RESUMEN
Chemotherapeutics continue to play a central role in the treatment of a wide variety of cancers. Conventional chemotherapy involving bolus intravenous doses results in severe side effects - in some cases life threatening - delayed toxicity and compromised quality-of-life. Attempts to deliver small drug molecules using liposomes, polymeric nanoparticles, micelles, lipid nanoparticles, etc. have produced limited nanoformulations for clinical use, presumably due to a lack of biocompatibility of the material, costs, toxicity, scalability, and/or lack of effective administration. Naturally occurring small extracellular vesicles, or exosomes, may offer a solution and a viable system for delivering cancer therapeutics. Combined with their inherent trafficking ability and versatility of cargo capacity, exosomes can be engineered to specifically target cancerous cells, thereby minimizing off-target effects, and increasing the efficacy of cancer therapeutics. Exosomal formulations have mitigated the toxic effects of several drugs in murine cancer models. In this article, we review studies related to exosomal delivery of both small molecules and biologics, including siRNA to inhibit specific gene expression, in the pursuit of effective cancer therapeutics. We focus primarily on bovine milk and colostrum exosomes as the cancer therapeutic delivery vehicles based on their high abundance, cost effectiveness, scalability, high drug loading, functionalization of exosomes for targeted delivery, and lack of toxicity. While bovine milk exosomes may provide a new platform for drug delivery, extensive comparison to other nanoformulations and evaluation of long-term toxicity will be required to fully realize its potential.
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Exosomas , Neoplasias , Femenino , Embarazo , Humanos , Animales , Ratones , Leche , Calostro/metabolismo , Exosomas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Sistemas de Liberación de MedicamentosRESUMEN
Complexes of curcumin with metals have shown much-improved stability, solubility, antioxidant capability, and efficacy when compared to curcumin. The present research investigates the relative bioavailability, antioxidant, and ability to inhibit inflammatory cytokine production of a curcuminoid metal chelation complex of tetrahydrocurcumin-zinc-curcuminoid termed TurmiZn. In vitro uptake assay using pig intestinal epithelial cells showed that TurmiZn has an ~3-fold increase (p ≤ 0.01) in uptake compared to curcumin and a ~2-fold increase (p ≤ 0.01) over tetrahydrocurcumin (THC). In a chicken model, an oral 1-g dose of TurmiZn showed a ~2.5-fold increase of a specific metabolite peak compared to curcumin (p = 0.004) and a ~3-fold increase compared to THC (p = 0.001). Oral doses (5 g/Kg) of TurmiZn in rats also showed the presence of curcumin and THC metabolites in plasma, indicating bioavailability across cell membranes in animals. Determination of the antioxidant activity by a 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging assay indicated that TurmiZn was about 13x better (p ≤ 0.0001) than curcumin and about 4X better (p ≤ 0.0001) than THC, in reducing free radicals. In vitro experiments further showed significant (p ≤ 0.01) reductions of lipopolysaccharide (LPS)-induced proinflammatory cytokines such as interleukin (IL) IL-6, IL-8, IL-15, IL-18, and tumor necrosis factor (TNF)-alpha, while showing a significant (p ≤ 0.01) increase of granulocyte-macrophage colony-stimulating factor (GM-CSF) in dog kidney cells. In vivo cytokine modulations were also observed when TurmiZn was fed for 6 weeks to newborn chickens. TurmiZn reduced IL-1 and IL-6, but significantly reduced (p ≤ 0.01) IL-10 levels while there was a concurrent significant (p = 0.02) increase in interferon gamma compared to controls. Overall, these results indicate that TurmiZn has better bioavailability and antioxidant capability than curcumin or THC and has the ability to significantly modulate cytokine levels. Thus, TurmiZn could be an excellent candidate for a novel ingredient that can be incorporated into food and supplements to help overall health during the aging process.
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Curcumina , Citocinas , Animales , Ratas , Porcinos , Perros , Antioxidantes/farmacología , Curcumina/farmacología , Interleucina-6 , Diarilheptanoides , Disponibilidad Biológica , Zinc , Pollos , Factor de Necrosis Tumoral alfaRESUMEN
Coronavirus disease 2019 (COVID-19) was first officially diagnosed in the city of Wuhan, China in January 2020. In reality, the disease was identified in December 2019 in the same city where patients began showing symptoms of pneumonia of unidentified origin. Very soon the disease became a global pandemic due to the suppression of information in the country of origin and inadequate testing for the COVID-19 virus. Currently, > 101 million people have been found positive for this virus and > 2.17 million people have died. There are no signs that COVID-19 is slowing down. This deadly virus affects multiple vital organs (lungs, heart, nervous system, blood, and immune system), yet its exact mechanism of pathophysiology remains obscure. Depending on the viral load, sick people often show symptoms of fever, cough, shortness of breath, coagulopathy, cardiac abnormalities, fatigue, and death. Great strides have been made in COVID-19 testing, thereby allowing timely therapeutic intervention. Currently, vaccines are on the market from Pfizer, Moderna and Astra Zeneca with limited supply. Phase III clinical trials are also underway from other manufacturers. In the current scenario, nutraceuticals and other phyto-mineral supplements appear to be promising alternative solutions for the prevention and treatment of COVID-19.
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COVID-19 , Oligoelementos , COVID-19/prevención & control , Prueba de COVID-19 , Suplementos Dietéticos , Humanos , Oligoelementos/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
Taurine is a naturally occurring amino acid involved in various functions, including regulating ion channels, cell volume, and membrane stabilization. However, how this molecule orchestrates such functions is unknown, particularly the dose response in exercised muscles. Therefore, this review aimed to systematically review the dose response of taurine on both aerobic and strength exercise performance. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, relevant articles were sought on PubMed, Medline, Web of Science, and Google Scholar using related terms, including taurine, exercise performance, exercise, muscle, physical training, running, strength, endurance exercise, resistance exercise, aerobic exercise, and swimming. Ten articles were retrieved, reviewed, and subjected to systematic analysis. The following parameters were used to assess exercise performance in the selected studies: creatine kinase (CK), lactic acid dehydrogenase, carbohydrate, fat, glycerol, malondialdehyde, enzymatic antioxidants, blood pH, taurine level, and muscular strength. From the selected literature, we observed that taurine supplementation (2 g three times daily) with exercise can decrease DNA damage. Furthermore, 1 g of acute taurine administration before or after exercise can decrease lactate levels. However, acute administration of taurine (6 g) at a high dose before the start of exercise had no effect on reducing lactate level, but increased glycerol levels, suggesting that taurine could be an effective agent for prolonged activities, particularly at higher intensities. However, further studies are warranted to establish the role of taurine in fat metabolism during exercise. Finally, we observed that a low dose of taurine (0.05 g) before performing strength enhancing exercises can decrease muscular fatigue and increase enzymatic antioxidants. Systematic Review Registration:http://www.crd.york.ac.uk/PROSPERO, PROSPERO (CRD42021225243).
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Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.
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Cuminum/química , Estradiol/toxicidad , Estrógenos/toxicidad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Mamarias Experimentales/prevención & control , Extractos Vegetales/farmacología , Animales , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Femenino , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , MicroARNs/genética , Ratas , Ratas Endogámicas ACIRESUMEN
PURPOSE: Vepoloxamer (VEPO), a rheologic agent, repairs damaged cell membranes, thus inhibiting unregulated Ca2+ entry into cardiomyocytes. This study examined the effects of i.v. infusion of VEPO on LV function in dogs with coronary microembolization-induced heart failure (HF) (LV ejection fraction, EF ~ 30%). METHODS: Thirty-five HF dogs were studied. Study 1: 21 of 35 dogs were randomized to 2-h infusion of VEPO at dose of 450 mg/kg (n = 7) or VEPO at 225 mg/kg (n = 7) or normal saline (control, n = 7). Hemodynamics were measured at 2 h, 24 h, 1 week, and 2 weeks after infusion. Study 2: 14 HF dogs were randomized to 2-h infusions of VEPO (450 mg/kg, n = 7) or normal saline (control, n = 7). Each dog received 2 infusions of VEPO or saline (pulsed therapy) 3 weeks apart and hemodynamics measured at 24 h, and 1, 2, and 3 weeks after each infusion. In both studies, the change between pre-infusion measures and measures at other time points (treatment effect, Δ) was calculated. RESULTS: Study 1: compared to pre-infusion, high dose VEPO increased LVEF by 11 ± 2% at 2 h, 8 ± 2% at 24 h (p < 0.05), 8 ± 2% at 1 week (p < 0.05), and 4 ± 2% at 2 weeks. LV EF also increased with low-dose VEPO but not with saline. Study 2: VEPO but not saline significantly increased LVEF by 6.0 ± 0.7% at 2 h (p < 0.05); 7.0 ± 0.7%% at 1 week (p < 0.05); 1.0 ± 0.6% at 3 weeks; 6.0 ± 1.3% at 4 weeks (p < 0.05); and 5.9 ± 1.3% at 6 weeks (p < 0.05). CONCLUSIONS: Intravenous VEPO improves LV function for at least 1 week after infusion. The benefits can be extended with pulsed VEPO therapy. The results support development of VEPO for treating patients with acute on chronic HF.
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Fármacos Cardiovasculares/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Poloxámero/administración & dosificación , Volumen Sistólico/efectos de los fármacos , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Animales , Señalización del Calcio/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Infusiones Intravenosas , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Gut health is the starting place for maintaining the overall health of an animal. Strategies to maintain gut health are, thus, an important part in achieving the goal of improving animal health. A new strategy to do this involves two molecules: the iron transport protein ovotransferrin (IT) and α-tocopheryl polyethylene glycol succinate (TPGS), which result in the novel formulation of ITPGS. These molecules help reduce gut pathogens, while enhancing the absorption and bioavailability of therapeutic drugs, phytomedicines, and nanomedicines. This, in turn, helps to maintain normal health in animals. Maintaining the gastrointestinal tract (GIT) in its normal condition is key for successful absorption and efficacy of any nutrient. A compromised GIT, due to an imbalance (dysbiosis) in the GIT microbiome, can lead to an impaired GI barrier system with impaired absorption and overall health of the animal. The molecules in ITPGS may address the issue of poor absorption by keeping the GI system healthy by maintaining the normal microbiome and improving the absorption of nutrients through multiple mechanisms involving antioxidative, anti-inflammatory, immunomodulatory, and antimicrobial activities. The ITPGS technology can allow the dose of active pharmaceutical or herbal medicine to be significantly reduced in order to attain equal or better efficacy. With complimentary actions between IT and TPGS, ITPGS presents a novel approach to increase the bioavailability of drugs, phytoconstituents, nutrients, and nanomedicines by enhanced transport to the tissues at the site of action, while reducing gut pathogen load. The ITPGS approach appears to be a novel strategy for maintaining the health of animals by manipulation of microbiota.
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Conalbúmina/farmacología , Tracto Gastrointestinal/efectos de los fármacos , Gastropatías/tratamiento farmacológico , Vitamina E/farmacología , Animales , Disponibilidad Biológica , Conalbúmina/química , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Tracto Gastrointestinal/microbiología , Hierro/metabolismo , Gastropatías/veterinaria , Vitamina E/químicaRESUMEN
OBJECTIVE: The aim of this study was to investigate the regulatory effects of taurine on the biochemical parameters of muscle injury by overuse. METHODS: Male Swiss mice were divided into four groups: control (Ctrl), overuse (Ov), taurine (Tau), and overuse plus taurine (OvTau). High-intensity exercise sessions were administered for 21 d with concomitant subcutaneous injections of taurine (150 mg/kg). The mice were then sacrificed. The quadriceps muscles were surgically removed for subsequent histologic analysis and evaluation of mitochondrial function, oxidative stress parameters, tissue repair, and DNA damage markers. RESULTS: The Ov group showed significant differences compared with the Ctrl group (all P <0.05). The fiber area decreased by 49.34%, whereas the centralized nuclei contents (Ctrl = 1.33%; Ov = 28.67%), membrane potential (Ctrlsuc = 179.05 arbitrary fluorescence units (AFUs), Ctrlsuc+ADP = 198.11 AFUs; Ovsuc = 482.95 AFUs, Ovsuc+ADP = 461.6 AFUs), complex I activity (Ctrl = 20.45 nmol â min â mg protein, Ov = 45.25 nmol â min â mg protein), hydrogen peroxide (Ctrlsuc = 1.08 relative fluorescence unit (RFU) â sec â mg protein, Ctrlsuc+ADP = 0.23 RFU â sec â mg protein; Ovsuc = 5.02 RFU â sec â mg protein, Ovsuc+ADP = 0.26 RFU â sec â mg protein) and malondialdehyde (Ctrl = 0.03 nmol â mg â protein, Ov = 0.06 nmol â mg â protein) levels, and DNA damage (Ctrlfreq = 7.17%, Ovfreq = 31.17%; Ctrlindex = 4.17, Ovindex = 72.5) were increased. Taurine administration reduced the number of centralized nuclei (OvTau = 5%), hydrogen peroxide levels (OvTausuc = 2.81 RFU â sec â mg protein, OvTaussuc+ADP = 1.54 RFU â sec â mg protein), membrane potential (OvTausuc = 220.18 AFUs, OvTaussuc+ADP = 235.28 AFUs), lipid peroxidation (OvTau = 0.02 nmol/mg protein), and DNA damage (OvTaufreq = 21.33%, OvTauindex = 47.83) and increased the fiber area by 54% (all P <0.05). CONCLUSION: Taken together, these data suggest that taurine supplementation modulates various cellular remodeling parameters after overuse-induced muscle damage, and that these positive effects may be related to its antioxidant capacity.
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Antioxidantes/farmacología , Trastornos de Traumas Acumulados/tratamiento farmacológico , Músculo Esquelético/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Taurina/farmacología , Animales , Trastornos de Traumas Acumulados/fisiopatología , Modelos Animales de Enfermedad , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Condicionamiento Físico Animal/fisiologíaRESUMEN
By the turn of the twenty-first century, the use of nutraceuticals became increasingly popular in both humans and animals due to their easy access, cost-effectiveness, and tolerability with a wide margin of safety. While some nutraceuticals are safe, others have a toxic potential. For a large number of nutraceuticals, no toxicity/safety data are available due to a lack of pharmacological/toxicological studies. The safety of some nutraceuticals can be compromised via contamination with toxic plants, metals, mycotoxins, pesticides, fertilizers, drugs of abuse, etc. Knowledge of pharmacokinetic/toxicokinetic studies appears to play a pivotal role in safety and toxicity assessment of nutraceuticals. Interaction studies are essential to determine efficacy, safety, and toxicity when nutraceuticals and therapeutic drugs are used concomitantly. This chapter describes various aspects of nutraceuticals, particularly their toxic potential, and the factors influencing their safety.
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Suplementos Dietéticos/efectos adversos , Descubrimiento de Drogas , Pruebas de Toxicidad , Animales , Biomarcadores , Descubrimiento de Drogas/métodos , Interacciones Farmacológicas , Humanos , Atención Perioperativa/métodosRESUMEN
Cervical cancer is caused by human papillomavirus (HPV). The disease develops over many years through a series of precancerous lesions. Cervical cancer can be prevented by HPV-vaccination, screening and treatment of precancer before development of cervical cancer. The treatment of high-grade cervical dysplasia (CIN 2+) has traditionally been by cervical conization. Surgical procedures are associated with increased risk of undesirable side effects including bleeding, infection, scarring (stenosis), infertility and complications in later pregnancies. An inexpensive, non-invasive method of delivering therapeutics locally will be favorable to treat precancerous cervical lesions without damaging healthy tissue. The feasibility and safety of a sustained, continuous drug-releasing cervical polymeric implant for use in clinical trials was studied using a large animal model. The goat (Capra hircus), non-pregnant adult female Boer goats, was chosen due to similarities in cervical dimensions to the human. Estrus was induced with progesterone CIDR® vaginal implants for 14days followed by the administration of chorionic gonadotropins 48h prior to removal of the progesterone implants to relax the cervix to allow for the placement of the cervical implant. Cervical implants, containing 2% and 4% withaferin A (WFA), with 8 coats of blank polymer, provided sustained release for a long duration and were used for the animal study. The 'mushroom'-shaped cervical polymeric implant, originally designed for women required redesigning to be accommodated within the goat cervix. The cervical implants were well tolerated by the animals with no obvious evidence of discomfort, systemic or local inflammation or toxicity. In addition, we developed a new method to analyze tissue WFA levels by solvent extractions and LS/MS-MS. WFA was found to be localized to the target and adjacent tissues with 12-16ng WFA/g tissue, with essentially no detectable WFA in distant tissues. This study suggests that the goat is a good large animal model for the future development and evaluation of therapeutic efficacy of continuous local drug delivery by cervical polymeric implants to treat precancerous cervical lesions.
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Sistemas de Liberación de Medicamentos , Infecciones por Papillomavirus/tratamiento farmacológico , Displasia del Cuello del Útero/tratamiento farmacológico , Witanólidos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Femenino , Cabras , Humanos , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Embarazo , Displasia del Cuello del Útero/complicaciones , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
Despite optimal diagnosis and early therapeutic interventions, the prognosis for ovarian cancer patients remains dismal because the efficacy of chemotherapy is limited by the development of resistance and off-site toxicity. Berry bioactives indicate preventive and therapeutic activities against various cancer types. Here, we examined the antiproliferative activity of berry anthocyanidins (Anthos) against drug-sensitive (A2780) and drug-resistant (A2780/CP70, OVCA432 and OVCA433) ovarian cancer cells. These drug-resistant ovarian cancer cell lines overexpress p-glycoproteins (PgP) and show >100-fold resistance to the chemotherapeutic drug cisplatin compared to A2780. We observed a dose-dependent growth inhibition of ovarian cancer cells with the Anthos. Furthermore, the treatment of drug-resistant ovarian cancer (OVCA433) cells with cisplatin in combination with the Anthos (75 µM) resulted in significantly higher cell killing. The cisplatin dose required to achieve this effect was 10 to 15-fold lower than the IC50 of cisplatin alone. However, many plant bioactives including Anthos face the challenge of poor oral bioavailability and stability. Recently, we have developed strategies to overcome these limitations by delivering Anthos via milk-derived exosomes. The exosomal Anthos (ExoAnthos) significantly enhanced the antiproliferative activity against the growth of ovarian cancer cells and inhibited tumor growth more efficiently compared to Anthos alone and a vehicle control. Often patients with cisplatin-resistant tumors retain sensitivity to paclitaxel (PAC). We prepared exosomal formulations of PAC (ExoPAC) for oral delivery as the systemic administration of PAC has severe side effects. ExoPAC delivered orally showed the same therapeutic efficacy as the free PAC delivered intraperitoneally. Finally, we report that the combination of the Anthos and PAC decreased the PgP level in a dose-dependent manner in OVCA432 cells. A significantly enhanced antitumor activity was observed with the combination of ExoPAC and ExoAnthos against A2780 tumor xenografts. Together, our data indicate that the berry Anthos are highly effective against ovarian cancer and that the milk exosomes serve as an excellent nano-carrier to enhance the drug's oral bioavailability for the management of ovarian cancer.
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Antocianinas/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Ováricas/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Animales , Antocianinas/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Portadores de Fármacos/química , Exosomas/química , Femenino , Frutas/química , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/fisiopatología , Extractos Vegetales/químicaRESUMEN
Diabetes is a complex condition with a variety of causes and pathophysiologies. The current single target approach has not provided ideal clinical outcomes for the treatment of the disease and its complications. Herbal medicine has been used for the management of various diseases such as diabetes over centuries. Many diabetic patients are known to use herbal medicines with antidiabetic properties in addition to their mainstream treatments, which may present both a benefit as well as potential risk to effective management of their disease. In this review we evaluate the clinical and experimental literature on herb-drug interactions in the treatment of diabetes. Pharmacokinetic and pharmacodynamic interactions between drugs and herbs are discussed, and some commonly used herbs which can interact with antidiabetic drugs summarised. Herb-drug interactions can be a double-edged sword presenting both risks (adverse drug events) and benefits (through enhancement). There is a general lack of data on herb-drug interactions. As such, more rigorous scientific research is urgently needed to guide clinical practice as well as to safeguard the wellbeing of diabetes patients.
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Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17ß-estrogen (E2)-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish) rat model. Female ACI rats were given either control diet (AIN 93M) or diet supplemented with 7.5% (w/w) of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold) enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA) in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα). The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92 days in control group. At the end of the study (25 weeks), the tumor incidence was 96% in the control group compared with only 70% in the caraway group. A significant reduction in tumor volume (661 ± 123 vs. 313 ± 81 mm³) and tumor multiplicity (4.2 ± 0.4 vs. 2.5 ± 0.5 tumors/animal) was also observed in the caraway group compared with the control group. Together, our data show dietary caraway can significantly delay and prevent the hormonal mammary tumorigenesis by modulating different cellular and molecular targets.
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Apiaceae/química , Transformación Celular Neoplásica/efectos de los fármacos , Quimioprevención , Suplementos Dietéticos , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/prevención & control , Especias , Animales , Biomarcadores , Peso Corporal , Proliferación Celular/efectos de los fármacos , Estradiol/efectos adversos , Estrógenos/sangre , Femenino , Neoplasias Mamarias Experimentales/sangre , Prolactina/sangre , Ratas , Carga TumoralRESUMEN
SCOPE: Syzygium cumini (jamun) is perhaps the only berry that has the diversity of anthocyanidins of blueberry and bilberry and the abundance of ellagitannins/ellagic acid of black raspberry. Here, we report the potential of jamun against 17ß-estrogen-mediated breast cancer and the role of miRNAs and other targets in disease inhibition. METHODS AND RESULTS: Female August-Copenhagen Irish rats were given AIN-93M diet or diet supplemented with jamun. Two weeks later, animals received 17ß-estradiol and were palpated weekly for the mammary tumors. At the end of 26 weeks, the jamun-diet significantly delayed the first tumor appearance by 21 days, and reduced the tumor incidence (65% versus 96%), tumor burden (313 ± 95 versus 661 ± 123 mm(3) ) and tumor multiplicity (1.8 ± 0.3 versus 4.2 ± 0.4 tumors/rat) compared to control. The experimental diet significantly reduced the estrogen-associated growth of pituitary prolactinomas, circulating prolactin and estradiol levels and offset estrogen-associated increases in mammary cell-proliferation, estrogen receptor-alpha (ER-α), and cyclinD1. miRNAs that were either overexpressed (miR-182 and miR-375) or underexpressed (miR-127 and miR-206) following estrogen-treatment were significantly protected by jamun diet. CONCLUSIONS: Together, our data show that jamun significantly offset estrogen-mediated alterations in mammary cell-proliferation, ER-α, cyclinD1, and candidate miRNAs, and that the modulation of these biomarkers correlated with a reduction in mammary carcinogenicity.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Dieta , Preparaciones de Plantas/farmacología , Syzygium/química , Animales , Antocianinas/farmacología , Proliferación Celular/efectos de los fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Ácido Elágico/farmacología , Estradiol/toxicidad , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Frutas/química , Regulación Neoplásica de la Expresión Génica , Taninos Hidrolizables/farmacología , Neoplasias Mamarias Experimentales , MicroARNs/genética , MicroARNs/metabolismo , Ratas , Ratas EndogámicasRESUMEN
The fruit pulp of Eugenia jambolana (jamun) is a rich source of anthocyanins (ACs). The purpose of the present study was to assess the effect of various physical and chemical factors on the stability of ACs and anthocyanidins (ACdn) in the crude, anthocyanins-enriched extract (ACs-EEX), anthocyanins-enriched sephadex extract (ACs-EES) and anthocyanidins-enriched extract (ACdn-EEX). ACs and ACdn contents were analyzed using a stability indicating HPLC analytical method. The ACs content reduced to 86.4% (crude extract), 60.9% (ACs-EEX), 36.0% (ACs-EES), 64.8% (ACs-EEX tablet), and 71.7% (ACs-EEX capsules) after 1 year at 5 °C. The ACdn content reduced to 83.1% (ACdn-EEX), 90.1% (ACdn-EEX tablet) and 93.8% (ACdn-EEX capsules) after 1 year at 5 °C. ACs and ACdn showed lesser degradation at low pH and higher degradation at high H2O2 concentration. The thermal degradation products of ACs were identified and quantified.
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Antocianinas/análisis , Cromatografía Líquida de Alta Presión/métodos , Frutas/química , Extractos Vegetales/química , Syzygium/químicaRESUMEN
Spices are used worldwide, particularly in the Asian and Middle Eastern countries, and considered protective against degenerative diseases, including cancer. Here, we report the efficacy of aqueous and non-aqueous extracts of 11 Apiaceae spices for free radical-scavenging activity and to inhibit cytochrome P450s in two separate reactions involving: 1) 4-hydroxy-17ß-estradiol (4E2), DNA, and CuCl2 and 2) 17ß-estradiol, rat liver microsomes, cofactors, DNA and CuCl2. Oxidative DNA adducts resulting from redox cycling of 4E2 were analyzed by (32)P-postlabeling. Aqueous (5 mg/ml) and non-aqueous extracts (6 mg/ml) substantially inhibited (83-98%) formation of DNA adducts in the microsomal reaction. However, in nonmicrosomal reaction, only aqueous extracts showed the inhibitory activity (83-96%). Adduct inhibition was also observed at five-fold lower concentrations of aqueous extracts of cumin (60%) and caraway (90%), and 10-fold lower concentrations of carrot seeds (76%) and ajowan (90%). These results suggests the presence of 2 groups of phytochemicals: polar compounds that have free radical-scavenging activity and lipophilic compounds that selectively inhibit P450 activity associated with estrogen metabolism. Because most of these Apiaceae spices are used widely with no known toxicity, the phytochemicals from the Apiaceae spices used in foods may be potentially protective against estrogen-mediated breast cancer.
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Antioxidantes/farmacología , Apiaceae/química , Extractos Vegetales/farmacología , Especias , Animales , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Aductos de ADN , Daño del ADN/efectos de los fármacos , Estradiol/metabolismo , Estrógenos de Catecol/metabolismo , Estrógenos de Catecol/farmacocinética , Depuradores de Radicales Libres/farmacología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Extractos Vegetales/química , Ratas , Testículo/efectos de los fármacos , Testículo/metabolismoRESUMEN
Eugenia jambolana, commonly known as 'jamun' or Indian blackberry, is an important source of bioactive compounds. All parts of the plant like stem bark, leaves, flower, fruit pulp and seeds are traditionally used for many diseases. Metabolite profiling in medicinally important plants is critical to resolve the problems associated with standardization and quality control. Metabolite profiling of the fruit pulp of Jamun was performed by NMR, HPLC, MS, GC-MS and MALDI-TOF mass spectrometry. These hyphenated techniques helped in the identification of 68 chemically-diverse metabolites of the fruit pulp. These include anthocyanins, anthocyanidins, sugars, phenolics and volatile compounds. Five extracts of fruit pulp were prepared i.e. hexane, chloroform, ethylacetate, butanol and aqueous methanolic. Twenty-five metabolites identified and quantified in the n-butanol and aqueous-methanolic extracts of ripe jamun fruit by qNMR. LC-PDA-MS and MALDI-TOF spectrometry helped in deciphering thirty-nine metabolites out of which thirteen were quantified.
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Frutas/química , Extractos Vegetales/química , Syzygium/química , Cromatografía Líquida de Alta Presión , Cromatografía de Gases y Espectrometría de Masas , India , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Syzygium/metabolismo , Espectrometría de Masas en TándemRESUMEN
Human papilloma virus (HPV) is the well-established etiological factor of cervical cancer. E6 and E7 oncoproteins expressed by HPV are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Tanshinone IIA (Tan IIA) is a diterpenoid naphthoquinone found in the traditional Chinese medicine Danshen (Salvia sp.). Tan IIA has been shown to possess anti-tumor activity against several cancer types. In this study we show that Tan IIA potently inhibited proliferation of the human cervical cancer CaSki, SiHa, HeLa and C33a cells. Mechanistically in HPV positive CaSki cells, Tan IIA was found to (i) downregulate expression of HPV E6 and E7 genes and modulate associated proteins E6AP and E2F1, (ii) cause S phase cell cycle arrest, (iii) induce accumulation of p53 and alter expression of p53-dependent targets, (iv) modulate pRb and related proteins, and (v) cause p53-mediated apoptosis by moderating Bcl2, Bax, caspase-3, and PARP cleavage expressions. In vivo, Tan IIA resulted in over 66% reduction in tumor volume of cervical cancer xenograft in athymic nude mice. Tan IIA treated tumor tissues had lower expression of proliferation marker PCNA and changes in apoptosis targets were in agreement with in vitro studies, further confirming reduced proliferation and involvement of multiple targets behind anti-cancer effects. This is the first demonstration of Tan IIA to possess significant anti-viral activity by repressing HPV oncogenes leading to inhibition of cervical cancer. Together, our data suggest that Tan IIA can be exploited as a potent therapeutic agent for the prevention and treatment of cervical and other HPV-related cancers.
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Abietanos/farmacología , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Represoras/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Animales , Western Blotting , Ciclo Celular , Proliferación Celular , Femenino , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Desnudos , Proteínas Oncogénicas Virales/genética , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/tratamiento farmacológico , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/genética , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/virología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Punicalagin (PC) is an ellagitannin found in the fruit peel of Punica granatum. We have demonstrated antioxidant and antigenotoxic properties of Punica granatum and showed that PC and ellagic acid (EA) are its major constituents. In this study, we demonstrate the antimutagenic potential, inhibition of BP-induced DNA damage, and antiproliferative activity of PC and EA. Incubation of BP with rat liver microsomes, appropriate cofactors, and DNA in the presence of vehicle or PC and EA showed significant inhibition of the resultant DNA adducts, with essentially complete inhibition (97%) at 40 µ M by PC and 77% inhibition by EA. Antimutagenicity was tested by Ames test. PC and EA dose-dependently and markedly antagonized the effect of tested mutagens, sodium azide, methyl methanesulfonate, benzo[a]pyrene, and 2-aminoflourine, with maximum inhibition of mutagenicity up to 90 percent. Almost all the doses tested (50-500 µ M) exhibited significant antimutagenicity. A profound antiproliferative effect on human lung cancer cells was also shown with PC and EA. Together, our data show that PC and EA are pomegranate bioactives responsible for inhibition of BP-induced DNA adducts and strong antimutagenic, antiproliferative activities. However, these compounds are to be evaluated in suitable animal model to assess their therapeutic efficacy against cancer.
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Aductos de ADN/efectos de los fármacos , Ácido Elágico/administración & dosificación , Taninos Hidrolizables/administración & dosificación , Extractos Vegetales/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Benzo(a)pireno/farmacología , Daño del ADN/efectos de los fármacos , Ácido Elágico/química , Humanos , Taninos Hidrolizables/química , Lythraceae/química , Mutagénesis/efectos de los fármacos , Extractos Vegetales/química , Ratas , Salmonella typhimurium/efectos de los fármacosRESUMEN
Dietary polyphenols may contribute to the prevention of several degenerative diseases, including cancer. Anthocyanins have been shown to possess potential anticancer activity. The aim of this study was to determine anthocyanin bioavailability in lung tissue of mice fed a blueberry diet (5% w/w) for 10 days or a bolus dose (10 mg/mouse; po) of a native mixture of bilberry anthocyanidins. All five anthocyanidins present in the blueberry were detected in the lung tissue using improved methods. The effect of various solvents on the stability of anthocyanins and their recovery from the biomatrix was analyzed. Detection of anthocyanins and their metabolites was performed by UPLC and LC-MS. Although anthocyanins were not detected, cyanidin was detected by UPLC-PDA and other anthocyanidins were detected by LC-MS, following conversion to anthocyanidins and selective extraction in isoamyl alcohol. The results show that anthocyanins can be detected in lung tissue of blueberry-fed mice and thus are bioavailable beyond the gastrointestinal tract.