Synergistic mutual potentiation of antifungal activity of Zuccagnia punctata Cav. and Larrea nitida Cav. extracts in clinical isolates of Candida albicans and Candida glabrata

Background: Zuccagnia punctata Cav. (Fabaceae) and Larrea nitida Cav. (Zygophyllaceae) are indistinctly or jointly used in traditional medicine for the treatment of fungal-related infections. Although their dichloromethane (DCM) extract have demonstrated moderate antifungal activities when tested on their own, antifungal properties of combinations of both plants have not been assessed previously. Purpose: The aim of this study was to establish with statistical rigor whether Z. punctata (ZpE) and L. nitida DCM extract (LnE) interact synergistically against the clinically important fungi Candida albicans and Candida glabrata and to characterize the most synergistic combinations. Study design: For synergism assessment, the statistical-based Boik's design was applied. Eight ZpE–LnE fixed-ratio mixtures were prepared from four different months of 1 year and tested against Candida strains. Lϕ (Loewe index) of each mixture at different fractions affected (ϕ) allowed for the finding of the most synergistic combinations, which were characterized by HPLC fingerprint and by the quantitation of the selected marker compounds. Methods: Lϕ and confidence intervals were determined in vitro with the MixLow method, once the estimated parameters from the dose–response curves of independent extracts and mixtures, were obtained. Markers (four flavonoids for ZpE and three lignans for LnE) were quantified in each extract and their combinations, with a valid HPLC–UV method. The 3D-HPLC profiles of the most synergistic mixtures were obtained by HPLC–DAD. Results: Three over four IC50ZpE/IC50LnE fixed-ratio mixtures displayed synergistic interactions at effect levels ϕ > 0.5 against C. albicans. The dosis of the most synergistic (Lϕ = 0.62) mixture was 65.96 µg/ml (ZpE = 28%; LnE = 72%) containing 8 and 36% of flavonoids and lignans respectively. On the other hand, one over four IC50ZpE/IC50LnE mixtures displays synergistic interactions at ϕ > 0.5 against C. glabrata. The dosis of the most synergistic (Lϕ = 0.67) mixture was 168.23 µg/ml (ZpE = 27%; LnE = 73%) with 9.7 and 31.6% of flavonoids and lignans respectively. Conclusions: Studies with the statistical-based MixLow method, allowed for the finding of the most ZpE–LnE synergistic mixtures, giving support to a proper joint use of both antifungal herbs in traditional medicine.Fil: Butassi, Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Svetaz, Laura Andrea. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ivancovich, Juan J.. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Feresin, Gabriela Egly. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tapia, Alejandro A.. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Zacchino, Susana Alicia Stella. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Ocean warming-acidification synergism undermines dissolved organic matter assembly.

Understanding the influence of synergisms on natural processes is a critical step toward determining the full-extent of anthropogenic stressors. As carbon emissions continue unabated, two major stressors--warming and acidification--threaten marine systems on several scales. Here, we report that a moderate temperature increase (from 30°C to 32°C) is sufficient to slow--even hinder--the ability of dissolved organic matter, a major carbon pool, to self-assemble to form marine microgels, which contribute to the particulate organic matter pool. Moreover, acidification lowers the temperature threshold at which we observe our results. These findings carry implications for the marine carbon cycle, as self-assembled marine microgels generate an estimated global seawater budget of ~1016 g C. We used laser scattering spectroscopy to test the influence of temperature and pH on spontaneous marine gel assembly. The results of independent experiments revealed that at a particular point, both pH and temperature block microgel formation (32°C, pH 8.2), and disperse existing gels (35°C). We then tested the hypothesis that temperature and pH have a synergistic influence on marine gel dispersion. We found that the dispersion temperature decreases concurrently with pH: from 32°C at pH 8.2, to 28°C at pH 7.5. If our laboratory observations can be extrapolated to complex marine environments, our results suggest that a warming-acidification synergism can decrease carbon and nutrient fluxes, disturbing marine trophic and trace element cycles, at rates faster than projected

Synergism of Saccharum officinarum and Ananas comosus extract additives on the quality of electroplated zinc on mild steel.

Synergism of Saccharum officinarum (sugarcane) and Ananas comosus (pineapple) extract additives on the quality of electroplated zinc on mild steel in acid chloride solution was investigated experimentally at ambient temperature (*28 �C). The experiments were performed at different plating times (15 and 18 min), additive concentrations (2, 2.5, 3 ml/50 ml of acid chloride solution), pH 5, temperature (27–30 �C), current (0.08 A), and voltage (13 V DC) conditions. Zinc electroplating on mild steel was performed using a DC-supply. The surface of the plated steel was examined with scanning electron microscopy, and energy dispersive spectroscopy for surface elemental composition analysis. Different surface characteristics were obtained depending upon the concentration of the additive and the plating time. The corrosion resistance of the plated surface was determined by a gravimetric method. Micro-structural morphology of the plated surface indicated a good quality electroplating that was better than either the sugarcane or pineapple extracts alone. The electroplating process was sensitive to changes in additive concentration and plating time. Any variation in the plating parameter produced an entirely new and different surface crystal morphology

Combined immunosuppressive therapy with low dose FK506 and antimetabolites in rat allogeneic heart transplantation

Following rat heterotopic heart allotransplantation, low to lethal doses of the antimetabolites mizoribine (MIZ), RS-61443 (RS), and AZA were given alone or in combination with subtherapeutic doses of FK506 (0.04 mg/kg/day) for 14 days after transplantation. With the median effect analysis of Chou and Kahan for quantitative drug interactions, substantial therapeutic synergism was demonstrated between FK506 and nontoxic doses of MĪZ (2.5, 5, and 10 mg/kg/day) or AZA (5, 30, and 45 mg/kg/day), which was particularly evident with the lowest dose MIZ (2.5 mg/kg/day). When FK506 was used in combination with MIZ or AZA but not with RS, the maximum effect (peak median graft survival) was enhanced significantly from 15 days (MIZ alone) to 26 days (P<0.05), and from 19 days (AZA alone) to 32 days (P<0.0l). In contrast, RS interacted with FK506 no more than additively. Although RS was the most powerful single antimetabolite, the best overall survival was obtained by combining AZA and FK506. The addition of FK506 did not significantly increase the percent mortality and LD50 of the antimetabolites. © 1994 by Williams and Wilkins

Synergistic up-regulation of CXCL10 by virus and IFN γ in human airway epithelial cells.

Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn't affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level

Synergistic Activity of Fosfomycin, Ciprofloxacin, and Gentamicin Against Escherichia coli and Pseudomonas aeruginosa Biofilms

Gram-negative (GN) rods cause about 10% periprosthetic joint infection (PJI) and represent an increasing challenge due to emergence of antimicrobial resistance. Escherichia coli and Pseudomonas aeruginosa are among the most common cause of GN-PJI and ciprofloxacin is the first-line antibiotic. Due to emergence of fluoroquinolone resistance, we evaluated in vitro the activity of fosfomycin, ciprofloxacin, and gentamicin, alone and in combinations, against E. coli and P. aeruginosa biofilms. Conventional microbiological tests and isothermal microcalorimetry were applied to investigate the anti-biofilm activity of the selected antibiotics against standard laboratory strains as well as clinical strains isolated from patients with prosthetic joint associated infections. The biofilm susceptibility to each antibiotic varied widely among strains, while fosfomycin presented a poor anti-biofilm activity against P. aeruginosa. Synergism of two-pair antibiotic combinations was observed against different clinical strains from both species. Highest synergism was found for the fosfomycin/gentamicin combination against the biofilm of E. coli strains (75%), including a gentamicin-resistant but fosfomycin-susceptible strain, whereas the gentamicin/ciprofloxacin combination presented synergism with higher frequency against the biofilm of P. aeruginosa strains (71.4%). A hypothetical bacteriolysis effect of gentamicin could explain why combinations with this antibiotic seem to be particularly effective. Still, the underlying mechanism of the synergistic effect on biofilms is unknown. In conclusion, combinatorial antibiotic application has shown to be more effective against biofilms compared to monotherapy. Further in vivo and clinical studies are essential to define the potential treatment regimen based on our results