Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150–550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC

Effects of plant-beneficial fungi on plant growth and herbivore resistance under contrasting fertilizer conditions

Aims Plant-beneficial fungi play an important role in enhancing plant growth and protecting plants from biotic and abiotic stresses. However, context-dependency of such effects and differences among fungi often lead to inconsistent results that hamper their widespread use. Here, we investigated the effect of plant-beneficial fungi on plant growth and herbivore resistance, and how effects are mediated by fertilization. Methods Sweet pepper (Capsicum annuum L.) plants were root-inoculated with the plant-beneficial fungi Beauveria bassiana ARSEF 3097 and Trichoderma harzianum T22 and grown in a low-nutrient potting mix, with or without additional nutrients. Plant growth and herbivore resistance against the southern green stink bug (Nezara viridula L.) were compared between fungal treatments and fertilization levels by measuring several growth traits and quantifying feeding damage and plant defense-related gene expression. Results Fertilization significantly increased plant growth, but at the same time made plants more susceptible to herbivory. Irrespective of fertilization, T. harzianum stimulated growth and reduced feeding damage (number of leaf punctures), while B. bassiana only enhanced growth. For both strains, fungal inoculation generally increased the expression of marker genes involved in salicylic acid- and jasmonic acid-dependent defense responses upon herbivory, but this was less pronounced for salicylic acid-dependent defense signaling under fertilization. Conclusions We conclude that fungal inoculation improved plant growth and generally elicited a stronger defense response to stink bug feeding. Accordingly, plant damage was reduced by T. harzianum. Overall these results show that plant-beneficial fungi have the potential to promote plant growth and reduce feeding damage, irrespective of fertilization

Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis

Energy-dependent intestinal calcium absorption is important for the maintenance of calcium and bone homeostasis, especially when dietary calcium supply is restricted. The active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is a crucial regulator of this process and increases the expression of the transient receptor potential vanilloid 6 (Trpv6) calcium channel that mediates calcium transfer across the intestinal apical membrane. Genetic inactivation of Trpv6 in mice (Trpv6(-/-)) showed, however, that TRPV6 is redundant for intestinal calcium absorption when dietary calcium content is normal/high and passive diffusion likely contributes to maintain normal serum calcium levels. On the other hand, Trpv6 inactivation impaired the increase in intestinal calcium transport following calcium restriction, however without resulting in hypocalcemia. A possible explanation is that normocalcemia is maintained at the expense of bone homeostasis, a hypothesis investigated in this study. In this study, we thoroughly analyzed the bone phenotype of Trpv6(-/-) mice receiving a normal (approximately 1%) or low (approximately 0.02%) calcium diet from weaning onwards using micro-computed tomography, histomorphometry and serum parameters. When dietary supply of calcium is normal, Trpv6 inactivation did not affect growth plate morphology, bone mass and remodeling parameters in young adult or aging mice. Restricting dietary calcium had no effect on serum calcium levels and resulted in a comparable reduction in bone mass accrual in Trpv6(+/+) and Trpv6(-/-) mice (-35% and 45% respectively). This decrease in bone mass was associated with a similar increase in bone resorption, whereas serum osteocalcin levels and the amount of unmineralized bone matrix were only significantly increased in Trpv6(-/-) mice. Taken together, our findings indicate that TRPV6 contributes to intestinal calcium transport when dietary calcium supply is limited and in this condition indirectly regulates bone formation and/or mineralization

Family business going abroad: the effect of family ownership on foreign market entry mode decisions

Research on family firms’ internationalization is growing, but empirical findings are mixed. To reconcile prior studies, we focus on strategic decisions related to internationalization, specifically the foreign market entry mode selection process. We suggest that the choice about entry mode is especially significant for family owners because it may either align or conflict with two key family-related goals: maintaining family control and keeping a long-term orientation of the business. We argue that these goals have different weights within family firms according to differences in ownership structure, with significant implications for international strategic decisions. We rely on a sample of medium-sized family-owned Italian firms and show that different types of family ownership structures affect entry mode decisions differently and specifically influence the time horizon of the foreign investment and willingness to cooperate with external actors. We also provide empirical evidence that the presence of a non-family manager moderates the relationship between family ownership and entry mode decisions. Our study expands on prior research by highlighting how family firms enter foreign markets and pointing out the strategic implications of family firm heterogeneity