The protective effects of silymarin nanoemulsion on 5-fluorouracil-induced gastrointestinal toxicity in rats

5-Fluorouracil (5FUra) is the third most popular chemotherapeutic component employed to treat solid tumors. In the present study, we aimed to appraise the silymarin (SM) and silymarin nanoemulsion (SMN) effect on 5FUra-induced gastrointestinal toxicity in adult male rats. A total of 30 male Wistar rats were divided into 6 groups including the control (Crl) group, and groups treated with SMN (5 mg.kg⁻¹), SM (5 mg.kg⁻¹), 5FUra + SMN (5 mg.kg⁻¹), and 5FUra + SM (5 mg.kg⁻¹) by IP injection for 14 days. And gastrointestinal toxicity was induced by a single intraperitoneal (IP) injection of 5FUra (100 mg.kg⁻¹) for the last group in the study. Treating rats with SM and SMN diminished elevating malondialdehyde (MDA) levels, and improved total antioxidant capacity (TAC) levels. Also, the intensity of mRNA expression of interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) caused by 5FUra in the gastrointestinal tissue tract, and macroscopic oral ulcerations decreased, ass well as weight loss was prevented, particularly in the SMN group. Moreover, in the microscopic scope, there were significant improvements in the levels of hyperemia, hyaline, and inflammatory cell infiltration in the tongue, esophagus, and intestinal tissues in the FUra + SMN and FUra + SM groups compared to 5FUra. Hence, treatment with SM and SMN reduced oxidative stress, histopathological degeneration, and gene expression of inflammatory markers in the gastrointestinal tract. According to the results, treatment with SM and SMN markedly decreases the gastrointestinal toxicity caused by 5FUra.     

Design, synthesis, and biological evaluation of novel 1, 2, 4-triazole derivatives as antifungal agent

A series of novel 1, 2, 4-triazole derivatives (9a?Cp) have been designed and synthesized as the potential antifungal agents. All compounds were characterized by ¹H-NMR, ¹³C-NMR, and LCMS. Their antifungal activities against seven human pathogenic fungi were evaluated in vitro by measuring the minimal inhibitory concentrations. Most of the tested compounds were found to be more potent against Candida albicans than the control drug fluconazole.     

Use of the index of ideality of correlation to improve predictive potential for biochemical endpoints

The CORAL software is a tool to build up quantitative structure-property/activity relationships (QSPRs/QSARs). The project of updated version of the CORAL software is discussed in terms of practical applications for building up various models. The updating is the possibility to improve the predictive potential of models using the so-called Index of Ideality of Correlation (IIC) as a criterion of the predictive potential for QSPR/QSAR models. Efficacy of the IIC is examined with three examples of building up QSARs: (i) models for anticancer activity; (ii) models for mutagenicity; and (iii) models for toxicity of psychotropic drugs. The validation of these models has been carried out with several splits into the training, invisible training, calibration, and validation sets. The ability of IIC to be an indicator of predictive potential of QSAR models is confirmed. The updated version of the CORAL software (CORALSEA-2017, http://www.insilico.eu/coral) is available on the Internet.     

Imaging Mass Spectrometry (IMS) for drug discovery and development survey: Results on methods,applications and regulatory compliance

Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.     

Design, synthesis, antimicrobial, anticancer evaluation, and QSAR studies of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones

A series of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones (1–17) was synthesized and tested in vitro for its antimicrobial and anticancer potentials. The biological screening results indicated that compounds having m-chloro substituent on benzaldehyde portion showed antimicrobial potential, whereas compounds having chloro, methoxy, and hydroxyl groups showed anticancer potential. The quantitative structure activity relationship (QSAR) studies indicated the importance of topological parameter, valence first order molecular connectivity index in describing antifungal activity. The developed QSAR models, however, were statistically insignificant with reference to anticancer activity of the synthesized compounds.     

Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of nicotinic acid benzylidene hydrazide derivatives

A series of nicotinic acid benzylidene hydrazide derivatives (1–18) was synthesized and tested in vitro for biological evaluations. The antimycobacterial activity results indicated that the presence of electron-withdrawing halogen groups at para position of the phenyl ring improved their activity. The results of antiviral evaluation depicted that none of the synthesized derivatives inhibited the replication of viruses at subtoxic concentration. Further, the antimicrobial screening results indicated that compounds having OCH₃ and NO₂ substituents were the most active ones. QSAR investigations revealed that multi-target QSAR models were effective in describing the antimicrobial activity.     

(Naphthalen-1-yloxy)-acetic acid benzylidene/(1-phenyl-ethylidene)-hydrazide derivatives: synthesis, antimicrobial evaluation, and QSAR studies

A series of (naphthalen-1-yloxy)-acetic acid hydrazides (1–36) was synthesized and screened, in vitro, for antibacterial, antifungal, and antiviral activities. The results of antiviral activity showed that none of the tested compounds was active against viruses at subtoxic concentrations. Further, the antimicrobial screening results demonstrated that compounds having 3,4,5-trimethoxy benzaldehyde (18), o-Br, p-CN (31), and m-NO₂ acetophenone (32) substituents were the most active ones against tested strains. QSAR investigations revealed that multi-target QSAR models were effective in describing the antimicrobial activity.     

An Evaluation of the Acute in Vivo Toxicity of Benzylidenechroman-4-Ones,L-Thiobenzylidenechroman-4-Ones and Benzylidenetetralones

ABSTRACT

A series of new compounds were evaluated for acute in vivo toxicity. Their synthesis ¹ and antifungal activity ² have previously been described by us. The naturally occurring class of compounds to which they belong—the benzylidenechroman-4-ones—have been identified as a potential source of new antifungal agents ³. These compounds were found to be less toxic, as judged by acute toxicity, than existing commercially available antifungals. A number of conclusions can be drawn about the relationship of structural changes in this series of compounds to increases or decreases in acute toxicity.     

The third intracellular loop of GPCRs: size matters

The third intracellular loop of G-protein-coupled receptors (GPCRs) shows remarkable diversity in sequence and overall length. Sadler and colleagues recently demonstrated that this domain acts as an 'autoregulator' of receptor activity and that its length contributes to receptor/G-protein coupling selectivity. These observations may prove useful for developing novel therapeutics.     

The end of the beginning in understanding SLC22 polyspecificity

SLC22 transporters involved in drug elimination and organ distribution are polyspecific. Now, the first cryo-EM structure of SLC22A3 (OCT3) is available from the Sitte and Korkhov groups. It paves the way for better understanding OCT3 function and for revealing the exact mechanisms conferring polyspecificity of the whole SLC22 family.     

CRISPR tiling screen reveals cancer epigenetic ‘Goldilocks’ state

CRISPR tiling screens offer an efficient way to identify gain-of-function mutations in targets of cancer therapy. Recently, by utilizing these screens, Kwok et al. unexpectedly discovered mutations conferring drug addiction in lymphoma, revealing a requirement for a ‘just right’ window of histone methylation crucial for cancer survival.     

Glycine: a long-sought novel ligand for GPR158

G-protein-coupled receptors (GPCRs) are important drug targets with chemically diverse ligands and varying intracellular coupling partners. Recent work by Laboute et al. deorphanized GPR158 as a metabotropic glycine receptor (mGlyR), thereby providing evidence of a novel neuromodulatory system involving this non-canonical Class C receptor with an impact on cognition and affective states.     

A deep dive into degrader-induced protein-protein interfaces

Targeted protein degradation (TPD) relies on a comprehensive understanding of interfaces between hijacked E3 ligases and their substrates. In vitro techniques often do not capture the interaction dynamics. Recently, Hanzl et al. introduced deep mutational scanning (DMS) in combination with structural and biochemical approaches to identify residues crucial for degrader activity.     

The utility of QSARs in predicting acute fish toxicity of pesticide metabolites: A retrospective validation approach

The European Plant Protection Products Regulation 1107/2009 requires that registrants establish whether pesticide metabolites pose a risk to the environment. Fish acute toxicity assessments may be carried out to this end. Considering the total number of pesticide (re-) registrations, the number of metabolites can be considerable, and therefore this testing could use many vertebrates. EFSA's recent “Guidance on tiered risk assessment for plant protection products for aquatic organisms in edge-of-field surface waters” outlines opportunities to apply non-testing methods, such as Quantitative Structure Activity Relationship (QSAR) models. However, a scientific evidence base is necessary to support the use of QSARs in predicting acute fish toxicity of pesticide metabolites. Widespread application and subsequent regulatory acceptance of such an approach would reduce the numbers of animals used.The work presented here intends to provide this evidence base, by means of retrospective data analysis. Experimental fish LC₅₀ values for 150 metabolites were extracted from the Pesticide Properties Database (http://sitem.herts.ac.uk/aeru/ppdb/en/atoz.htm). QSAR calculations were performed to predict fish acute toxicity values for these metabolites using the US EPA's ECOSAR software. The most conservative predicted LC₅₀ values generated by ECOSAR were compared with experimental LC₅₀ values.There was a significant correlation between predicted and experimental fish LC₅₀ values (Spearman r_s = 0.6304, p < 0.0001). For 62% of metabolites assessed, the QSAR predicted values are equal to or lower than their respective experimental values. Refined analysis, taking into account data quality and experimental variation considerations increases the proportion of sufficiently predictive estimates to 91%. For eight of the nine outliers, there are plausible explanation(s) for the disparity between measured and predicted LC₅₀ values.Following detailed consideration of the robustness of this non-testing approach, it can be concluded there is a strong data driven rationale for the applicability of QSAR models in the metabolite assessment scheme recommended by EFSA. As such there is value in further refining this approach, to improve the method and enable its future incorporation into regulatory guidance and practice.     

Hedgehog signalling in allograft vasculopathy: a new therapeutic target?

Allograft vasculopathy (AV) leads to chronic rejection of organ transplants, but its causes are obscure. New research from the Jane-Wit laboratory showed that Sonic Hedgehog (SHH) signalling from damaged graft endothelium drives vasculopathy by promoting proinflammatory cytokine production and NLRP3-inflammasome activation in alloreactive CD4⁺PTCH1^hiPD-1^hiT memory cells, offering new diagnostic and therapeutic strategies.     

Privigen® has similar pharmacokinetic properties in primary and secondary immune deficiency

PurposePrimary (PID) and secondary immune deficiencies (SID) represent diverse groups of diagnoses, yet both can be effectively treated with intravenous immunoglobulin (IVIG) replacement therapy. Guidelines for the use of IVIG in SID vary due to the paucity of data. The objective was to analyze available IVIG Privigen® (IgPro10, CSL Behring, Bern, Switzerland) data on Efficiency Index (EI) and pharmacokinetic (PK) parameters in patients with PID and SID.MethodsThree Privigen® studies (NCT00168025, NCT00322556, and the observational study IgPro10_5001) were used to identify patients with PID and SID meeting the qualifying criteria for the PK analysis. PK properties of IVIG were estimated using a population PK model based on a standard two-compartment PK model. Immunoglobulin G (IgG) EI was calculated as the gain in serum IgG level per unit external IgG dose.ResultsA similar IVIG dose-serum IgG concentration relationship was observed in patients with PID (N = 90) and SID (N = 91). IgG EI was inversely proportional to the endogenous IgG concentration and comparable in PID (slope = −1.079) and SID (slope = −2.12).ConclusionsThese findings indicate that the disposition of Privigen® is similar during IgG replacement therapy in PID and SID. The results contribute to the understanding of IVIG treatment of SID and may support an evidence-based approach for the use of IVIG in SID in the future.     

Design,synthesis, and evaluation of novel 2-substituted 1,4-benzenediol library as antimicrobial agents against clinically relevant pathogens

Development of new antimicrobial agents, capable of combating resistant and multidrug-resistant fungal and bacterial clinical strains, is necessary. This study presents the synthesis and antimicrobial screening of 42 2-substituted-1,4-benzenediols, being 10 novel compounds. In total, 23 compounds showed activity against fungi and/or bacteria. Benzenediol compounds 2, 5, 6, 8, 11, and 12 demonstrated broad spectrum antimicrobial actions, including resistant and multidrug-resistant species of dermatophytes (Trichophyton mentagrophytes), Candida spp. and the ESKAPE panel of bacteria. Minimum inhibitory concentrations of these compounds for fungi and bacterial strains ranged from 25 to 50 µg/ml and 8–128 µg/ml, respectively. The antifungal mechanism of action is related to the fungal cell wall of dermatophytes and membrane disruption to dermatophytes and yeasts, in the presence of compound 8. Specific structural changes, such as widespread thinning along the hyphae and yeast lysis, were observed by scanning electron microscopy. The effects of compound 8 on cell viability are dose-dependent; however they did not cause genotoxicity and mutagenicity in human leukocyte cells nor haemolysis. Moreover, the compounds were identified as nonirritant by the ex-vivo Hen’s egg test-chorioallantoic membrane (HET-CAM). The furan-1,4-benzenediol compound 5 showed in vivo efficacy to combat S. aureus infection using embryonated chicken eggs. Therefore, the compounds 8, and 5 are promising as hits for the development of new antimicrobial drugs with reduced toxicity.