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Conventional chemotherapeutic drugs are used for cancer management, but recently nanoparticles have also been shown to contribute towards controlling cancer cell proliferation. In the present study, we focussed on analyzing the combinatorial effect of Cerium oxide (CeO 2) nanoparticles and Doxorubicin (Dox) on melanoma cancer cells in vitro and in vivo. We entrapped CeO 2 , Dox, and CeO 2 +Dox in a hybrid polymer matrix of alginate and chitosan (Alg-Cs) and used them in both in vitro and in vivo studies to compare their anticancer effect. Scratch assay using A549 lung cancer cells showed delayed wound healing when exposed to a low and high dose of CeO 2 +Dox, compared to individual components. In order to determine a safe dose of the nanoformulations, zebrafish embryos were used. Further, i n vivo, testing was done on Swiss albino female mice where the melanoma was induced by applying Benzopyrene followed by UV irradiation. The animals were treated with CeO 2 , Dox, and CeO 2 + Dox that were entrapped in Alg-Cs for further 21 days. From both in vivo and in vitro results, we concluded that CeO 2 and Dox in combination had superior therapeutic efficiency in cancer cells and animals than the nude drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

The fattening technology of shelf cattle is widely used in most beef cattle farms at present. It has the advantages of improving beef quality, reducing feed cost, shortening fattening time and gain weight quickly. However, some farms still have problems such as waste of feed resources and low daily gain of beef cattle, which seriously affect the breeding efficiency. The article summarizes the research progress of roughage processing and combination, the preparation and application of shelf cattle total mixed ration and stage feeding mode, to provide reference for the relevant research and practical production application of shelf cattle total mixed ration preparation and stage fattening.' [ABSTRACT FROM AUTHOR]

The study aims to explore the combinatorial effect of naringin with antibiotics, ciprofloxacin and tetracycline on Pseudomonas aeruginosa biofilms. The antibiofilm efficacy of selected treatment regimes against P. aeruginosa biofilm were quantified by crystal violet assay, MTT assay, Congo red binding assay, and were visualized by confocal laser scanning microscopy and scanning electron microscopy. All the assays reflected antibiofilm activities, however, combinatorial performances of naringin with antibiotics were found to be more significant. A significant reduction in swimming and swarming motilities along with pellicle formation and altered colony morphology were observed as a result of combinatorial effect. The cytotoxicity of naringin and its antibiotic combinations was assayed on murine macrophage cell line. The applicability of such combinations was tested for their relative eradication against pre-formed biofilm on urinary catheter surface. This finding indicated that naringin potentiates the efficacy of both ciprofloxacin and tetracycline on P. aeruginosa biofilm in comparison to their solo treatment. The finding would help to open hitherto unexplored possibilities of establishing naringin as a potential antibiofilm agent and suggest on the possibility of its use in drug-herb combinations for managing biofilm-associated bacterial infections.

Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.

Object: To compare the molecular activity of curcumin and resveratrol on selected breast cancer protein receptors and to investigate their combination for synergism against human breast cancer MCF-7 cell line. Method: Curcumin and resveratrol were subjected to insilico docking studies using glide to investigate the drug activity against HER2, human oestrogen receptor, ERBB2, epidermal growth factor tyrosine protein kinase C-SRC, and HSP90 proteins. MTT assay was used to assess cell viability of curcumin and resveratrol individually and in combination at 1:1,1:3 and 3:1 ratio respectively. Results: The insilico study revealed good glide score and glide energy for these drugs against breast cancer protein. Curcumin and resveratrol has more binding affinity for proteins with varying amino acid interaction sites. IC50 for curcumin and resveratrol was observed to be 21.29 and 38.30 µg/ml respectively. IC50 for the combined treatment with curcumin and resveratrol at the ratio of 1:1,1:3 and 3:1 were observed to be 28.06, 15.20 and 8.29 µg/ml respectively. Combined treatment of curcumin and resveratrol at equal ratio exhibited additive effects while at the ratio of 1:3 and 3:1 exhibited a strong synergistic effect on the cytotoxicity of MCF-7 cell line. Conclusion: Insilico docking analysis helped in identifying and organizing the structural similarity/diversity at the molecular level activity of curcumin and resveratrol. In vitro cell line study provides an insight into the potential application of curcumin and resveratrol codelivery for the chemoprevention and treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Objective To compare cytotoxicity and genotoxicity of novel urethane-based monomer FIT-852 and monoacylphosphine oxide photoinitiator (Lucirin TPO) with conventional Bisphenol A-glycidyl-methacrylate (BisGMA) and triethylene glycol dimethacrylate (TEGDMA) monomers and camphorquinone (CQ)/amine photoinitiator system, respectively. Moreover, we quantified and analyzed the combinatorial effects of individual substances in resin-based mixtures concerning the nature of the combinatorial effects. Methods Cytotoxic and genotoxic effects of BisGMA, FIT, TEGDMA, CQ, DMAEMA and TPO and their combined toxicity in four clinically relevant mixtures (FIT/TPO, FIT/CQ, BisGMA/TPO, BisGMA/CQ) were tested on human fetal lung fibroblasts MRC-5 using MTT and Comet assays. We assessed combination effects of monomers and photoinitiators on overall toxicity from the measured concentration-effect relationships. Combination index (CI) was calculated on the basis of the median-effect equation derived from the mass-action law principle. Results Individual substances showed decreasing cytotoxic effects in the following order: BisGMA>TPO>FIT>CQ>DMAEMA>TEGDMA. Experimental mixtures showed decreasing cytotoxic effects in the order BisGMA/TPO>BisGMA/CQ>FIT/CQ>FIT/TPO. FIT-based mixtures exhibited antagonistic cytotoxic effects between components while BisGMA-based mixtures demonstrated synergistic effects at ED 50. TPO amplified both antagonistic and synergistic cytotoxic effects in mixtures. Pure substances showed genotoxicity in the following order: TPO>BisGMA>FIT>CQ>TEGDMA. We did not detect the genotoxic potential of DMAEMA. The rank of genotoxic concentrations of the mixtures was: BisGMA/TPO>BisGMA/CQ>FIT/CQ>FIT/TPO. Significance Lower cytotoxicity and genotoxicity of FIT than BisGMA suggests its greater biocompatibility. Conversely, photoinitiator TPO was significantly more cytotoxic and genotoxic than both CQ and DMAEMA. CI values showed that components of FIT-based mixtures exhibit an antagonistic cytotoxic effect, while compontents of BisGMA-based mixtures show synergism. [ABSTRACT FROM AUTHOR]

The specific sensitivity of different organisms, cells, and tissues against chemicals, the huge number of produced and applied substances, and the combinatorial explosion of effects by the combination of substances demand new concepts for the efficient determination of toxicological dose/response relations. The generation, processing, and characterization of microdroplets of different chemical compositions enable microfluidic approaches to offer a very promising strategy for strongly miniaturized toxicological screenings. Over the last decade, several developments demonstrated the applicability of droplet-based microfluidic systems for toxicological studies. We review the current state of developments in microfluidics for toxicological applications. These have become powerful alternatives to microtiter plates and are very promising for replacing the standard methods in many fields. This article will focus on toxicological dose/response screenings with the variation of droplet composition, particularly on the possibility of generating 'concentration spaces,' as well as on the applied sensing principles of organisms and cells inside the microdroplets. [ABSTRACT FROM AUTHOR]

The recent emergence of antimicrobial resistance has become a major concern for worldwide policy makers as very few new antibiotics have been developed in the last twenty-five years. To prevent the death of millions of people worldwide, there is an urgent need for a cheap, fast and accurate set of tools and techniques that can help to discover and develop new antimicrobial drugs. In the past decade, microfluidic platforms have emerged as potential systems for conducting pharmacological studies. Recent studies have demonstrated that microfluidic platforms can perform rapid antibiotic susceptibility tests to evaluate antimicrobial drugs’ efficacy. In addition, the development of cell-on-a-chip and organ-on-a-chip platforms have enabled the early drug testing, providing more accurate insights into conventional cell cultures on the drug pharmacokinetics and toxicity, at the early and cheaper stage of drug development, i.e., prior to animal and human testing. In this review, we focus on the recent developments of microfluidic platforms for rapid antibiotics susceptibility testing, investigating bacterial persistence and non-growing but metabolically active (NGMA) bacteria, evaluating antibiotic effectiveness on biofilms and combinatorial effect of antibiotics, as well as microfluidic platforms that can be used for in vitro antibiotic toxicity testing.

Variation in genes encoding retinoid acid-inducible gene I (RIG-I)-like receptors (RLRs) has been implicated in the pathogenesis of autoimmune disorders. We investigated if polymorphisms in the IFIH1 , RIG - I , LGP2 and VISA genes influence the risk for multiple sclerosis (MS) in a German case–control cohort comprising 716 patients and 706 controls. Evaluation of 18 single nucleotide polymorphisms (SNPs) in the four genes did not reveal significant single-SNP associations with MS risk, but two VISA polymorphisms were modestly associated with age of onset. Further, we provide initial evidence for combinatorial effects of polymorphic variants in the RIG - I , LGP2 and IFIH1 genes on MS risk. [ABSTRACT FROM AUTHOR]

Fluconazole (FLCZ) is a first-line drug for treating Candida albicans infections, but clinical failure due to reduced sensitivity is a growing concern. Our previous study suggested that certain drug combinations pose a particular challenge in potently reducing FLCZ's anti- C. albicans activity, and cyclooxygenase inhibitors formed the major group of these attenuating drugs in combination with FLCZ. In this study, we examined the effects of diclofenac sodium (DFNa) and related compounds in combination with FLCZ against C. albicans , and investigated their possible mechanisms of interaction. DFNa, ibuprofen, and omeprazole elevated the minimum inhibitory concentration (MIC) of FLCZ by 8-, 4-, and 4-fold, respectively; however, loxoprofen sodium and celecoxib did not. An analogue of DFNa, 2,6-dichlorodiphenylamine, also elevated the MIC by 4-fold. Gene expression analysis revealed that diclofenac sodium induced CDR1 efflux pump activity, but not CDR2 activity. In addition, an efflux pump CDR1 mutant, which was manipulated to not be induced by DFNa, showed less elevation of MIC compared to that shown by the wild type. Therefore, DFNa and related compounds are potent factors for reducing the sensitivity of C. albicans to FLCZ partly via induction of an efflux pump. Although it is not known whether such antagonism is relevant to the clinical treatment failure observed, further investigation of the molecular mechanisms underlying the reduction of FLCZ's anti- C. albicans activity is expected to promote safer and more effective use of the drug. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aim of the present study was to analyze in vitro the combinatorial effects of the antibiotic combination of amoxicillin plus metronidazole on subgingival bacterial isolates. Design: Aggregatibacter (Actinobacillus) actinomycetemcomitans, Prevotella intermedia/nigrescens, Fusobacterium nucleatum and Eikenella corrodens from our strain collection and subgingival bacteria isolated from patients with periodontitis were tested for their susceptibility to amoxicillin and metronidazole using the Etest. The fractional inhibitory concentration index (FICI), which is commonly used to describe drug interactions, was calculated. Results: Synergy, i.e. FICI values≤0.5, between amoxicillin and metronidazole was shown for two A. actinomycetemcomitans (FICI: 0.3), two F. nucleatum (FICI: 0.3 and 0.5, respectively) and one E. corrodens (FICI: 0.4) isolates. Indifference, i.e. FIC indices of >0.5 but ≤4, occurred for other isolates and the 14 P. intermedia/nigrescens strains tested. Microorganisms resistant to either amoxicillin or metronidazole were detected in all samples by Etest. Conclusion: Combinatorial effects occur between amoxicillin and metronidazole on some strains of A. actinomycetemcomitans, F. nucleatum and E. corrodens. Synergy was shown for a few strains only. [Copyright &y& Elsevier]

The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naïve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an anti-viral state. After naïve DCs were exposed to either IFNβ or to paracrine signaling released by DCs infected by Newcastle disease virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naïve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies), we identified five cytokines (IFNβ,TNFα, IL-1β,TNFSF15, and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNβ, TNFα, and IL1β as the major contributors to this anti-viral state. This finding was supported by infection studies in vitro, by T-cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune, and immunosurveillance-related diseases. [ABSTRACT FROM AUTHOR]

Abstract: An emerging new class of targeted therapeutic molecules against the enzyme fatty acid amide hydrolase (FAAH) is a novel series of pyrrolo-1,5-benzoxa(thia)zepine compounds. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), is a tubulin depolymerizing agent displaying a proapoptotic activity in a variety of human tumor cell types, including those derived from both solid and hematological malignancies, with minimal toxicity towards normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines. The compound, used at doses equal to or greater than 1μM inhibits the proliferation of human CRC cell lines in a dose- and time-dependent manner, inducing a significant cell cycle arrest in the G2/M phase. DNA fragmentation assays and western blot analysis demonstrated that treatments prolonged over 48h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-3, caspase-9 and PARP. Moreover, nanomolar doses of PBOX-15, unable to cause microtubule depolymerization, significantly improved the oxaliplatin and 5-fluouracil-induced anti-proliferative effects in CRC cell lines. These results showed, for the first time, that PBOX-15 represents a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options. [Copyright &y& Elsevier]

The study aims to explore the combinatorial effect of naringin with antibiotics, ciprofloxacin and tetracycline on Pseudomonas aeruginosa biofilms. The antibiofilm efficacy of selected treatment regimes against P. aeruginosa biofilm were quantified by crystal violet assay, MTT assay, Congo red binding assay, and were visualized by confocal laser scanning microscopy and scanning electron microscopy. All the assays reflected antibiofilm activities, however, combinatorial performances of naringin with antibiotics were found to be more significant. A significant reduction in swimming and swarming motilities along with pellicle formation and altered colony morphology were observed as a result of combinatorial effect. The cytotoxicity of naringin and its antibiotic combinations was assayed on murine macrophage cell line. The applicability of such combinations was tested for their relative eradication against pre-formed biofilm on urinary catheter surface. This finding indicated that naringin potentiates the efficacy of both ciprofloxacin and tetracycline on P. aeruginosa biofilm in comparison to their solo treatment. The finding would help to open hitherto unexplored possibilities of establishing naringin as a potential antibiofilm agent and suggest on the possibility of its use in drug-herb combinations for managing biofilm-associated bacterial infections. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV. [ABSTRACT FROM AUTHOR]

The recent emergence of antimicrobial resistance has become a major concern for worldwide policy makers as very few new antibiotics have been developed in the last twenty-five years. To prevent the death of millions of people worldwide, there is an urgent need for a cheap, fast and accurate set of tools and techniques that can help to discover and develop new antimicrobial drugs. In the past decade, microfluidic platforms have emerged as potential systems for conducting pharmacological studies. Recent studies have demonstrated that microfluidic platforms can perform rapid antibiotic susceptibility tests to evaluate antimicrobial drugs' efficacy. In addition, the development of cell-on-a-chip and organ-on-a-chip platforms have enabled the early drug testing, providing more accurate insights into conventional cell cultures on the drug pharmacokinetics and toxicity, at the early and cheaper stage of drug development, i.e., prior to animal and human testing. In this review, we focus on the recent developments of microfluidic platforms for rapid antibiotics susceptibility testing, investigating bacterial persistence and non-growing but metabolically active (NGMA) bacteria, evaluating antibiotic effectiveness on biofilms and combinatorial effect of antibiotics, as well as microfluidic platforms that can be used for in vitro antibiotic toxicity testing.