoplasias , Línea Celular Tumoral , Doxorrubicina/farmacología , Liberación de Fármacos , Neoplasias/tratamiento farmacológico , FototerapiaRESUMEN
The matrix remodeling associated 7 (MXRA7) gene had been ill-studied and its biology remained to be discovered. Inspired by our previous findings and public datasets concerning MXRA7, we hypothesized that the MXRA7 gene might be involved in bone marrow mesenchymal stem cells (BMSCs) functions related to bone formation, which was checked by utilizing in vivo or in vitro methodologies. Micro-computed tomography of MXRA7-deficient mice demonstrated retarded osteogenesis, which was reflected by shorter femurs, lower bone mass in both trabecular and cortical bones compared with wild-type (WT) mice. Histology confirmed the osteopenia-like feature including thinner growth plates in MXRA7-deficient femurs. Immunofluorescence revealed less osteoblasts in MXRA7-deficient femurs. Polymerase chain reaction or western blot analysis showed that when WT BMSCs were induced to differentiate toward osteoblasts or adipocytes in culture, MXRA7 messenger RNA or protein levels were significantly increased alongside osteoblasts induction, but decreased upon adipocytes induction. Cultured MXRA7-deficient BMSCs showed decreased osteogenesis upon osteogenic differentiation induction as reflected by decreased calcium deposition or lower expression of genes responsible for osteogenesis. When recombinant MXRA7 proteins were supplemented in a culture of MXRA7-deficient BMSCs, osteogenesis or gene expression was fully restored. Upon osteoblast induction, the level of active ß-catenin or phospho-extracellular signal-regulated kinase in MXRA7-deficient BMSCs was decreased compared with that in WT BMSCs, and these impairments could be rescued by recombinant MXRA7 proteins. In adipogenesis induction settings, the potency of MXRA7-deficient BMSCs to differentiate into adipocytes was increased over the WT ones. In conclusion, this study demonstrated that MXRA7 influences bone formation via regulating the balance between osteogenesis and adipogenesis in BMSCs.
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Enfermedades Óseas Metabólicas/metabolismo , Diferenciación Celular , Fémur/metabolismo , Proteínas de la Membrana/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Osteogénesis , Adipocitos/metabolismo , Adipocitos/patología , Adipogénesis , Animales , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/patología , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fémur/patología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Células Madre Mesenquimatosas/patología , Ratones Noqueados , Osteoblastos/patología , Fenotipo , Transducción de Señal , beta Catenina/metabolismoRESUMEN
Drug metabolizing enzymes (DMEs) and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC) is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE) on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2) cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(P)H: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate-cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant increase in the intracellular level of glutathione and total glutathione S-transferase content. SCE significantly elevated the messenger ribonucleic acid and protein levels of P-glycoprotein and multidrug resistance-associated protein 2 and 4, whereas the expression of organic anion transporting peptide 1A2 and 1B1 was significantly downregulated by SCE. Knockdown of Nrf2 by small interfering ribonucleic acid attenuated the regulatory effect of SCE on these DMEs and drug transporters. SCE significantly upregulated Nrf2 and promoted the translocation of Nrf2 from cytoplasm to the nuclei. Additionally, SCE significantly suppressed the expression of cytosolic Kelch-like ECH-associated protein 1 (the repressor of Nrf2) and remarkably increased Nrf2 stability in HepG2 cells. Taken together, our findings suggest that the hepatoprotective effects of SCE may be partially ascribed to the modulation of DMEs and drug transporters via Nrf2-mediated signaling pathway. SCE may alter the pharmacokinetics of other coadministered drugs that are substrates of these DMEs and transporters and thus cause unfavorable herb-drug interactions.
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Medicamentos Herbarios Chinos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Preparaciones Farmacéuticas/metabolismo , Schisandra/química , Transducción de Señal/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Glutamato-Cisteína Ligasa/metabolismo , Glutatión Transferasa/metabolismo , Hemo-Oxigenasa 1/metabolismo , Células Hep G2 , Humanos , Medicina Tradicional China , Estructura Molecular , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Danshen Injection, the aqueous extracts of Radix Salvia miltiorrhiza (S. miltiorrhiza), is one of the most commonly used traditional Chinese herbs in chronic renal failure treatment. In present study, the mechanism of the renoprotective effect of Danshen Injection was analyzed on streptozocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Diabetic experimental model was established in male Sprague-Dawley (SD) rats by intraperitoneal injection of STZ. Rats with blood glucose concentration of higher than 300 mg/dl were intraperitoneally administered with Danshen Injection at a dose of 0.78 ml/kgday. The blood glucose, 24h urinary protein excretion, serum creatinine (sCr), blood urea nitrogen (BUN), advanced glycation end products (AGEs), lipid peroxide (LPO), antioxidant enzyme of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), transforming growth factor-ß1 (TGF-ß1), and histomorphological changes in kidney of diabetic rats were analyzed during the course of Danshen Injection administration, as well as the tubular function index of albumin reabsorption of fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA). RESULTS: The intraperitoneal administration of Danshen Injection could ameliorate the physiological dysfunctions of increased 24h urinary protein excretion((48.21 ± 8.04)%), sCr((39.4 ± 3.7)%), and BUN((43.37 ± 6.74)%), alleviate the ultrastructural abnormalities of hypertrophy, matrix expansion, and fibrosis in glomerulus, decrease the TGF-ß1 expression, AGEs and LPO accumulation, and increase the activity of SOD and GSH-Px in kidney of diabetic rats, but did not significantly influence the blood glucose. Besides these, the Danshen Injection administration also partly restored the decrease of megalin expression in tubules and reabsorptive function of FITC-BSA, in diabetic rats. CONCLUSION: The renoprotection of Danshen Injection on diabetic rats was associated with the preservation of tubular function and structure from the hyperglycemia induced toxicities of inappropriate cytokines secretion, oxidative stress, advanced glycation stress, and megalin expression deletion.
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Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/prevención & control , Medicamentos Herbarios Chinos/farmacología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/fisiología , Animales , Regulación de la Expresión Génica , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Salvia miltiorrhiza , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVE: To investigate the effect of Chinese herbal medicine with Supplement Qi and Activating Blood Circulation (huangqi and danshen) on urinary protein, kidney function and tubular reabsorption of diabetic nephropathy rats. METHODS: SD rats were randomly divided into a nondiabetic control group (normal group) and three groups in which diabetes were induced by a single intraperitoneal injection of freshly prepared streptozotocin( STZ,55 mg/kg body weight). Then the diabetes rats were randomly assigned to three groups: diabetic model group, Supplement Qi and Activating Blood Circulation traditional Chinese medicine group (huangqi and danshen group) and Gliquidone group (as a reference hypoglycemic drug). Each group was treated with corresponding drugs for 6 weeks. At the end of the study, the rats from each group were injected with FITC-labeled BSA through tail vein. The 24 h urinary protein excretion were measured and blood was collected for measuring plasma glucose levels, serum creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG) and total cholesterol (T-CHO). Renal tissue was used to measure the level of LPO,SOD,GSH-Px and AGEs and Paraffin-embedded sections were stained with HE, PAS and immunohistochemistry. RESULTS: The plasma glucose, the 24 h urinary protein excretion, the levels of serum Cr, BUN, TG and T-CHO in STZ-induced diabetic rats were higher than those of nondiabetic rats. Diabetic rats showed significantly increase in LPO and AGEs (P < 0.01) and decrease in antioxidant enzyme activity (both GSH-Px and SOD) (P < 0.05) as compared with non-diabetic control rats. Treatment with the Supplement Qi and Activating Blood Circulation traditional Chinese medicine for 6 weeks in diabetic rats significantly reduced the 24 h urinary protein excretion compared with model control (P < 0.01), and markedly decreased the levels of serum Cr,BUN,TG and T-CHO as compared with those of diabetic rat (P < 0.05). The levels of LPO and AGEs were decreased and the activity of GSH-Px was increased by Supplement Qi and Activating Blood Circulation treatment. The kidney proximal tubule lesions were improved and the reabsorption of FITC-BSA in tubular was increased in diabetic rats treated by huangqi and danshen, and the expression of megalin in proximal tubular was enhanced as compared with diabetic rats. CONCLUSION: Diabetic nephropathy rats treated with traditional Chinese medicine therapeutic principles "Supplement Qi and Activating Blood Circulation" can reduce the 24 h urinary protein excretion and improve the function of tubular reabsorption. These protect effects may be in correlation with enhancement the renal tissue activity of antioxidant and up-regulation the expression of megalin in renal tubular epithelial cells in diabetic rats.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Túbulos Renales/efectos de los fármacos , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Absorción/efectos de los fármacos , Animales , Astragalus propinquus/química , Biomarcadores/sangre , Biomarcadores/orina , Glucemia/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/administración & dosificación , Pruebas de Función Renal , Túbulos Renales/metabolismo , Túbulos Renales/fisiopatología , Masculino , Fitoterapia/métodos , Ratas , Ratas Sprague-Dawley , Salvia miltiorrhiza/química , EstreptozocinaRESUMEN
Gossypol (C(30)H(30)O(8)) is a polyphenolic compound derived from the cotton plant (genus Gossypium, family Malvaceae). The presence of six phenolic hydroxyl groups and two aldehydic groups makes gossypol chemically reactive. Gossypol can undergo Schiff base formation, ozonolysis, oxidation, and methylation to form gossypol derivatives. Gossypol and its derivatives have been the target of much research due to their multifaceted biological activities including antifertility, antivirus, anticancer, antioxidant, antitrypanosomal, antimicrobial, and antimalarial activities. Because of restricted rotation of the internaphthyl bond, gossypol is a chiral compound, which has two atropisomers (i.e., (+)- and (-)-gossypol) that exhibit different levels of biological activities. This chapter covers the physiochemical properties, analyses, biological properties, and agricultural and clinical implications of gossypol.