Interaction of antivirals with a heptameric bundle model of the p7 protein of hepatitis C virus

A series of ligands are known experimentally to affect the infectivity cycle of the hepatitis C virus. The target protein for the ligands is proposed to be p7, a 63 amino acid polytopic channel‐forming protein, with possibly two transmembrane domains. Protein p7 is found to assemble into functional oligomers of various sizes, depending on the genotype (GT). Nine ligands are docked to various sites of a computationally derived heptameric bundle of p7 of GT1a. The energy of interaction, here binding energy, is calculated using three different docking programs (Autodock , MOE , LeadIT ). Three protein regions are defined to which the ligands are placed, the loop region and the site with the termini as well as the mid‐region which is supposed to track poses inside the putative pore. A common feature is that the loop sites and poses either within the pore or at the intermonomer space of the bundle are preferred for all ligands with proposed binding energies smaller than −10 kJ/mol. BIT225, benzamine, amantadine, and NN‐DNJ show good overall scoring.     

Considerations in establishing bioequivalence of inhaled compounds

Introduction: Generic inhalers are often perceived as inferior to their branded counterparts; however, they are safe and effective if they can meet the regulatory requirements. The approach to assess bioequivalence (BE) in oral dosage form products is not sufficient to address the complexities of inhalational products (e.g., patient-device interface); hence, more considerations are needed and caution should be applied in determining BE of inhaled compounds.

Areas covered: This review outlines the evaluation process for generic inhalers, explores the regulatory approaches in BE assessment, and highlights the considerations and challenges in the current in vitro and in vivo approaches (lung deposition, pharmacokinetic, pharmacodynamic/clinical studies, and patient-device interface) for establishing BE of inhaled compounds.

Expert opinion: The ultimate goals in this field are to establish uniformity in the regulatory approaches to speed the drug submission process in different regions, clear physicians’ misconception of generic inhalers, and have meaningful clinical endpoints such as improvement in patient quality of life when compared to placebo and brand name drugs. As inhalational drugs become more common for other indications such as antibiotics, the technologies developed for inhaled compounds in the treatment of chronic pulmonary diseases may be extrapolated to these other agents.     

Analysis of electrocautery smoke released from the tissues frequently cut in orthopedic surgeries

BACKGROUND Electrosurgical smoke could be different by the device of cutting or the type of tissue that is being cut.AIM To analyze the electrocautery smoke released from the tissues that are frequently cut in orthopedic surgeries.METHODS The released smoke from electrocautery of five different tissue types(meniscus,ligament,adipose,muscle,and synovium) of five patients who underwent total knee arthroplasty were collected and analyzed for volatile organic compounds(VOCs) and 27 candidate polycyclic aromatic hydrocarbons(n = 25).Surgical smoke was produced with an electrocautery device for 4 min.RESULTS None of the 27 evaluated polycyclic aromatic hydrocarbons compounds were detectable in electrocautery smoke collected from the surgical cutting of the different tissues.The number and identity of detected VOCs were similar between the patients but not between tissue types.The number of detected VOCs was the highest in synovial tissue(n = 21) and the lowest in the meniscus and adipose tissue(n = 12).The number of toxic and/or carcinogenic VOCs were the most in the muscle and meniscus tissues(Toluene,Ethylbenzene,and Styrene).No toxic and/or carcinogenic VOCs were identified in the ligament and adipose tissue.CONCLUSION Meniscus and muscle tissue are associated with the highest number of toxic and/or carcinogenic VOCs.Therefore,we recommend that surgeons avoiding the electrocautery of these tissues.     

Analytical methodology optimization to estimate the content of non-flavonoid phenolic compounds in Argentine propolis extracts

Context: Traditionally, the content of total phenolics (flavonoid phenolics (FP) and non-flavonoid phenolics (NFP)) and flavonoids (flavone/flavonol and flavonone/dihydroflavonol) in propolis has been determined by different methodologies. Until now, the percentage of total phenolic (TP) compounds that corresponds to FP and NFP, expressed in the same units by a spectrophotometric method, has not been determined.

Objective: The current study proposes a quick and simple methodology that separates FP and NFP in propolis samples and determines TP, FP, and NFP by the same method.

Materials and methods: Propolis samples from five Argentine provinces (Tucumán, Santiago del Estero, Salta, Misiones, and Jujuy) were used. Extraction of TP from the propolis samples was carried out by maceration with 80% ethanol and quantified by Folin–Ciocalteu reagent (FC-R). Then, FP was precipitated with formaldehyde in acid medium. After centrifugation, NFP were determined in the supernatant using FC-R. FP content was calculated as the difference between the content of TP and NFP. The method was also validated using commercial flavonoids and chalcones.

Results: FP recovery in all experiments was between 85.95% and 98.29%. Propolis from Tucumán had significantly higher amounts of total phenols than propolis from other provinces. SE5 showed higher content of FP (81.52%) followed by SA1 (74.75%). The propolis from TUC4, SA4, SE3, and MI showed the lowest FP content and highest content of NFP.

Conclusions: This method provides a simple, reliable, and specific spectrophotometric assay to estimate the content of NFP, FP, and TP in propolis samples.     

Mechanism and Site of Inhibition of AMPA Receptors: Pairing a Thiadiazole with a 2,3-Benzodiazepine Scaffold

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Network pharmacology-based strategy for predicting therapy targets of Tripterygium wilfordii on acute myeloid leukemia

This is a study on the potential therapeutic targets and pharmacological mechanism of Tripterygium wilfordii (TW) in acute myeloid leukemia (AML) based on network pharmacology.Active components of TW were obtained by network pharmacology through oral bioavailability, drug-likeness filtration. Comparative analysis was used to investigate the overlapping genes between active ingredient''s targets and AML treatment-related targets. Using STRING database to analyze interactions among overlapping genes. Both KEGG pathway analysis and Gene Ontology enrichment analysis were conducted in DAVID. These genes were analyzed for survival in OncoLnc database.We screened 53 active ingredients; the results of comparative analysis showed that 8 active ingredients had an effect on AML treatment. On the basis of the active ingredients and overlapping genes, we constructed the Drug-Compounds-Genes-Disease Network. Survival analysis of overlapping genes indicated that some targets possessed a significant influence on patients’ survival and prognosis. The enrichment analysis showed that the main pathways of targets were Toll-like receptor signaling pathway, NF-kappa B signaling pathway, and HIF-1 signaling pathway.This study, using a network pharmacologic approach, provides another strategy that can help us to understand the mechanisms by which TW treats AML comprehensively.     

Anticancer properties of novel pyrazole‐containing biguanide derivatives with activating the adenosine monophosphate‐activated protein kinase signaling pathway

Biguanides, including metformin and phenformin, have emerged as promising anticancer agents. However, the high dose needed for their efficient anticancer properties restricts their clinical application. In an attempt to obtain higher active compounds than these parent compounds, pyrazole‐containing biguanide derivatives were synthesized and screened for in vitro cytotoxicity against human cancer cell lines. Clonogenic assays and scratch wound healing assays demonstrated that these new derivatives profoundly inhibit cell proliferation and migration. Compounds 10b and 10d exhibited strong potency with low IC₅₀ values in the range of 6.9‐28.3 μM, far superior to phenformin and metformin. Moreover, 20 μM 10b and 10d resulted in 72.3‐88.2% (p < 0.001) inhibition of colony formation and 29.3‐60.7% (p < 0.05) inhibition of cell migration. Mechanistically, 10b and 10d activated adenosine monophosphate‐activated protein kinase, leading to inactivation of the mammalian target of rapamycin (mTOR) signaling pathway with the regulation of 4EBP1 and p70S6K. These results suggest the value of these novel biguanide derivatives as candidates with therapeutic potential for the treatment of bladder and ovarian cancer.     

Study on combined effects of blanching and sonication on different quality parameters of carrot juice

This study was conducted to evaluate the combined effects of blanching and sonication on carrot juice quality. Carrots were blanched at 100?°C for 4?min in normal and acidified water. Juice was extracted and sonicated at 15?°C for 2?min keeping pulse duration 5?s on and 5?s off (70% amplitude level and 20?kHz frequency). No significant effect of blanching and sonication was observed on Brix, pH and titratable acidity except acidified blanching that decreased pH and increased acidity significantly. Peroxidase was inactivated after blanching that also significantly decreased total phenol, flavonoids, tannins, free radical scavenging activity, antioxidant capacity and ascorbic acid and increased cloud and color values. Sonication could improve all these parameters significantly. The present results suggest that combination of blanching and sonication may be employed in food industry to produce high-quality carrot juice with reduced enzyme activity and improved nutrition.