Consistent Synergism Research Articles

Crucial role of humic substance type in Cr(VI) reduction by humic substance-Fe(III) coprecipitates but not in adsorption

Wetlands exhibit a self-purification effect on Cr(VI) owing to the adsorption and reduction capabilities of their humic substance (HS)-Fe(III) coprecipitates. However, the similarities and differences in the adsorption and reduction of Cr(VI) by different types of HS-Fe(III) coprecipitates remains unknown. In this study, fulvic acid (FA)- and humic acid (HA)-Fe(III) coprecipitates were synthesized with initial C/Fe ratios ranging from 0.25 to 15, and a comparative analysis of their adsorption and reduction effects was conducted. The results showed that FA- and HA-Fe(III) coprecipitates exhibit similar abilities to adsorb Cr(VI) by forming inner-sphere complexes with ferrihydrite (Fh), as well as with FA/HA. The association between FA/HA and Fe(III) not only blocked certain FeOH adsorption sites, but also enhanced the electrostatic repulsion towards Cr(VI), resulting in a proportionate decrease in their adsorption ability. For reduction, inductive and intrinsic reduction were involved in both FA- and HA-Fe(III) coprecipitates. However, the synergism/antagonism differed with the inherent sites (e.g., phenolic hydroxyl, ArOH) and activated sites (e.g., alcoholic hydroxyl, AlOH). Based on the size differences between FA and HA, the AlOH contained in FA was more easily activated by Fe(III) than that in HA, owing to the shorter induction path required. Thus, consistent synergism was observed in FA-Fe(III) coprecipitates regardless of Fe(III) species. In contrast, synergism was only observed in HA-Fe(III) coprecipitates containing Fh, because the inductive ability of Fe(III) cations was too weak to activate AlOH through the longer path. Moreover, with irreversible consumption of AlOH, intrinsic reduction became the dominant pathway at concentrations >1 mM Cr(VI). The preferential elimination of ArOH subsequently led to a transition to antagonism. These outcomes deepen our scientifical understanding of the environmental effects of HS-Fe(III) coprecipitates and offer new perspectives for exploring their potential applications in the remediation of Cr-contaminated sites.

An alternative strategy for combination therapy: Interactions between polymyxin B and non-antibiotics

Antimicrobial resistance is increasing and few new antibiotics are in the development pipeline. Alternative strategies to treat infectious diseases, such as combination therapy, are urgently needed. Polymyxin B is a neglected and disused antibiotic with moderate antibacterial activity. In this study, we aimed to find synergistic interactions between polymyxin B and a wide range of non-antibiotics (non-ABs) to improve its efficacy. Thirty non-AB compounds from various drug classes were screened for synergistic potential with sub-minimum inhibitory concentrations (MICs) of polymyxin B in an agar diffusion assay against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa (3 isolates per species). Potential candidates were further studied in in vitro checkerboard assays, up to 5 isolates per species, using optical density to assess growth. Interactions were assessed with fractional inhibitory concentration index (FICi) analysis and surface response analysis with Loewe, Bliss and Highest Single Agent analysis using the Combenefit program. Twenty non-ABs enhanced polymyxin B activity in the agar diffusion test in one or more species. Of these, three showed a consistent synergistic effect (FICi ≤ 0.5) in the checkerboard assay for at least one species: citalopram, sertraline and spironolactone. Surface response analyses were largely in concordance, and further assessment showed only spironolactone was synergistic with polymyxin B at clinically relevant levels. The screening strategy used showed consistent synergism in vitro between polymyxin B and some non-ABs for A. baumannii, E. coli and K. pneumoniae. The synergistic interactions found merit further exploration as alternative strategies for difficult-to-treat infections.

Synergistic Interactions in Microbial Biofilms Facilitate the Establishment of Opportunistic Pathogenic Fungi in Household Dishwashers.

Biofilms formed on rubber seals in dishwashers harbor diverse microbiota. In this study, we focussed on the microbial composition of bacteria and fungi, isolated from a defined area of one square centimeter of rubber from four domestic dishwashers and assessed their abilities to in vitro multispecies biofilm formation. A total of 80 isolates (64 bacterial and 16 fungal) were analyzed. Multiple combinations of bacterial isolates from each dishwasher were screened for synergistic interactions. 32 out of 140 tested (23%) four-species bacterial combinations displayed consistent synergism leading to an overall increase in biomass, in all experimental trails. Bacterial isolates from two of the four dishwashers generated a high number of synergistically interacting four-species consortia. Network based correlation analyses also showed higher co-occurrence patterns observed between bacterial members in the same two dishwasher samples, indicating cooperative effects. Furthermore, two synergistic four-species bacterial consortia were tested for their abilities to incorporate an opportunistic fungal pathogen, Exophiala dermatitidis and their establishment as biofilms on sterile ethylene propylene diene monomer M-class (EPDM) rubber and polypropylene (PP) surfaces. When the bacterial consortia included E. dermatitidis, the overall cell numbers of both bacteria and fungi increased and a substantial increase in biofilm biomass was observed. These results indicate a novel phenomenon of cross kingdom synergy in biofilm formation and these observations could have potential implications for human health.

Predicting Drug Combination Index and Simulating the Network-Regulation Dynamics by Mathematical Modeling of Drug-Targeted EGFR-ERK Signaling Pathway

Synergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect. The predicted CIs and combination therapeutic effects of the EGFR-BRaf, BRaf-MEK, FTI-MEK, and FTI-BRaf inhibitor combinations showed consistent synergism. Our results suggest that existing pathway models may be potentially extended for developing drug-targeted pathway models to predict drug combination CI values, isobolograms, and drug-response surfaces as well as to analyze the dynamics of individual and combinations of drugs. With our model, the efficacy of potential drug combinations can be predicted. Our method complements the developed in-silico methods (e.g. the chemogenomic profile and the statistically-inferenced network models) by predicting drug combination effects from the perspectives of pathway dynamics using experimental or validated molecular kinetic constants, thereby facilitating the collective prediction of drug combination effects in diverse ranges of disease systems.

Efficacy of Genetically Modified Bt Toxins Alone and in Combinations Against Pink Bollworm Resistant to Cry1Ac and Cry2Ab

Evolution of resistance in pests threatens the long-term efficacy of insecticidal proteins from Bacillus thuringiensis (Bt) used in sprays and transgenic crops. Previous work showed that genetically modified Bt toxins Cry1AbMod and Cry1AcMod effectively countered resistance to native Bt toxins Cry1Ab and Cry1Ac in some pests, including pink bollworm (Pectinophora gossypiella). Here we report that Cry1AbMod and Cry1AcMod were also effective against a laboratory-selected strain of pink bollworm resistant to Cry2Ab as well as to Cry1Ab and Cry1Ac. Resistance ratios based on the concentration of toxin killing 50% of larvae for the resistant strain relative to a susceptible strain were 210 for Cry2Ab, 270 for Cry1Ab, and 310 for Cry1Ac, but only 1.6 for Cry1AbMod and 2.1 for Cry1AcMod. To evaluate the interactions among toxins, we tested combinations of Cry1AbMod, Cry1Ac, and Cry2Ab. For both the resistant and susceptible strains, the net results across all concentrations tested showed slight but significant synergism between Cry1AbMod and Cry2Ab, whereas the other combinations of toxins did not show consistent synergism or antagonism. The results suggest that the modified toxins might be useful for controlling populations of pink bollworm resistant to Cry1Ac, Cry2Ab, or both.

Early timing and new combinations to increase the efficacy of neonicotinoid–entomopathogenic nematode (Rhabditida: Heterorhabditidae) combinations against white grubs (Coleoptera: Scarabaeidae)

An investigation was carried out to determine whether new neonicotinoid-nematode combinations and earlier applications against younger larval stages could increase the efficacy of synergistic neonicotinoid-entomopathogenic nematode combinations against white grubs. In the laboratory, combinations of the neonicotinoids imidacloprid and clothianidin and the nematodes Heterorhabditis bacteriophora Poinar and H. zealandica Poinar against third instars were compared. In Anomala orientalis (Waterhouse) and Popillia japonica Newman, H. bacteriophora-imidacloprid combinations showed the most consistent synergism but did not cause significantly higher mortality than H. zealandica-imidacloprid combinations. In Cyclocephala borealis Arrow, there was no clear trend as to which combinations caused the most consistent synergism, but H. zealandica-imidacloprid combinations tended to cause the highest mortalities. In the laboratory, imidacloprid-H. bacteriophora combinations provided more consistent synergism against third-instar than against second-instar A. orientalis, but mortality was higher in second instars. In field experiments, imidacloprid-H. bacteriophora combinations against A. orientalis and P. japonica provided more consistent synergism when applied in mid-September but more consistent control when applied in late August. Imidacloprid is a better synergist for entomopathogenic nematodes than clothianidin. Imidacloprid-nematode combinations are more effective against second instars than against third instars, allowing rate reductions of both agents to make this approach more competitive with full-rate applications of neonicotinoid alone.

Comparison of neonicotinoid insecticides as synergists for entomopathogenic nematodes

Abstract In previous greenhouse and field studies, the neonicotinoid insecticide imidacloprid and the entomopathogenic nematodes Heterorhabditis bacteriophora and Steinernema glaseri interacted synergistically against third-instars of the Japanese beetle, Popillia japonica , the oriental beetle, Exomala (= Anomala ) orientalis , and three masked chafer species, Cyclocephala hirta , C . pasadenae , and C . borealis (Coleoptera: Scarabaeidae). We tested whether this interaction would also occur with other neonicotinoids, primarily thiamethoxam. In laboratory, greenhouse and field experiments, imidacloprid provided stronger and more consistent synergism with nematodes than thiamethoxam. White grub mortality resulting from nematode–neonicotinoid combinations was synergistic/additive/antagonistic in 75/25/0% of our observations with imidacloprid and 37/42/21% of our observations with thiamethoxam. Neonicotinoid–nematode interactions varied with white grub species. Imidacloprid always interacted synergistically with nematodes against E . orientalis and P . japonica , whereas no enhancement occurred against Rhizotrogus majalis and Maladera castanea . Against E . orientalis , imidacloprid interacted synergistically with five nematode species, H . bacteriophora , H . megidis , H . marelatus , S . glaseri , and S . feltiae . Synergistic combinations of nematodes and a neonicotinoid insecticide could be used for curative treatments of white grub infestations, especially against E . orientalis and P . japonica . This combination may allow spot-treatment of turf areas that exceed damage thresholds, thereby limiting the environmental impact of the insecticide application.

Pharmacodynamic interaction of doxycycline and artemisinin in Plasmodium falciparum.

Parallel in vitro tests, assessing the inhibition of schizont maturation, were conducted with 31 fresh isolates of Plasmodium falciparum from Thailand, using artemisinin, doxycycline, and combinations of both. The activities of artemisinin and doxycycline are obviously not correlated. Both compounds showed consistent synergism at 50% effective concentration (EC(50)), EC(90), and EC(99) levels.

Synergistic effect between doxorubicin and a low dose of all-trans-retinoic acid in MCF-7 breast cancer cell line.

The effect of doxorubicin (DOX) used in combination with a low dose (10(-7) M) of all-trans-retinoic acid (tRA) was tested on MCF-7 breast carcinoma cell line. Both drugs are able to inhibit cell proliferation in these cells in a dose-dependent way. The combined treatment with DOX and tRA was more effective in inhibiting cell growth than each of the two compounds alone. This was evidenced in the following experimental conditions: pre-treatments with tRA, for 72 h or 18 h, before DOX incubation; post-treatment with tRA for 18 h after DOX incubation. A consistent synergism was reached by 72 h pre-treatment with tRA and also with brief pre- and post-treatments, but only if tRA was also present during DOX incubation (co-treatments). The mechanisms involved in this interaction between chemotherapeutics and differentiating agents are as yet unclear and should be evaluated further.

Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro.

Utilizing a microplate ATP bioluminescence assay, two human breast carcinoma cell lines, MCF-7 and MDA-MB-231, were tested against doxorubicin (DOX), cisplatin (DDP), and paclitaxel (Tx) alone and in combination with ascorbic acid (Vit C). In both cell lines, Vit C exhibited cytotoxic activity at high concentrations (i.e. 10(2)-10(3) microM). Both cell lines also were resistant to DOX. MCF-7 was found to be DDP-resistant, MDA-MB-231 was moderately sensitive to DDP. Both cell lines were strongly sensitive to Tx. Vit C both at non-cytotoxic (1 microM) and moderately cytotoxic concentrations (10(2) microM) improved the cytotoxicity of DOX, DDP, and Tx significantly. Combination effects between Vit C and DDP or Tx were partly synergistic and partly additive or subadditive whereas a consistent synergism was found between Vit C and DOX. The mechanisms by which Vit C potentiates the cytostatics studied are yet unclear and should be evaluated further.

The Effect of Anticancer Drug Sequence in Experimental Combination Chemotherapy

A series of drug combination sequence studies was conducted in vitro using HEC-1A human endometrial carcinoma cells or 8226 myeloma cells. Four drugs were evaluated for schedule-dependent and sequence-dependent inhibition of human tumor colony formation in soft agar. Six different two-drug combinations were analyzed using the median dose effect method, and three different three-drug combinations were examined using the cumulative surviving fraction method. The results show that the specific sequence and method of drug exposure significantly influenced the production of antagonistic, additive, or synergistic cytotoxicity patterns. Drug combinations that were consistently synergistic included bleomycin or mitomycin C and cisplatin in 8226 cells, and etoposide plus bleomycin in human endometrial cancer (HEC-1A) cells. Most other two-drug combinations of bleomycin, etoposide, cisplatin, and mitomycin C were antagonistic in vitro, irrespective of the sequence of exposure. Among the three-drug combinations tested, consistent synergism was noted with cisplatin, etoposide, and bleomycin when either of the latter two agents was tested as a continuous exposure in vitro. Within individual two- and three-drug combinations, it was possible to observe synergism, additivity, or antagonism based on the particular exposure sequence tested. These results suggest that antitumor agent cytotoxicity in vitro can be radically influenced by the sequence of drug administration, a feature commonly overlooked in many clinical combination drug regimens.

Synergistic Infectivity of Highly and Minimally Infectious Clones of Human Immunodeficiency Virus In Vitro

To explore the biologic significance of the presence of a heterogeneous human immunodeficiency virus (HIV) population within infected individuals with regard to ultimate disease progression, the effect of coinfection of more than one variant of HIV on infectivity and cytopathogenicity in CD4-positive cells was examined. Using the lowest and highest infectious clones of HIV obtained by the plaque-cloning method, a clear consistent synergism of infectivity and cytopathic effects was detected when different cell lines were coinfected with a mixture of the two clones. These data suggest that the emergence of a highly infectious variant of HIV due to mutation may modify the infectivity of a minimally infectious latent variant with the final progression of HIV infection to overt AIDS.

Potentiation of immunosuppressive effects of cyclosporin A by 1α,25-dihydroxyvitamin D 3

Both cyclosporin A (CsA) and 1α,25-dihydroxyvitamin D 3 (vitamin D 3) inhibit T-cell functions. Because CsA has a dose-related systemic toxicity, there is a need for approaches by which the dosage of CsA could be reduced while maintaining the required immunosuppression. Therefore, we examined for any potentiating effect of vitamin D 3 on CsA-induced suppression of T cell functions in vitro. Peripheral blood mononuclear cells were stimulated with phytohemagglutinin in the presence or absence of various concentrations of CsA (1.6–13.2 μg/ml) or vitamin D 3 (10 −10–10 −7 M) or both together and [ 3H]thymidine incorporation (TdR), interleukin 2 (IL-2) production, IL-2 receptor (IL-2R) expression, and the response to exogenous recombinant IL-2 (rIL-2) on TdR were measured. IL-2 production was measured on CTLL cell line and IL-2R expression with anti-Tac monoclonal antibody using FACScan. There was a dose-dependent inhibition of TdR, IL-2 production, and IL-2R expression by CsA. Vitamin D 3 inhibited TdR and IL-2 production in a dose-dependent manner but had no significant ( P > 0.1) effect on IL-2R expression. Recombinant IL-2 had no effect on CsA-induced inhibition of TdR, whereas rIL-2 completely reversed the vitamin D 3-induced inhibition of TdR. A significantly ( P < 0.05) increased inhibition of TdR and IL-2 production was observed when two agents were used together as compared to expected inhibition by the addition of each agent separately. A consistent synergism was observed between all concentrations of CsA used and vitamin D 3 (10 −8 and 10 −7 M). This study shows that the potentiation of immunosuppressive effects of CsA by vitamin D 3 could be used as an approach to reduce the dosage of CsA in clinical use without compromising immunosuppression, thus preventing or minimizing the dose-related toxic effects of CsA.

Different sites of membrane action for tetrodotoxin and lipid-soluble anesthetics.

1. To examine whether different local anesthetics act on different or similar sites in the nerve membrane, the effects of combinations of lipid-soluble anesthetics and tetrodotoxin (TTX) were studied on the compound action potential of the frog sciatic nerve. 2. The nerve-blocking potency of TTX was potentiated 5-fold by benzyl alcohol and 10-fold by lidocaine, at concentrations of these latter two drugs which were just barely anesthetic; no such synergism occurred between saxitoxin (STX) and TTX, their combined effect being merely additive. 3. Simple additive effects also occurred between benzyl alcohol and phenol, benzyl alcohol and urethane, as well as lidocaine with a spirosuccinimide, RAC 109 II. 4. Synergism occurred between STX and 2-aminobenzimidazole. 5. A small but consistent synergism occurred between lidocaine and benzyl alcohol. 6. It is concluded that uncharged anesthetics, tertiary amines, and TTX act via different membrane binding sites which are all closely associated with the Na+ conductance channels.