Synergy最新文献

Recent publication evidenced about rationality and efficacy of combinatory therapy of antibiotic resistance, diabetes, obesity, cancer, viral infections, inflammatory bowel disease, etc. The combination of nutrients and pharmaceuticals has a good chance of contributing to a modern strategy of multi-target drug discovery. Different approaches and methods for the investigation of combinatory modes of action can be roughly classified into: in vitro, in vivo, in silico and in clinic. There is no true "gold standard" method that can be used uniformly to detect and quantify combinatory modes of action in pharmacology. Different methods of testing for synergism can sometimes produce different conclusions for the same combination. Great efforts in the translation of in vitro and in vivo results into clinical benefits of combinatory modes of action of nutrients and pharmaceuticals are compulsory.

The unified theory of the median-effect equation (MEE) of the mass-action law (MAL) indicates that dose and effect are interchangeable, and all dose-effect curves can be transformed into straight-lines by the median-effect plot. Therefore, it allows pharmacodynamics (PD) analysis using small size experimentation for in vitro and in vivo studies. Further, extension of MEE has proven that the Combination Index Equation (CIE) which defines Synergism (CI < 1), Additive Effect (CI = 1) and Antagonism (CI > 1), can be automatically simulated by CompuSyn software within one second after data entries. With adequate experimental accuracy of measurements, the minimum number of only 10 data points are required for quantitative synergy determination in two-drug combinations, even in animals or in clinical trials. Three articles introducing the CI method (in 1984), the review (2006), and the perspectives (2011) have been well recognized and cited 5516, 2382, and 1701 times in 1117, 768 and 530 biomedical journals, respectively (as of 2.10.2018) [Google Scholar Citations- Ting-Chao Chou]. However, the academic societies and governmental regulatory agencies are still lack of guideline on synergy definition, despite over 20 arbitrary, non-quantitative synergy definitions are still applied and reported. As drug combination is the most widely used therapies for the most dreadful diseases such as cancer and AIDS, a call for open forum on scientific credibility and accountability in these matters is warranted.

Synergy is a phenomenon of life. It has been observed that combinatory treatments may achieve more stable “network responses’’ than single drugs. Drug combination treatments are routinely applied in an increasing number of disciplines in medicine. Single drug treatments are less effective than drug combinations in complex treatment regimes. Plant derived herbal drugs or phytopharmaceuticals can be considered a natural “model” for combinatory treatments. Specific compositions of multi-component mixtures represent combined actions of single substances. Ayurveda, the traditional medicine of India has played an important role in disease management and health for many centuries, their present frequent use is challenged by the necessity to determine their complex composition and their multitarget mode of action. Ancient Ayurvedic literature like Sarangadhar Samhita focuses on the idea of synergy or ‘samyoga’. Network pharmacology research focuses on excellent systems biology techniques like protein interaction, genomic expression and mRNA expression data, which are employed to gain insight into the mechanism of action (MoA) prediction and validation. The following brief review provides valuable perspective regarding the bridge of Ayurveda and synergy research using network pharmacology as the tool to understand the molecular combination mechanism.

Background

Airway mucus hypersecretion is the typical feature of COPD and asthma. Hypersecretion is caused by reactive oxygen species (ROS) and links the COPD-bronchitis phenotype to frequent exacerbations. Since the monoterpene 1,8-cineole is known for its secretolytic activity, we studied the antioxidant activity of 1,8-cineole.

Methods

Using a culture model of fetal calf serum (FCS)-stimulated human monocytes, we determined the effects of 1,8-cineole, at therapeutic concentrations (10⁻¹⁰–10⁻⁵ M) on superoxide anions (O₂⁻), superoxide dismutase (SOD), hydrogen peroxide (H₂O₂) and of LPS-stimulated 8-isoprostanes (8-IsoP) and TNF-α. The effect of formoterol (F), budesonide (BUD), BUD + F without and with 1,8-cineole were determined on O₂⁻-release.

Results

1,8-cineole (10⁻⁵ M) strongly inhibited O₂⁻ (−53%, p < 0.001), partially inhibited SOD (−28%, p = 0.0039) and inhibited H₂O₂ in an undulating manner at 10⁻¹⁰ M (−48%, p = 0.0274), while total cellular antioxidant activity as determined by inhibition of 8-IsoP increased dose-dependently from 10⁻⁶ M (−42%, p = 0.0288) to 10⁻⁵ M (−84%, p < 0.0001) comparable to TNF-α. Only weak antioxidant and, at higher concentrations, even pro-oxidant effects were detectable for F and BUD, respectively, but no pro- or antioxidant effects of F + BUD. The antioxidant effects of 1,8-cineole were not substantially influenced during co-incubation with F + BUD.

Conclusions

We report an inhibition of superoxide anions, balancing partial dismutation of superoxide anions and independent inhibition of H₂O₂ by 1,8-cineole. These results suggest a non-specific combined, antioxidant and anti-inflammatory mode of action of 1,8-cineole as bifunctional drug for further clinical evaluation in mild to severe COPD and as adjunctive therapy to control disease progression.

Background

Curcumin (CUR) is a well established cardioprotective phytoconstituent, but the poor bioavailability associated with it is providing a scope to do further research to improvise therapeutic efficacy of CUR. The present study was designed to address this challenge by combining with bio-enhancer like Quercetin (QUE) against ischemia reperfusion injury (IRI) induced myocardial toxicity in rats.

Materials and Methods

Rats (n = 8) were treated with CUR (200 mg/kg, p.o.) alone and combination of CUR (200 mg/kg, p.o.) and QUE (10 mg/kg, p.o.) for 30 days. Twenty four hour after last treatment Ischemia reperfusion injury was induced by modified Lagendorff apparatus, and the effect of different treatments was evaluated by percentage recovery in terms of heart rate and developed tension, biomarkers, heart tissue antioxidant levels and histopathological examination. Influence of QUE on pharmacokinetic of CUR was studied by HPLC method. Results obtained were assessed by one‑way analysis of variance followed by Tukey–Karmer multiple comparison test.

Results

CUR and QUE demonstrated significant myocardial potency compared to CUR alone‑treated group. Significant increase in bioavailability and half life, along with significant decrease in clearance was observed for CUR in combination group compared to CUR alone treated group.

Conclusion

From this study it can be concluded that combination of CUR and QUE exhibited profound protection compared to CUR alone treated group against IRI induced myocardial toxicity. Findings of pharmacokinetic interaction justified the results of pharmacodynamic interaction.

There are many efforts to diminish risks associated with the use of cancer chemotherapeutic agents through design and utilization of new strategies including gene therapy. We previously showed knockdown of dff45 or overexpression of dff40, the important apoptosis regulators, resulted in enhanced sensitization of cancer cells to chemotherapeutic agents. Here we show that pre-treatment with dff45-siRNA additively increased the overall cytotoxic effects of methotrexate (MTX), at its partially safe concentration (30 μM with almost 37% of killing potency), up to 85%. This is approximately 51% greater than MTX treatment, and about 20% greater than siRNA treatment alone. The main mechanism of cell death by MTX treatment was through AIF-induced caspase-independent apoptosis, as well as the less common Atg5 and DRAM-induced apoptosis. Investigation of apoptosis with dff45-siRNA treatment showed the canonical caspase-dependent apoptosis as the main mechanism of cell death. This was also true for MTX+siRNA treatment. We did not observe a sharp increase in expression of autophagy genes in cells incubated with dff45-siRNA. However, treatment with MTX+siRNA may trigger autophagy via an Atg5-independent pathway.

Dietary supplementation with omega-3 fatty acids have been advocated because of the global preference for the omega-6 fatty acids - rich Western style diet. The study investigated the effects of omega-3 fatty acids (combination of N-3: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); EPA/DHA ratio = 3/2) compared to livolin (Phosphatidylcholin + vitamins) on biochemical and haematological parameters in diclofenac (DF) - induced hepatotoxicity in male Wistar rats. Twenty five rats were used. They were divided into 5 groups (n = 5) which included: Group 1-Control (untreated); Group 2-DF control; Group 3-DF + Low N-3; Group 4-DF+High N-3; and, Group 5-DF + Livolin. Group 2 received DF at 10 mg/kg b.w. (i.m.) during the first 7days of the experiment, thereafter; they were administered distilled water (0.1 ml) for three weeks. Groups 3, 4, and 5 were pre-treated with DF during the first 7days of the experiment, afterwards, they were post-treated with N-3 and livolin at 100, 300, and 5.2 mg/kg b.w. (p.o.) respectively for 21days.The results showed that DF caused significant increases in MDA, LDH, proinflammatory markers, ALT, AST, and ALP activities, but, significant decreases in antioxidant indices. However, post-treatment with N-3 or livolin corrected these deviations. Although there was evidence of the dose dependent effects of N-3, the high dose was not always the most effective. The histological results proved that livolin has a more hepatoprotective action than N-3, although the biochemical and haematological findings attested that both therapies have comparable effects. It was concluded that livolin proffers a more protective effect than N-3 in DF-induced hepatotoxicity.

Background

The assessment of the potential significance of synergistic interaction between adverse ecological factors acting together at the level of intensities found in the biosphere is still intriguing and unresolved problem.

Objective

This study aims to analyze synergistic effects for various biological objects, tests, and interacting agents to provide conclusive evidence of possible synergistic interactions of natural intensities of environmental factors on cell growth.

Methods

Four dose-effect curves were obtained for each object and interacting factors: after the individual action of agents, after their simultaneous action and theoretically expected curve after independent addition of the effects produced by each agent. The synergistic enhancement ratio (SER) and its dependence on intensities of agents were quantitatively estimated based on these curves.

Results

The extent of synergistic interaction was shown to be dependent on the intensity of physical factors or concentration of chemicals in such a manner that there were optimal conditions at which the greatest synergy may be achieved. The lesser the intensity of one of the agents applied, the smaller intensity of another agent has to be used to provide the highest synergistic interaction. In investigations where SER > 1, CI < 1.

Conclusion

The existence of optimal conditions providing the greatest synergistic effect and its dependence on the intensity of applied agents was demonstrated. Common patterns were identified. It is concluded that synergistic interactions are important for the evaluation of biological consequences and risk assessment from combined effects at low intensities of ionizing radiation, UV-light, electromagnetic fields, or small concentration of chemicals.