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1.
Toxicol Mech Methods ; 30(4): 306-315, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32028820

RESUMEN

Angiogenesis, disturbance in redox homeostasis, and deregulated redox signaling are considered as common hallmarks of cancer progression and chemo resistance. In this context, PERK (protein kinase PKR-like ER kinase) branch of the unfolded protein response (UPR), an adaptive mechanism triggered by endoplasmic reticulum (ER) stress to cope with protein misfolding and perturbed proteostasis, has shown to regulate angiogenesis and oxidative stress. This study aimed to investigate the impact of morin, a poly phenolic compound from the family of Moraceae on PERK-Nrf2-VEGF axis in experimental rats challenged with the colon specific procarcinogen 1,2-dimethylhydrazine (DMH). Male albino Wistar rats were randomized into four groups (n = 6) viz., control, morin control, DMH control, and DMH administered rats treated with morin. Immunohistochemical analysis of colonic cross-section revealed that DMH alone administered rats showed significantly increased expression of Nrf2 predominantly in the cytoplasm. Angiogenic growth factors viz., VEGF, PDGF, and bFGF are also shown to be increased in the DMH alone administered tumor bearing rats as compared to control. Significant downregulation was also observed in the downstream targets of Nrf2 such as hemeoxygenase 1 (HO1), glutathione peroxidase 2 (GPX2), thioredoxin (TRXN), glutathione S transferase (GST), and uridine glucuronyl transferase (UGT) as evidenced by the qPCR analysis. Immunoblot analysis revealed that onset of oxidative stress and angiogenesis in the colon of DMH alone administered rats were due to downregulation of pPERK along with its downstream targets such as peIF2α and CHOP. Supplementation of morin reversed the DMH-induced alterations and suppresses oxidative stress and angiogenesis via PERK phosphorylation.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Colon/efectos de los fármacos , Flavonoides/farmacología , Neovascularización Patológica/prevención & control , Estrés Oxidativo/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , eIF-2 Quinasa/metabolismo , 1,2-Dimetilhidrazina/toxicidad , Inhibidores de la Angiogénesis/aislamiento & purificación , Animales , Antioxidantes/metabolismo , Colon/irrigación sanguínea , Colon/metabolismo , Modelos Animales de Enfermedad , Flavonoides/aislamiento & purificación , Expresión Génica/efectos de los fármacos , Masculino , Moraceae/química , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Distribución Aleatoria , Ratas , Ratas Wistar , Transducción de Señal
2.
Pharm Biol ; 53(11): 1591-601, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25857436

RESUMEN

CONTEXT: Ferulic acid (FA) is a potent ubiquitous plant antioxidant found in cereals such as brown rice, whole wheat, and oats. Phytochemical-based antioxidants are shown to be effective in neurodegenerative diseases. This study hypothesizes that supplementation of FA might combat oxidative stress-induced Parkinson's disease (PD). OBJECTIVE: To explore the effect of FA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced neurotoxicity. MATERIALS AND METHODS: Mice were randomized into five groups: Group I mice served as control. Group II mice received 5 × MPTP [25 mg/kg body weight (i.p.)] in saline 24 h apart starting from the 3rd day and continued till the last day of the experimental period of 7 d. In addition to MPTP injections, mice in Groups III, IV, and V were given FA at a dose of 20, 40, and 80 mg, respectively, for 7 d. Mice were subjected to a battery of behavioral tests along with histological investigations. RESULTS: Our histological findings revealed that MPTP administration enhanced Bax/Bcl2 ratio and microglial cells activation reflecting induction of apoptosis and inflammation, respectively. This dopaminergic neuronal loss caused impairment in motor balance and coordination in MPTP mice as assessed by various behavioral tests. FA at a dose of 40 mg/kg/d body weight effectively attenuated MPTP-induced neurotoxicity. DISCUSSION: Antioxidant, free-radical quenching, and anti-inflammatory activities of FA could contribute to its neuroprotective effect. CONCLUSION: This study provides elementary evidence for the neuroprotective action of FA against MPTP-induced PD in mice and warrants further studies.


Asunto(s)
Ácidos Cumáricos/administración & dosificación , Intoxicación por MPTP/inducido químicamente , Intoxicación por MPTP/prevención & control , Trastornos de la Destreza Motora/inducido químicamente , Trastornos de la Destreza Motora/prevención & control , Fármacos Neuroprotectores/administración & dosificación , Animales , Muerte Celular/efectos de los fármacos , Intoxicación por MPTP/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos de la Destreza Motora/patología
3.
J Nanobiotechnology ; 11: 39, 2013 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-24298944

RESUMEN

BACKGROUND: The biosynthesis of metal nanoparticles by marine resources is thought to be clean, nontoxic, and environmentally acceptable "green procedures". Marine ecosystems are very important for the overall health of both marine and terrestrial environments. The use of natural sources like Marine biological resources essential for nanotechnology. Seaweeds constitute one of the commercially important marine living renewable resources. Seaweeds such as green Caulerpa peltata, red Hypnea Valencia and brown Sargassum myriocystum were used for synthesis of Zinc oxide nanoparticles. RESULT: The preliminary screening of physico-chemical parameters such as concentration of metals, concentration of seaweed extract, temperature, pH and reaction time revealed that one seaweed S. myriocystum were able to synthesize zinc oxide nanoparticles. It was confirmed through the, initial colour change of the reaction mixture and UV visible spectrophotometer. The extracellular biosynthesized clear zinc oxide nanoparticles size 36 nm through characterization technique such as DLS, AFM, SEM -EDX, TEM, XRD and FTIR. The biosynthesized ZnO nanoparticles are effective antibacterial agents against Gram-positive than the Gram-negative bacteria. CONCLUSION: Based on the FTIR results, fucoidan water soluble pigments present in S. myriocystum leaf extract is responsible for reduction and stabilization of zinc oxide nanoparticles. by this approach are quite stable and no visible changes were observed even after 6 months. These soluble elements could have acted as both reduction and stabilizing agents preventing the aggregation of nanoparticles in solution, extracellular biological synthesis of zinc oxide nanoparticles of size 36 nm.


Asunto(s)
Antibacterianos/biosíntesis , Antifúngicos/metabolismo , Nanopartículas/química , Algas Marinas/metabolismo , Óxido de Zinc/química , Antibacterianos/farmacología , Antifúngicos/farmacología , Aspergillus niger/efectos de los fármacos , Aspergillus niger/crecimiento & desarrollo , Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Caulerpa/química , Caulerpa/metabolismo , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/crecimiento & desarrollo , Tecnología Química Verde , Concentración de Iones de Hidrógeno , Microscopía de Fuerza Atómica , Microscopía Electrónica de Rastreo , Oxidación-Reducción , Polisacáridos/química , Polisacáridos/metabolismo , Rhodophyta/química , Rhodophyta/metabolismo , Sargassum/química , Sargassum/metabolismo , Algas Marinas/química
4.
J Glaucoma ; 32(10): 860-868, 2023 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-37523650

RESUMEN

PRCIS: This study describes the impact of monocular (M/O) and binocular (B/O) visual function decline, primarily the contrast sensitivity (CS) and visual field (VF) defect severity and its location, on the subjective perception of quality of life (QoL) among the Indian glaucoma population with spared central acuity. AIM: To investigate the influence of M/O and B/O visual function parameters on vision-related QoL (VRQoL) in glaucoma with spared central visual acuity. MATERIALS AND METHODS: Glaucoma subjects underwent M/O and B/O visual acuity, CS assessment, followed by the M/O perimetry from which the integrated VF was estimated (B/O summation method). VRQoL was evaluated using the Glaucoma Quality Of Life-15 (GQL-15) and Visual Function Questionnaire-Utility Index (VFQ-UI) questionnaires. The relationship between CS and VF defect (VFD) with the composite VRQoL scores was analyzed. RESULTS: A total of 154 glaucoma subjects with a median age of 61 (range: 24-83) years were enrolled. Subjects with severe VFD reported poor composite scores for GQL-15 and VFQ-UI when compared with unilateral and mild groups ( P < 0.001, Dunn post hoc). Both the composite scores were negatively correlated with M/O and B/O CS and VF mean deviation ( r range: -0.3 to -0.5, P < 0.001, Spearman rank correlation). B/O VFD in the inferior central zone contributed to poor GQL-15 score [odds ratio: 1.14 (95% CI: 1.10-1.29), P = 0.04] irrespective of sex, whereas females with increasing B/O VFD reported poor QoL score in VFQ-UI [odds ratio: 4.09 (95% CI: 1.77-9.43), p=0.003]. CONCLUSIONS: Poor GQL-15 and VFQ-UI scores were reported with increasing disease severity. B/O VFD in the inferior central region was found to contribute predominantly to the poor GQL-15 scores while both disease severity and sex influenced VFQ-UI scores.

5.
Biochimie ; 175: 69-76, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32422159

RESUMEN

Glucose regulated protein 78 (GRP 78), a master regulator of endoplasmic reticulum stress has been reported to be up regulated in various cancers and remains a crucial link between tumor glycolysis and tumor microenvironment. Overexpressed GRP78 has also shown to induce immune suppressive molecules and thereby tumor immune evasion. On the other hand emerging reports indicates that the next generation hallmarks viz., metabolic reprogramming and immune evasion, the two distinct processes are suggested to be fundamentally linked which is yet to be explored. Our concern is, if GRP78 is considered as a connecting link between these two different processes then targeting this triangle would be a promising approach in anticancer drug discovery. Lack of sufficient literature on this aspect represents GRP78 as an under explored target in anti-cancer research. The objective of this review is to provide a concise and integrated information on GRP78 and its association with tumor glycolysis and immune evasion which will revive and draw attention of the researchers to consider GRP78 as a potential drug target for cancer intervention and it also highlights few potential natural products investigated so far as GRP78 inhibitors.


Asunto(s)
Sistemas de Liberación de Medicamentos , Proteínas de Choque Térmico , Proteínas de Neoplasias , Neoplasias , Escape del Tumor/inmunología , Microambiente Tumoral/inmunología , Quimioprevención , Chaperón BiP del Retículo Endoplásmico , Glucólisis/efectos de los fármacos , Glucólisis/inmunología , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/inmunología , Humanos , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/prevención & control , Escape del Tumor/efectos de los fármacos
6.
Eur J Cancer Prev ; 28(6): 472-482, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30407216

RESUMEN

Suppression of colorectal cancer by means of chemoprevention is gaining great attention owing to promising outcomes with less adverse effects in preclinical and clinical trials. The present study aims to explore the mechanism of chemoprevention by p-coumaric acid (p-CA) in a short-term preclinical model of colon cancer. 1,2-dimethylhydrazine-administered rats supplemented with p-CA showed downregulation of the expression of colonic proteins, namely, cyclin B1, cdc2 and mdm2, which regulate cell cycle, and immediate early response genes, namely, c-fos, c-jun and c-myc, which regulate cell proliferation. Apoptosis induction was also observed in the colon of p-CA-supplemented rats as assessed by the Bax/Bcl-2 ratio. Immunohistochemistry, immunoblotting and real-time polymerase chain reaction analysis revealed that supplementation of p-CA improved the in-vivo detoxification potential by modulating the cytoplasmic-to-nuclear ratio of nuclear factor erythroid 2-related factor 2, favouring the induction of genes responsible for cytoprotection and detoxification. The outcome of these findings suggests that p-CA inhibited polyp formation by improving the process of detoxification and apoptosis in the colon of 1,2-dimethylhydrazine-administered rats.


Asunto(s)
Antioxidantes/farmacología , Neoplasias del Colon/prevención & control , Suplementos Dietéticos , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Propionatos/farmacología , 1,2-Dimetilhidrazina/toxicidad , Animales , Apoptosis , Carcinógenos/toxicidad , Proliferación Celular , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ácidos Cumáricos , Masculino , Factor 2 Relacionado con NF-E2/genética , Ratas , Ratas Wistar
7.
Chem Biol Interact ; 291: 16-28, 2018 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-29879413

RESUMEN

p-CA is a naturally occurring phenolic acid present in most plants and in all commonly consumed vegetables and fruits. Here we demonstrated the anti-cancer effect of the food borne phytochemical p-CA both in vitro and in vivo models of colon cancer using growth rate and tumor incidence as endpoints. Glucose regulated protein (GRP78) induction and UPR activation plays a key role in oncogenic progression, therefore increased dependence of cancer cells on these UPR signaling pathways for survival can be exploited for anti-cancer research. Hence we investigated the effect of p-CA on Grp78 a molecular chaperone often upregulated in colon cancer and its impact on unfolded protein response (UPR). Administration of the procarcinogen 1,2- dimethylhydrazine (DMH) causes Grp78 upregulation and tumor adaptation via UPR activation. The adaptive activity of UPR activates antiapoptotic NF-κB that results in upregulation of the markers of inflammation and angiogenesis. Supplementation of p-CA downregulated Grp78 and activated UPR mediated apoptosis both in in vitro and in vivo models of colon cancer. Further we observed that p-CA significantly reduced inflammation by decreasing the expression of cytokines COX-2, IL-6, TNF-α and PGE2 as analyzed by q-PCR and also reduced the expression of p-p65 and p-IκBα as analyzed by western blot. Further mechanistic insights revealed that p-CA inhibits Grp78 upregulation in cancer cells through activation of PERK-eIF2α-ATF-4-CHOP pathway that culminates in apoptosis inducing effect of p-CA.


Asunto(s)
Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Regulación hacia Abajo/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Propionatos/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Neoplasias del Colon/irrigación sanguínea , Neoplasias del Colon/tratamiento farmacológico , Ácidos Cumáricos , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Nitrato de Plata/metabolismo , Carga Tumoral/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo
8.
Biomed Pharmacother ; 100: 367-373, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29453046

RESUMEN

Colorectal cancer is the third most common cancer worldwide. The development of effective, inexpensive and safe chemopreventive agents would be of great benefit as it involves use of natural products to prevent or suppress the progression of precursor lesions. Morin a flavonoid found in figs (Ficus carica) and other plants is shown to inhibit 1,2-dimethylhydrazine (DMH) induced colon cancer progression in a short term and long term model of colon cancer rats; however, the molecular target for the colon cancer chemoprotective efficacy of morin is yet to be discovered. The present study aims to explore the molecular basis of how morin contributes to the chemoprevention with a focus on NF-κB signaling pathway. The effect of morin on NF-κB signaling in DMH-induced carcinogenic events such as inflammation and apoptosis were analyzed by studying the histopathological analysis using Hematoxylin and Eosin staining (H &E), mRNA expression using q-PCR, protein expression using Immunohistochemistry (IHC) and western blot. Morin supplementation to DMH administered rats down regulated NF-κB pathway and its downstream inflammatory mediators like tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase 2 (COX-2) and prostaglandin (PGE-2). Morin supplementation to DMH administered rats alters BAX/BCL2 ratio favoring apoptosis in carcinogen treated rats. Our findings explored that molecular chemoprevention of morin targets NF-κB and acts as a potent anti-inflammatory and pro-apoptotic agent for colon cancer prevention.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias del Colon/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Flavonoides/administración & dosificación , FN-kappa B/metabolismo , Animales , Quimioprevención/métodos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Masculino , FN-kappa B/antagonistas & inhibidores , Distribución Aleatoria , Ratas , Ratas Wistar
9.
Eur J Pharmacol ; 795: 169-178, 2017 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-27940056

RESUMEN

Multistep model of colon carcinogenesis has provided the framework to advance our understanding of the molecular basis of colon cancer. This multistage process of carcinogenesis takes a long period to transform from a normal epithelial cell to invasive carcinoma. Thus, it provides enough time to intervene the process of carcinogenesis especially through dietary modification. In spite of the in-depth understanding of the colon cancer etiology and pathophysiology and its association with diet, colon cancer remains a major cause of cancer mortality worldwide. Phytochemicals and their derivatives are gaining attention in cancer prevention and treatment strategies because of cancer chemotherapy associated adverse effects. Being the largest group of phytochemicals traditionally used for medicinal purpose in India and China, terpenoids are recently being explored as anticancer agents. Anticancer properties of terpenoids are associated with various mechanisms like counteraction of oxidative stress, potentiating endogenous antioxidants, improving detoxification potential, disrupting cell survival pathways and inducing apoptosis. This review gives a comprehensive idea of naturally occurring terpenoids as useful agents for the prevention of colon cancer with reference to their classes, sources and molecular targets. Based on the explored molecular targets further research in colon cancer chemoprevention is warranted.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Terpenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias del Colon/patología , Humanos , Terpenos/química , Terpenos/uso terapéutico
10.
Biomed Pharmacother ; 94: 577-588, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28780474

RESUMEN

Oxidative stress and gut microbial enzymes are intricately linked to the onset of colon carcinogenesis. Phytochemicals that modulate these two factors hold promise for the development of such agents as anticancer drugs. The present study evaluates the chemopreventive potential of p-coumaric acid (p-CA) - a phenolic acid in rats challenged with the colon specific procarcinogen DMH (1,2 di-methyl hydrazine). Rats were randomized into six groups (n=7/group). Group 1 (control); Group 2 (p-CA 200mg/kg b.w.); Group 3 (DMH 40mg/kg b.w.); Groups 4 (DMH+p-CA 50mg/kg b.w.) and Group 5 (DMH+p-CA 100mg/kg b.w.) and Group 6 (DMH+p-CA 200mg/kg b.w.). After the experimental duration of 15 weeks' rats were subjected to necropsy and tissues were collected for the histological and biochemical investigations. DMH induced colonic preneoplastic lesions viz., aberrant crypt foci (ACF), dysplastic ACF (DACF), mucin depleted foci (MDF) and beta catenin accumulated crypts (BCAC) were significantly suppressed by p-CA supplementation. Glucuronide conjugation of DMH in liver and its subsequent deconjugation mediated by microbes in the colon induced the formation of colonic preneoplastic lesions. p-CA inhibited these lesions and protected the rat colon against genotoxic insult by scavenging the free radicals via its strong antioxidant response and detoxification mechanism as measured by TBARS and enzymic antioxidants in control and experimental rats. Of the three tested doses, p-CA at a dose of 100mg/kg body weight is found to exhibit a significant optimum effect compared to the other two doses 50mg/kg body weight and 200mg/kg body weight.


Asunto(s)
Anticarcinógenos/farmacología , Colon/patología , Neoplasias del Colon/prevención & control , Propionatos/farmacología , 1,2-Dimetilhidrazina/toxicidad , Focos de Criptas Aberrantes/patología , Animales , Carcinogénesis/efectos de los fármacos , Carcinógenos/toxicidad , Ácidos Cumáricos , Modelos Animales de Enfermedad , Masculino , Estrés Oxidativo/efectos de los fármacos , Lesiones Precancerosas/prevención & control , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
11.
Eur J Pharmacol ; 796: 20-31, 2017 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-27989504

RESUMEN

Targeting tumor metabolism by natural products is a novel approach and provides rationale for anti-cancer drug discovery. The present study aims to explore the impact of morin and/or esculetin on c-myc induced energy metabolism in 1,2-dimethylhydrazine (DMH) induced colon cancer in rats. In order to achieve this aim we analyzed the expression of glucose and glutamine transporters and the key enzymes of glycolytic pathway besides the markers of neoplastic changes viz., mucin depleted foci (MDF), beta catenin accumulated crypts (BCAC), and markers of cell proliferation viz., proliferating cell nuclear antigen (PCNA), argyrophilic nucleolar antigen (AgNOR), c-myc, c-jun and c-fos. All the parameters tested in the present study are highly influenced by the phytochemicals morin and/or esculetin in a way to prevent colon carcinogenesis. Morin and/or esculetin supplementation effectively targets tumor metabolism via ß-cateinin/c-myc signaling and affects glycolysis and glutaminolysis to abrogate colon cancer in rats. The anti-cancer effect of morin is more pronounced than esculetin. The effect obtained through the combined treatment of morin and esculetin is comparable to that of individual supplementation of morin and there is no synergistic effect. Overall individual supplementation of morin scores well as a potential anticancer agent targeting glycolysis and glutaminolysis in colon cancer.


Asunto(s)
1,2-Dimetilhidrazina/toxicidad , Carcinogénesis/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Metabolismo Energético/efectos de los fármacos , Flavonoides/farmacología , Umbeliferonas/farmacología , Animales , Anticarcinógenos/farmacología , Peso Corporal/efectos de los fármacos , Carcinogénesis/inducido químicamente , Proliferación Celular/efectos de los fármacos , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/prevención & control , Glucólisis/efectos de los fármacos , Masculino , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Tasa de Supervivencia , Carga Tumoral/efectos de los fármacos , beta Catenina/metabolismo
12.
Life Sci ; 145: 74-84, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26679106

RESUMEN

Recent studies have shown that tumor development and progression depend not only on the perturbed genes that govern cell proliferation, but is also highly determined by the non-tumor cells of the stromal compartment surrounding the tumor called tumor microenvironment (TME). These findings highlight the importance of targeting the microenvironment in combination with therapies aimed at tumor cells as a valuable approach. The innate and adaptive immune cells in the TME interact among themselves and also with the endothelial cells, pericytes and mast cells of the stromal compartment through various autocrine and paracrine manner to regulate abnormal cell proliferation. Direct cytotoxic killing of cancer cells and/or reversion of the immunosuppressive TME are to be considered as better strategies for chemoprevention and chemotherapy. With a growing emphasis on a "hallmark targeting" strategy for cancer therapy, the TME now appears as a promising target for cancer prevention using natural products. Clarification on the nontumor stromal cells, the mediators involved, interactions with immune response cells, and immune-evasive mechanisms are needed in order to manipulate the characteristics of the TME by natural pharmacological agents to design effective therapies. This review will provide a glimpse on the roles played by various non-tumor cells in tumor progression and their intervention by pharmacological agents.


Asunto(s)
Anticarcinógenos/farmacología , Inmunidad Celular/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/prevención & control , Microambiente Tumoral/efectos de los fármacos , Animales , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/inmunología , Fibroblastos/patología , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/patología , Macrófagos/inmunología , Macrófagos/patología , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/patología , Neoplasias/patología , Pericitos/efectos de los fármacos , Pericitos/inmunología , Pericitos/patología
13.
Oncotarget ; 6(38): 41146-61, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26510913

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.


Asunto(s)
Caquexia/prevención & control , Metaboloma/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Silimarina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antioxidantes/farmacología , Caquexia/etiología , Caquexia/metabolismo , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Glucólisis/efectos de los fármacos , Humanos , Immunoblotting , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones Desnudos , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Silibina , Carga Tumoral/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
14.
N Am J Med Sci ; 6(3): 119-25, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24741550

RESUMEN

BACKGROUND: In future, increase in the number of healthcare professionals is dependent on the career interest among present undergraduate medical students. Based on their interest to pursue their specialty, the availability of medical doctors in each specialty could be done. AIMS: This study was to find out future career interest and factors that influence undergraduate medical students to choose their future specialization. MATERIALS AND METHODS: The study was carried out among first-year medical students from five countries. The students were asked to complete an 8-item questionnaire. Two thousand one hundred fifty three participants were enrolled in the study. Data were analyzed in Microsoft-Excel and Statistical Package for the Social Sciences. RESULTS: Of the 2153 participants, only 1470 responded. Among the 1470 participants, 169 participants were excluded due to the ambiguity in responses, finally making it to 1301participants. Among them, Anatomy (49.3%) followed by Biochemistry (26.7%) and Physiology (24%) were the most preferred subjects. CONCLUSIONS: Anatomy was the most preferred basic science subject among the other subjects and the students were interested to pursuing surgery in future. Furthermore, the most preferred future specialties were surgery, internal medicine and pediatrics with gender variations; males preferring surgery and females in obstetrics and gynecology.

15.
Bioinformation ; 8(22): 1096-104, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23251044

RESUMEN

Synonymous codon usage of 53 protein coding genes in chloroplast genome of Coffea arabica was analyzed for the first time to find out the possible factors contributing codon bias. All preferred synonymous codons were found to use A/T ending codons as chloroplast genomes are rich in AT. No difference in preference for preferred codons was observed in any of the two strands, viz., leading and lagging strands. Complex correlations between total base compositions (A, T, G, C, GC) and silent base contents (A(3), T(3), G(3), C(3), GC(3)) revealed that compositional constraints played crucial role in shaping the codon usage pattern of C. arabica chloroplast genome. ENC Vs GC(3) plot grouped majority of the analyzed genes on or just below the left side of the expected GC(3) curve indicating the influence of base compositional constraints in regulating codon usage. But some of the genes lie distantly below the continuous curve confirmed the influence of some other factors on the codon usage across those genes. Influence of compositional constraints was further confirmed by correspondence analysis as axis 1 and 3 had significant correlations with silent base contents. Correlation of ENC with axis 1, 4 and CAI with 1, 2 prognosticated the minor influence of selection in nature but exact separation of highly and lowly expressed genes could not be seen. From the present study, we concluded that mutational pressure combined with weak selection influenced the pattern of synonymous codon usage across the genes in the chloroplast genomes of C. arabica.

16.
PLoS One ; 7(6): e37711, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22701577

RESUMEN

OBJECTIVES: To estimate the cost and patterns of expenditure of dry eye treatment. METHODOLOGY: We retrieved data on the type and cost of dry eye treatment in Singapore National Eye Centre from pharmacy and clinic inventory databases over a 2 year period (2008-2009) retrospectively. According to the type of treatment, data were sorted into 7 groups; meibomien gland disease (MGD) treatment, preservative free lubricant eye drops, preserved lubricant eye drops, lubricant ointments and gels, cyclosporine eye drops, oral supplements and non-pharmacological treatments/procedures. Each recorded entry was considered as one patient episode (PE). Comparisons in each group between two years were carried out using Pearson Chi-Square test. Significance level was set at alpha  =  0.05. RESULTS: Cost data from 54,052 patients were available for analysis. Total number of recorded PEs was 132,758. Total annual expenditure on dry eye treatment for year 2008 and 2009 were US$1,509,372.20 and US$1,520,797.80 respectively. Total expenditure per PE in year 2008 and 2009 were US$22.11 and US$23.59 respectively. From 2008 to 2009, there was a 0.8% increase in total annual expenditure and 6.69% increase in expenditure per PE. Pharmacological treatment attributes to 99.2% of the total expenditure with lubricants accounting for 79.3% of the total pharmacological treatment expenditure. Total number of units purchased in preservative free lubricants, cyclosporine eye drops and MGD therapy have increased significantly (p<0.001) whereas number of units purchased in preserved lubricants and ointments/gels have reduced significantly (p<0.001) from 2008 to 2009. CONCLUSION: Dry eye imposes a significant direct burden to health care expenditure even without considering indirect costs. Health care planners should be aware that these direct costs appear to increase over the time and more so for particular types of medications. Given the limitations of socio-economic data, true societal costs of Dry eye syndrome are likely to be much higher than estimated.


Asunto(s)
Síndromes de Ojo Seco/tratamiento farmacológico , Síndromes de Ojo Seco/economía , Costos de la Atención en Salud/estadística & datos numéricos , Oftalmología/economía , Síndromes de Ojo Seco/epidemiología , Síndromes de Ojo Seco/terapia , Humanos , Soluciones Oftálmicas/economía , Estudios Retrospectivos , Singapur/epidemiología
17.
Hypertens Res ; 32(11): 975-82, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19713968

RESUMEN

Blood pressure has a significant effect on retinal arterioles. There are few data on whether this effect varies by race/ethnicity. We examined the relationship of blood pressure and retinal vascular caliber in a multi-ethnic Asian population. The study is population-based and cross sectional in design. A total of 3749 Chinese, Malay and Indian participants aged > or =24 years residing in Singapore were included in the study. Retinal vascular caliber was measured using a computer program from digital retinal photographs. The associations of retinal vascular caliber with blood pressure and hypertension in each racial/ethnic group were analyzed. The main outcome measures are retinal arteriolar caliber and venular caliber. The results show that retinal arterioles were narrower in persons with uncontrolled/untreated hypertension (140.0 microm) as compared with persons with controlled hypertension (142.1 microm, P=0.0001) and those with no hypertension (146.0 microm, P<0.0001). On controlling for age, gender, body mass index, lipids and smoking, each 10 mm Hg increase in mean arterial blood pressure was associated with a 3.1 microm decrease in arteriolar caliber (P<0.0001), with a similar magnitude seen in all three racial/ethnic groups: 3.1 microm in Chinese, 2.8 microm in Malays and 3.2 microm in Indians (P<0.0001 for all). Each 10 mm Hg increase in mean arterial blood pressure was associated with a 1.8 microm increase in venular caliber (P<0.0001); furthermore, the magnitude of this effect was similar across the three racial/ethnic groups. The effect of blood pressure on the retinal vasculature was similar across three major racial/ethnic groups in Asia.


Asunto(s)
Presión Sanguínea/fisiología , Vasos Retinianos/fisiología , Adulto , Anciano , Pueblo Asiatico , China/etnología , Estudios de Cohortes , Estudios Transversales , Etnicidad , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , India/etnología , Modelos Logísticos , Malasia/etnología , Masculino , Persona de Mediana Edad , Vasos Retinianos/anatomía & histología , Singapur
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