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1.
Front Immunol ; 15: 1303115, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38420119

RESUMEN

Many studies have investigated the antiviral activity of cytokines, including interleukin-6 (IL-6), interleukin-22 (IL-22), interleukin-32 gamma (IL-32γ), and interferon-lambda (IFN-λ) in diverse populations. This study aims to evaluate the role of these cytokines in inhibition of various human and animal viruses when administered exogenously. A comprehensive meta-analysis and systematic review were conducted on all the relevant studies from three databases. Standard mean differences (SMDs) of overall viral inhibition were used to generate the difference in the antiviral efficacy of these cytokines between control and experimental groups. A total of 4,618 abstracts for IL-6, 3,517 abstracts for IL-22, 2,160 abstracts for IL-32γ, and 1,026 abstracts for IFN-λ were identified, and 7, 4, 8, and 35 studies were included, respectively, for each cytokine. IFN-λ (SMD = 0.9540; 95% CI: 0.69-0.22) and IL-32γ (SMD = 0.459; 95% CI: 0.02-0.90) showed the highest influence followed by IL-6 (SMD = 0.456; CI: -0.04-0.95) and IL-22 (SMD = 0.244; 95% CI: -0.33-0.81). None of the cytokines represented heterogeneity (tau² > 0), but only IFN-λ indicated the funnel plot asymmetry (p = 0.0097). Results also indicated that IFN-λ and IL-32γ are more potent antivirals than IL-6 and IL-22. The collective findings of this study emphasize that exogenously administered pro-inflammatory cytokines, specifically IFN-λ and IL-32, exhibit a significant antiviral activity, thereby underscoring them as potent antiviral agents. Nonetheless, additional research is required to ascertain their clinical utility and potential for integration into combinatorial therapeutic regimens against viral infections.


Asunto(s)
Interleucina-6 , Virus , Animales , Humanos , Interferón lambda , Interleucina-22 , Citocinas , Antivirales/farmacología
2.
Molecules ; 28(2)2023 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-36677632

RESUMEN

Sepsis is a serious health concern globally, which necessitates understanding the root cause of infection for the prevention of proliferation inside the host's body. Phytochemicals present in plants exhibit antibacterial and anti-proliferative properties stipulated for sepsis treatment. The aim of the study was to determine the potential role of Carica papaya leaf extract for sepsis treatment in silico and in vitro. We selected two phytochemical compounds, carpaine and quercetin, and docked them with bacterial proteins, heat shock protein (PDB ID: 4PO2), surfactant protein D (PDB ID: 1PW9), and lactobacillus bacterial protein (PDB ID: 4MKS) against imipenem and cyclophosphamide. Quercetin showed the strongest interaction with 1PW9 and 4MKS proteins. The leaves were extracted using ethanol, methanol, and water through Soxhlet extraction. Total flavonoid content, DPPH assay, HPTLC, and FTIR were performed. In vitro cytotoxicity of ethanol extract was screened via MTT assay on the J774 cell line. Ethanol extract (EE) possessed the maximum number of phytocomponents, the highest amount of flavonoid content, and the maximum antioxidant activity compared to other extracts. FTIR analysis confirmed the presence of N-H, O-H, C-H, C=O, C=C, and C-Cl functional groups in ethanol extract. Cell viability was highest (100%) at 25 µg/mL of EE. The present study demonstrated that the papaya leaves possessed antibacterial and cytotoxic activity against sepsis infection.


Asunto(s)
Carica , Sepsis , Extractos Vegetales/farmacología , Extractos Vegetales/química , Proteínas Bacterianas , Carica/química , Simulación del Acoplamiento Molecular , Quercetina , Antibacterianos/farmacología , Fitoquímicos/análisis , Flavonoides , Etanol , Sepsis/tratamiento farmacológico , Hojas de la Planta/química
3.
Maedica (Bucur) ; 16(3): 400-404, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34925594

RESUMEN

Background:Anterior communicating artery connects the two anterior cerebral arteries across the commencement of the longitudinal fissure. Anterior communicating artery is an important artery to form the circle of Willis. The present study was conducted to know the variations of anterior communicating artery, including number, diameter, length, course and direction of placement. Knowledge of the variations of anterior communicating artery is important for radiologists, neurosurgeons and anatomists. Materials and methods: This was a retrospective study with a duration of more than eight years, which was conducted on 100 adult embalmed human cadaveric brains conducted in the Department of Anatomy, Subharti Medical College, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India. After removal of the brain from cadavers used in routine educational dissection for MBBS students, the anterior communicating artery was dissected and cleaned, then measurements were taken and digitally photographed. Results:Among the 100 adult brains, the anterior communicating artery was absent in 3% of specimens. The course was oblique in 56% of specimens and horizontally placed in the remaining 44%. No duplication or triplication was seen. The mean length was 2.80 mm and mean diameter 1.11 mm. Conclusions:From the present study we conclude that the variations of anterior communicating artery are common. The anterior communicating artery was absent in 3% of specimens. Oblique and horizontal patterns were also seen. There was no duplication or triplication. Knowledge about the wide range of variations of this artery is important for neurosurgeons, radiologists and anatomists.

4.
Comb Chem High Throughput Screen ; 24(8): 1309-1321, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32928084

RESUMEN

BACKGROUND: Boswellic acids are the main constituents of Boswellia serrata gum. These comprise of four pentacyclic triterpenes, 11-keto-ß-boswellic acid (KBA) being one of them. OBJECTIVES: Comparing the extraction efficiency of KBA through microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE) followed by optimizing the extraction process using response surface methodology (RSM) and validation of HPTLC. METHODS: UAE and MAE of KBA were carried out employing methanol as an extracting solvent. To figure out the better mode of extraction, single factorial experiments were conducted for further optimization. Design expert software was used for optimization purposes where solvent to drug ratio, extraction temperature and extraction time were taken as input variables. Quantification of KBA in each extract was done through High-Performance Thin Layer Chromatography (HPTLC), and the method was validated as per International Council for Harmonization (ICH) guidelines. RESULTS: UAE stood out to be a better mode of extraction for KBA. Solvent to drug ratio of 20.42 mL/gram, extraction temperature of 44.01°C and extraction time of 11.54 minutes were established as optimum conditions, which yielded 8.44%w/w of KBA. Regarding HPTLC, the Rf value of KBA was measured, and the correlation coefficient was calculated from the standard curve. Accuracy, precision and recovery were found within limits. CONCLUSION: From this study, it was concluded that a non-thermal method is a better choice of extraction for KBA. All the input variables significantly affected KBA content, which was confirmed by model fitting. Moreover, the HPTLC method was developed for the quantification of KBA, which was found to be accurate, reliable and highly sensitive.


Asunto(s)
Boswellia , Olíbano , Triterpenos , Boswellia/química , Cromatografía en Capa Delgada/métodos , Extractos Vegetales/química , Triterpenos/química
5.
Exp Mol Pathol ; 101(1): 12-21, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27235383

RESUMEN

Celastrol (CEL), a plant-derived triterpenoid, is a known inhibitor of Hsp90 and NF-κB activation pathways and has recently been suggested to be of therapeutic importance in various cancers. However, the molecular mechanisms of celastrol-mediated effects in lung cancer are not systematically studied. Moreover, it suffers from poor bioavailability and off-site toxicity issues. This study aims to study the effect of celastrol loaded into exosomes against two non-small cell-lung carcinoma (NSCLC) cell lines and explore the molecular mechanisms to determine the proteins governing the cellular responses. We observed that celastrol inhibited the proliferation of A549 and H1299 NSCLC cells in a time- and concentration-dependent manner as indexed by MTT assay. Mechanistically, CEL pre-treatment of H1299 cells completely abrogated TNFα-induced NF-κB activation and upregulated the expression of ER-stress chaperones Grp 94, Grp78, and pPERK. These changes in ER-stress mediators were paralleled by an increase in apoptotic response as evidenced by higher annexin-V/PI positive cells evaluated by FACS and immunoblotting which showed upregulation of the ER stress specific pro-apoptotic transcription factor, GADD153/CHOP and alteration of Bax/Bcl2 levels. Exosomes loaded with CEL exhibited enhanced anti-tumor efficacy as compared to free CEL against lung cancer cell xenograft. CEL did not exhibit any gross or systemic toxicity in wild-type C57BL6 mice as determined by hematological and liver and kidney function test. Together, our data demonstrate the chemotherapeutic potential of CEL in lung cancer and that exosomal formulation enhances its efficacy and reduces dose related toxicity.


Asunto(s)
Exosomas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Triterpenos/uso terapéutico , Células A549 , Animales , Apoptosis/efectos de los fármacos , Bovinos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Neoplasias Pulmonares/patología , Ratones Desnudos , FN-kappa B/metabolismo , Triterpenos Pentacíclicos , Triterpenos/química , Triterpenos/farmacología , Triterpenos/toxicidad , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Cancer Prev Res (Phila) ; 7(4): 456-65, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24501322

RESUMEN

Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17ß-estradiol (E2)-mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm(3) vs. 280 ± 141 mm(3); P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered.


Asunto(s)
Implantes Absorbibles , Antineoplásicos/administración & dosificación , Transformación Celular Neoplásica/efectos de los fármacos , Curcumina/administración & dosificación , Dieta , Estrógenos/toxicidad , Neoplasias Mamarias Experimentales/prevención & control , Animales , Antineoplásicos/farmacocinética , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/patología , Curcumina/farmacocinética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Ratas , Ratas Endogámicas ACI , Distribución Tisular
7.
Cancer Lett ; 332(1): 35-45, 2013 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-23340170

RESUMEN

Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB's cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB's cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos de Sulfhidrilo/metabolismo , Triterpenos/farmacología , Acetilcisteína/farmacología , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Animales , Antineoplásicos Fitogénicos/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Glutatión/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Espectrometría de Masas , Ratones , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Chaperonas Moleculares , Oxidación-Reducción , Transducción de Señal/efectos de los fármacos , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Factores de Tiempo , Triterpenos/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
8.
Cancer Lett ; 326(1): 33-40, 2012 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-22820161

RESUMEN

Poor oral bioavailability limits the use of many chemopreventives in the prevention and treatment of cancer. To overcome this limitation, we report an improvised implant formulation ("coated" implants) using curcumin, individual curcuminoids, withaferin A and oltipraz. This method involves the coating of blank polycaprolactone implants with 20-30 layers of 10-20% polycaprolactone solution in dichloromethane containing 0.5-2% of the test agent. The in vitro release showed that while oltipraz was released with almost zero-order kinetics over 8 weeks, curcumin, individual curcuminoids and withaferin A were released with some initial burst. The in vivo release was determined by grafting implants subcutaneously in A/J mice. When delivered by coated implants, oltipraz significantly diminished lung DNA adducts in mice treated with dibenzo[a,l]pyrene compared with sham treatment (28 ± 7 versus 54 ± 17 adducts/10(9) nucleotides). Withaferin A also diminished DNA adducts, but it was insignificant. Curcumin and individual curcuminoids were ineffective. Analysis of lung, liver and brain by UPLC-fluorescence showed the presence of the three test curcuminoids indicating effectiveness of the implant delivery system. Further, based on its known antitumor activity in vivo, withaferin A given via the implants significantly inhibited human lung cancer A549 xenograft in athymic nude mice, while it was ineffective when the same total dose was administered i.p. and required over 2-fold higher dose to elicit effectiveness. Together, our data suggest that coated polymeric implants can accommodate heat-labile compounds, can furnish sustained release for long duration, and elicit DNA damage-inhibiting and anti-tumor activities.


Asunto(s)
Anticarcinógenos/administración & dosificación , Bombas de Infusión Implantables , Poliésteres/administración & dosificación , Polímeros/administración & dosificación , Animales , Anticarcinógenos/toxicidad , Disponibilidad Biológica , Materiales Biocompatibles Revestidos/administración & dosificación , Curcumina/administración & dosificación , Aductos de ADN , Femenino , Humanos , Bombas de Infusión Implantables/efectos adversos , Ratones , Ratones Desnudos , Pirazinas/administración & dosificación , Tionas , Tiofenos , Distribución Tisular , Witanólidos/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Carcinogenesis ; 33(8): 1608-15, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22696595

RESUMEN

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo.


Asunto(s)
Anticarcinógenos/administración & dosificación , Neoplasias Pulmonares/prevención & control , Animales , Anticarcinógenos/farmacocinética , Disponibilidad Biológica , Preparaciones de Acción Retardada , Implantes de Medicamentos , Femenino , Humanos , Ratones , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Distribución Tisular
10.
Cancer Lett ; 325(1): 54-62, 2012 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-22659736

RESUMEN

Berry anthocyanidins (cyanidin, malvidin, peonidin, petunidin and delphinidin) have increasingly been explored for their anticancer effects; however, their combinatorial effects as a mixture, as present in blueberry, bilberry and Indian blackberry ('Jamun') remain untested. In this study, we demonstrate for the first time that the combination of suboptimal concentrations of equimolar anthocyanidins synergistically inhibited growth of two aggressive non-small-cell lung cancer cell lines, with minimal effects on non-tumorigenic cell viability. The induction of cell-cycle arrest, apoptosis and suppression of NSCLC cell invasion and migration were also significantly greater with the mixture than individual anthocyanidins. The superior effects of the combinatorial treatment presumably resulted from its effects on the oncogenic Notch and WNT pathways and their downstream targets (ß-catenin, c-myc, cyclin D1, cyclin B1, pERK, MMP9 and VEGF proteins), enhanced cleavage of the apoptotic mediators Bcl2 and PARP and enhanced inhibition of TNFα-induced NF-kappa B activation. In vivo, both the native mixture of anthocyanidins from bilberry (0.5mg/mouse) and the most potent anthocyanidin, delphinidin (1.5mg/mouse) significantly inhibited the growth of H1299 xenografts in nude miceby ≈60%. Notably, the effective dose of delphinidin in the anthocyanidin mixture was 8-fold lower than delphinidin alone, further emphasizing synergism. Our results thus demonstrate therapeutic potential of berries rich in this mixture of diverse anthocyanidins for non-small-cell lung cancer treatment and to prevent its future recurrence and metastasis.


Asunto(s)
Antocianinas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Sinergismo Farmacológico , Femenino , Frutas/química , Fase G2/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Invasividad Neoplásica , Poli(ADP-Ribosa) Polimerasas/metabolismo , Receptores Notch/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Proteína Letal Asociada a bcl/metabolismo
11.
Nutr Cancer ; 64(3): 428-38, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22420901

RESUMEN

Colored fruits, particularly berries, are highly chemoprotective because of their antioxidant, antiproliferative, and antiinflammatory activities. We report the cancer chemoprotective potential of Syzygium cumini L., commonly known as jamun or Indian blackberry. Anthocyanins and other polyphenolics were extracted with acidic ethanol and enriched by amberlite XAD7/HP20 (1:1). The pulp powder was found to contain 0.54% anthocyanins, 0.17% ellagic acid/ellagitannins, and 1.15% total polyphenolics. Jamun seed contained no detectable anthocyanins but had higher amounts of ellagic acid/ellagitannins (0.5%) and total polyphenolics (2.7%) than the pulp powder. Upon acid hydrolysis, the pulp extract yielded 5 anthocyanidins by HPLC: malvidin (44.4%), petunidin (24.2%), delphinidin (20.3%), cyanidin (6.6%), and peonidin (2.2%). Extracts of both jamun pulp (1,445 ± 64 µmol of trolox equivalent (TE)/g) and seeds (3,379 ± 151 µM of TE/g) showed high oxygen radical absorbance capacity. Their high antioxidant potential was also reflected by 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)- and 2,2-diphenyl-1-picrylhydrazyl-scavenging and ferrous ion-chelating activities. We also analyzed antiproliferative activity of jamun extracts against human lung cancer A549 cells. The hydrolyzed pulp and seed extracts showed significant antiproliferative activity. However, unhydrolyzed extracts showed much less activity. These data showed that in addition to 5 anthocyanidins, jamun contains appreciable amounts of ellagic acid/ellagitannins, with high antioxidant and antiproliferative activities.


Asunto(s)
Antocianinas/farmacología , Antioxidantes/farmacología , Proliferación Celular/efectos de los fármacos , Taninos Hidrolizables/farmacología , Extractos Vegetales/farmacología , Syzygium/química , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Frutas/química , Humanos , Semillas/química
12.
Eur J Pharm Biopharm ; 80(3): 571-7, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22227368

RESUMEN

Curcumin possesses potent anti-inflammatory and anti-proliferative activities but with poor biopharmaceutical attributes. To overcome these limitations, curcumin implants were developed and tissue (plasma, brain and liver) curcumin concentrations were measured in female ACI rats for 3 months. Biological efficacy of tissue levels achieved was analyzed by modulation of hepatic cytochromes. Curcumin implants exhibited diffusion-mediated biphasic release pattern with ∼2-fold higher in vivo release as compared to in vitro. Plasma curcumin concentration from implants was ∼3.3 ng/ml on day 1, which dropped to ∼0.2 ng/ml after 3 months, whereas only 0.2-0.3 ng/ml concentration was observed from 4-12 days with diet and was undetected subsequently. Almost 10-fold higher curcumin levels were observed in brain on day 1 from implants compared with diet (30.1 ± 7.3 vs 2.7 ± 0.8 ng/g) and were still significant even after 90 days (7.7 ± 3.8 vs 2.2 ± 0.8 ng/g). Although curcumin levels were similar in liver from both the routes (∼25-30 ng/g from day 1-4 and ∼10-15 ng/g at 90 days), implants were more efficacious in altering hepatic CYP1A1 levels and CYP3A4 activity at ∼28-fold lower doses at 90 days. Curcumin implants provided much higher plasma and tissue concentrations and are a viable alternative for delivery of curcumin to various organs like brain.


Asunto(s)
Implantes Absorbibles , Curcumina/administración & dosificación , Curcumina/farmacocinética , Polímeros/administración & dosificación , Administración Oral , Animales , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos/efectos de los fármacos , Citocromos/metabolismo , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos/métodos , Femenino , Glutatión Transferasa/genética , Cinética , Hígado/efectos de los fármacos , Hígado/metabolismo , Fase I de la Desintoxicación Metabólica/genética , Fase II de la Desintoxicación Metabólica/genética , Microsomas Hepáticos/metabolismo , Polímeros/farmacocinética , Ratas , Ratas Endogámicas ACI , Distribución Tisular/efectos de los fármacos
13.
Food Res Int ; 49(1): 345-353, 2012 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-23493479

RESUMEN

Ellagitannins are the most abundant polyphenols in pomegranate (Punica granatum) husk and contribute greatly towards its biological properties. A pre-enriched pomegranate husk powder was extracted with water and then further purified by an Amberlite XAD-16 column. Punicalagin (PC) anomers were eluted using a gradient of methanol and water. Fractions eluted with 20% and 25% methanol yielded 1.08 g of light brown powder (purity > 97%) from a total of 40 g of extract. This fraction was identified as PC by HPLC-UV using reference compounds and confirmed by FTICR-MS analysis. PC (10-40 µM) was found to significantly inhibit oxidative DNA products, about 70% inhibition at 40 µM (p=0.0017), resulting from Cu2+-catalyzed redox cycling of 4-hydroxy-17ß-estradiol as analyzed by 32P-postlabeling. Evidence of high antioxidant activity of PC was also obtained based on ORAC assay (1556±79 µmol of TE/g), as well as by 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS)-, 2,2-diphenyl-1-picrylhydrazyl (DPPH)-, hydrogen peroxide (H2O2) scavenging and ferrous ion-chelating activities (IC50=1.1, 17.1, 24 and 45.4 µg/ml, respectively). Further, PC exhibited strong anti-proliferative activity against the human lung, breast and cervical cancer cell lines. Together, these data suggest that PC can be isolated in its purified form by simple column chromatography, inhibits oxidative DNA damage and possesses high anti-proliferative activity.

14.
Carcinogenesis ; 32(11): 1697-705, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21859835

RESUMEN

Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Repression of HPV oncoproteins would therefore result in reactivation of tumor suppressor pathways and cause apoptosis in cancer cells. Withaferin A (WA), the active component of the medicinal plant Withania Somnifera, has exhibited inhibitory effects against several different cancers. We examined the activity of WA on human cervical cancer cells in vitro and in vivo. WA potently inhibited proliferation of the cervical cancer cells, CaSki (IC(50) 0.45 ± 0.05 µM). Mechanistically, WA was found to (i) downregulate expression of HPV E6 and E7 oncoproteins, (ii) induce accumulation of p53, (iii) increase levels of p21(cip1/waf1) and its interaction with proliferating cell nuclear antigen (PCNA), (iv) cause G(2)/M cell cycle arrest, associated with modulation of cyclin B1, p34(cdc2) and PCNA levels, (v) decrease the levels of STAT3 and its phosphorylation at Tyr(705) and Ser(727) and (vi) alter expression levels of p53-mediated apoptotic markers-Bcl2, Bax, caspase-3 and cleaved PARP. In vivo, WA resulted in reduction of nearly 70% of the tumor volume in athymic nude mice with essentially similar trend in the modulation of molecular markers as in vitro. This is the first demonstration indicating that WA significantly downregulates expression of HPV E6/E7 oncogenes and restores the p53 pathway, resulting in apoptosis of cervical cancer cells. Together, our data suggest that WA can be exploited as a potent therapeutic agent for the treatment and prevention of cervical cancer without deleterious effects.


Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Represoras/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Witanólidos/farmacología , Animales , Western Blotting , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunoprecipitación , Ratones , Ratones Desnudos , Proteínas Oncogénicas Virales/antagonistas & inhibidores , Proteínas E7 de Papillomavirus/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/antagonistas & inhibidores , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Neoplasias del Cuello Uterino/patología
15.
Drug Deliv Transl Res ; 1(4): 332-41, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25788367

RESUMEN

Curcumin, an anti-oxidant, anti-inflammatory, and anti-neoplastic agent, exhibited limited oral efficacy due to its poor bioavailability. To overcome this limitation, polymeric implants for continuous systemic delivery of curcumin were developed and tested for their safety and biocompatibility. Two 2-cm polycaprolactone implants containing polyethylene glycol and 20% (w/w) curcumin were grafted subcutaneously at the back of the Augustus Copenhagen Irish rats. Rats were euthanized and blood was analyzed for various hematological parameters; biochemical markers of liver/kidney function and local tissues were analyzed for local inflammatory reactions. Curcumin implants exhibited biphasic release kinetics with ∼3.6 + 0.8, 5.8 ± 1.1, 13.1 ± 2.1, 21.8 ± 0.3, 38.1 ± 0.6, and 47.2 ± 1.6 mg cumulative curcumin being released from both the implants after 1, 4, 12, 25, and 90 days. No significant differences in various hematological parameters (like white blood cells, red blood cells, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), liver enzymes (like aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, amylase, or lipase), or biochemical parameters of kidney function (like blood urea nitrogen, creatinine, Ca(2+), Na(+), and Cl(-) levels) were observed at any of these time points. However, a significant increase in serum phosphorus levels was observed at all the time points in sham implants as well as in curcumin diet and implant groups. Local implantation site showed foreign body granulomatous reaction with influx of histiocytes and occasional multi-nucleated giant cells with sham implants and was minimal around the curcumin implants. These polymeric implants were found to have little or no systemic toxicity with an acute reaction at local site which was reduced significantly by curcumin implants.

16.
Am J Physiol Renal Physiol ; 298(1): F49-61, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19726550

RESUMEN

Hyperglycemia induces p38 MAPK-mediated renal proximal tubular cell (RPTC) apoptosis. The current study hypothesized that alteration of the Akt signaling pathway by hyperglycemia may contribute to p38 MAPK activation and development of diabetic nephropathy. Immunoblot analysis demonstrated a hyperglycemia-induced increase in Akt phosphorylation in diabetic kidneys at 1 mo, peaking at 3 mo, and dropping back to baseline by 6 mo. Immunohistochemical staining with anti-pAkt antisera localized Akt phosphorylation to renal tubules. Maximal p38 MAPK phosphorylation was detected concomitant with increase in terminal uridine deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and caspase-3 activity in 6-mo diabetic kidneys. Exposure of cultured RPTCs to high glucose (HG; 22.5 mM) significantly increased Akt phosphorylation at 3, 6, and 9 h, and decreased thereafter. In contrast, p38 MAPK phosphorylation was detected between 9 and 48 h of HG treatment. Increased p38 MAPK activation at 24 and 48 h coincided with increased apoptosis, demonstrated by increased caspase-3 activity at 24 h and increased TUNEL-positive cells at 48 h of HG exposure. Blockade of p38 cascade with SB203850 inhibited HG-induced caspase-3 activation and TUNEL-positive cells. Overexpression of constitutively active Akt abrogated HG-induced p38 MAPK phosphorylation and RPTC apoptosis. In addition, blockade of the phosphatidylinositol-3 kinase/Akt pathway with LY294002 and silencing of Akt expression with Akt small interfering RNA induced p38 MAPK phosphorylation in the absence of HG. These results collectively suggest that downregulation of Akt activation during long-term hyperglycemia contributes to enhanced p38 MAPK activation and RPTC apoptosis. Mechanism of downregulation of Akt activation in 6-mo streptozotocin diabetic kidneys was attributed to decreased Akt-heat shock protein (Hsp) 25, Akt-p38 interaction, and decreased PTEN activity. Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK-mediated diabetic complications.


Asunto(s)
Apoptosis/fisiología , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Túbulos Renales/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Caspasa 3/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Modelos Animales de Enfermedad , Humanos , Hiperglucemia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Túbulos Renales/patología , Masculino , Ratones , Ratones Endogámicos , Fosfohidrolasa PTEN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Estreptozocina
17.
J Biol Chem ; 282(30): 21598-608, 2007 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-17510053

RESUMEN

We have shown previously that Akt exists in a signal complex with p38 MAPK, MAPK-activated protein kinase-2 (MK2), and heat shock protein 27 (Hsp27) and MK2 phosphorylates Akt on Ser-473. Additionally, dissociation of Hsp27 from Akt, prior to Akt activation, induced polymorphonuclear leukocyte (PMN) apoptosis. However, the role of Hsp27 in regulating Akt activation was not examined. This study tested the hypothesis that Hsp27 regulates Akt activation and promotes cell survival by scaffolding MK2 to the Akt signal complex. Here we show that loss of Akt/Hsp27 interaction by anti-Hsp27 antibody treatment resulted in loss of Akt/MK2 interaction, loss of Akt-Ser-473 phosphorylation, and induced PMN apoptosis. Transfection of myristoylated Akt (AktCA) in HK-11 cells induced Akt-Ser-473 phosphorylation, activation, and Hsp27-Ser-82 phosphorylation. Cotransfection of AktCA with Hsp27 short interfering RNA, but not scrambled short interfering RNA, silenced Hsp27 expression, without altering Akt expression in HK-11 cells. Silencing Hsp27 expression inhibited Akt/MK2 interaction, inhibited Akt phosphorylation and Akt activation, and induced HK-11 cell death. Deletion mutagenesis studies identified acidic linker region (amino acids 117-128) on Akt as an Hsp27 binding region. Deletion of amino acids 117-128 on Akt resulted in loss of its interaction with Hsp27 and MK2 but not with Hsp90 as demonstrated by immunoprecipitation and glutathione S-transferase pulldown studies. Co-transfection studies demonstrated that constitutively active MK2 (MK2EE) phosphorylated Aktwt (wild type) on Ser-473 but failed to phosphorylate Akt(Delta117-128) mutant in transfixed cells. These studies collectively define a novel role of Hsp27 in regulating Akt activation and cellular apoptosis by mediating interaction between Akt and its upstream activator MK2.


Asunto(s)
Proteínas de Choque Térmico/fisiología , Proteínas de Neoplasias/fisiología , Neutrófilos/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Animales , Apoptosis , Línea Celular , Cromatografía en Gel , Glutatión Transferasa/metabolismo , Proteínas de Choque Térmico HSP27 , Proteínas de Choque Térmico/sangre , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Chaperonas Moleculares , Mutagénesis Sitio-Dirigida , Proteínas de Neoplasias/sangre , Neutrófilos/citología , Proteínas Serina-Treonina Quinasas/sangre , Proteínas Proto-Oncogénicas c-akt/sangre , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Recombinantes/metabolismo , Valores de Referencia , Transducción de Señal , Transfección
18.
J Biol Chem ; 280(36): 31870-81, 2005 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-16027165

RESUMEN

Hypoxia is a common environmental stress that influences signaling pathways and cell function. Previous studies from our laboratory have identified significant differences in cellular responses to sustained or intermittent hypoxia with the latter proving more cytotoxic. We hypothesized that differences in susceptibility of neurons to intermittent (IH) and sustained hypoxia (SH) are mediated by altered Akt signaling. SH, but not IH, induced a significant increase in Akt activation in rat CA1 hippocampal region extracts compared with room air controls. Akt immunoprecipitations followed by proteomic analysis identified valosin-containing protein (VCP) as an Akt-binding protein. In addition, VCP expression and association with Akt was enhanced during SH, and this association was decreased upon phosphoinositide 3-kinase/Akt pathway blockade with LY294002. Active recombinant Akt phosphorylated recombinant VCP in vitro. Site-directed mutagenesis studies identified Ser352, Ser746, and Ser748 as Akt phosphorylation sites on VCP. In addition, rat CA1 hippocampal tissue exposed to SH exhibited an acidic pI shift of VCP. Protein phosphatase 2A treatment inhibited this acidic shift consistent with SH-induced phosphorylation of VCP in vivo. PC-12 cells transfected with active Akt, but not dominant negative Akt or vector, induced VCP expression and an acidic shift in VCP pI, which was inhibited by protein phosphatase 2A treatment. Furthermore, VCP association with ubiquitinated proteins was demonstrated in vector-transfected PC-12 cell lysates, whereas active Akt-transfected cells demonstrated a marked decrease in association of VCP with ubiquitinated proteins. We concluded that Akt phosphorylates VCP in vitro and in vivo, and VCP phosphorylation releases it from ubiquitinated substrate protein(s) possibly allowing ubiquitinated protein(s) to be degraded by the proteosome.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Ubiquitina/metabolismo , Adenosina Trifosfatasas , Animales , Encéfalo/metabolismo , Proteínas de Ciclo Celular/química , Hipoxia/metabolismo , Punto Isoeléctrico , Masculino , Células PC12 , Fosfatidilinositol 3-Quinasas/fisiología , Complejo de la Endopetidasa Proteasomal/fisiología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Sprague-Dawley , Serina/metabolismo , Treonina/metabolismo , Proteína que Contiene Valosina
19.
Cancer Lett ; 192(2): 151-60, 2003 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-12668279

RESUMEN

Palm oil is a rich source of vitamin E, carotenoids, tocotrienols and tocopherols which are natural antioxidants and act as scavengers of oxygen free radicals. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) is a known oxidant that promotes tumorigenesis in mouse skin through the elaboration of oxidative stress. In this study we therefore assessed the anti-tumor promoting potential of palm oil against TPA-mediated skin tumorigenesis in 7,12-dimethylbenz[a]anthracene-initiated Swiss albino mice. Topical application of palm oil 1 h prior to application of TPA resulted in a significant protection against skin tumor promotion. The animals pre-treated with palm oil showed a decrease in both tumor incidence and tumor yield as compared to the TPA (alone)-treated group. Palm oil application also reduced the development of malignant tumors. Since TPA-induced epidermal ornithine decarboxylase (ODC) activity and [(3)H]thymidine incorporation are conventionally used markers of skin tumor promotion, we also assessed the effect of pre-application of palm oil on these parameters, and it was observed that the application of palm oil prior to the application of TPA alleviated both these TPA-induced markers of tumor promotion. The effect of pre-application of palm oil on TPA-mediated depletion in the non-enzymatic and enzymatic molecules was also assessed and it was observed that palm oil application prior to TPA application resulted in the recovery of TPA-mediated depletion in the levels of these molecules viz. glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and catalase. Similarly, palm oil also exhibited a protective effect against Fe(2+)-ascorbate-induced lipid peroxidation in the epidermal microsomes. The results of the present study thus suggest that palm oil possesses anti-skin tumor promoting effects, and that the mechanism of such effects may involve the inhibition of tumor promoter-induced epidermal ODC activity, [(3)H]thymidine incorporation and cutaneous oxidative stress.


Asunto(s)
Aceites de Plantas/farmacología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Acetato de Tetradecanoilforbol/farmacología , Administración Tópica , Animales , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ratones , Aceite de Palma , Aceites de Plantas/administración & dosificación , Aceites de Plantas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Factores de Tiempo
20.
Arch Biochem Biophys ; 409(2): 262-73, 2003 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-12504893

RESUMEN

Iron overload has been shown to enhance chemically mediated cutaneous tumor promotion in animals. However, the majority of these animal studies have used high concentrations of iron before initiating tumor development. The current study was designed to evaluate the effect of small doses of iron on the promotion stage of chemically mediated cutaneous carcinogenesis. We found an increased tumor response in mice initiated with dimethylbenz(a)anthracene (DMBA) when iron at the dose levels of 0.5, 1.0, and 1.5mg/mouse was injected (intramuscularly) once a week into mice at the promotion stage of skin carcinogenesis, employing 12-O-tetradecanoyl phorbol-13-acetate (TPA)/benzoyl peroxide (BPO) as tumor promoter. The appearance of first papilloma and the number of tumors/mouse were recorded weekly. When compared to the control (non-iron-treated) group, the iron-treated groups showed an augmented incidence of tumors and number of tumors/mouse. In iron-treated mice, tumors appeared earlier than in the control group. TPA/BPO treatment resulted in a significant decrease in the activities of antioxidant enzymes and depletion in the level of epidermal reduced glutathione (GSH). TPA treatment in non-iron-treated mice resulted in approximately 20-40% decrease in GSH level and in the activities of antioxidant enzymes, whereas 1.5-mg iron treatment along with TPA treatment resulted in about approximately 30-70% decrease in GSH level and in the activities of antioxidant enzymes. Similarly, treatment of iron along with BPO treatment resulted in a dose-dependent higher depletion of GSH and the antioxidant enzymes as compared to non-iron-treated animals treated with BPO. Further, TPA/BPO-mediated induction in ornithine decarboxylase activity and [3H]thymidine incorporation in cutaneous DNA was approx two- to threefold higher in mice treated with iron as compared to non-iron-treated mice. Cutaneous lipid peroxidation and iron levels were also higher in mice treated with iron as compared to non-iron-treated mice. These data suggest that progressive iron overload can enhance the tumor promotion ability of TPA/BPO in DMBA-initiated murine skin.


Asunto(s)
Glutatión/metabolismo , Sobrecarga de Hierro/metabolismo , Neoplasias Cutáneas/inducido químicamente , 9,10-Dimetil-1,2-benzantraceno , Animales , Antioxidantes/farmacología , Peróxido de Benzoílo , Carcinógenos , Catalasa/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inducción Enzimática/efectos de los fármacos , Represión Enzimática/efectos de los fármacos , Hierro/administración & dosificación , Hierro/farmacología , Peroxidación de Lípido/efectos de los fármacos , Ratones , Ornitina Descarboxilasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Papiloma/inducido químicamente , Papiloma/metabolismo , Papiloma/patología , Especies Reactivas de Oxígeno/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Acetato de Tetradecanoilforbol , Factores de Tiempo
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