The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus,and Coronavirus Replication by Altering RNA Processing/Accumulation

Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC₅₀ ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.     

Clinical implications of hepatic progenitor cell activation in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is one of the most prominent causes of liver-related morbidity in the Western world. NAFLD is a chronic disease charac...     

Chemical and biological studies on the soft coral Nephthea sp.

Soft corals belonging to the family Nephtheidae have been appreciated as marine sources of diverse metabolites with promising anticancer potential. In view of that, the current work investigates the anti-proliferative potential of the crude extract, different fractions, and green synthesized silver nanoparticles (AgNPs) of the Red Sea soft coral, Nephthea sp. against a panel of tumor cell lines. The metabolic pool of the soft coral under study was also explored via an LC-HR-ESI-MS metabolomics approach, followed by molecular docking analysis of the characterized metabolites against the target proteins, EGFR, VEGFR, and HER2 (erbB2) that are known to be involved in cancer cell proliferation, growth, and survival. Overall, the n-butanol fraction of Nephthea sp. exhibited the highest inhibitory activities against MCF7 (breast cancer) and A549 (lung cancer) cell lines, with interesting IC₅₀ values of 2.30 ± 0.07 and 3.12 ± 0.10 μg ml⁻¹, respectively, whereas the maximum growth inhibition of HL60 (leukemia) cells was recorded by the total extract (IC₅₀ = 2.78 ± 0.09 μg ml⁻¹). More interestingly, the anti-proliferative potential of the total soft coral extract was evidently improved when packaged in the form of biogenic AgNPs, particularly against A549 and MCF7 tumor cells, showing IC₅₀ values of 0.72 ± 0.06 and 9.32 ± 0.57 μg ml⁻¹, respectively. On the other hand, metabolic profiling of Nephthea sp. resulted in the annotation of structurally diverse terpenoids, some of which displayed considerable binding affinities and molecular interactions with the studied target proteins, suggesting their possible contribution to the anti-proliferative properties of Nephthea sp. via inhibition of tyrosine kinases, especially the EGFR type. Taken together, the present findings highlighted the relevance of Nephthea sp. to future anticancer drug discovery and provided a base for further work on the green synthesis of a range of bioactive NPs from marine soft corals.

The cytotoxic potential of the crude extract, different fractions, and green synthesized nanoparticles of the soft coral Nephthea sp. was studied, supported by LC-HR-ESI-MS metabolomics analysis and molecular docking of the dereplicated compounds.     

The modified superiorly based pharyngeal flap. Part IV. Position of the base of the flap.

The modified superiorly based pharyngeal flap surgical technique developed by Epker et al. was performed on 13 patients with moderate to severe hypernasality. The flap base was attached close to the level of the palatal plane and was found to maintain a consistent longitudinal relationship to the level of the atlas. This technique corrected hypernasality in a range of patients with velopharyngeal incompetence, as predicted.     

Non-alcoholic steatohepatitis in liver transplant recipients diagnosed by serum cytokeratin 18 and transient elastography: A prospective study

BACKGROUNDNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) seem common after liver transplantation.AIMTo investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients, namely controlled attenuation parameter (CAP) and the serum biomarker cytokeratin 18 (CK-18). We also evaluated the diagnostic accuracy of CK-18 and CAP compared to liver histology.METHODSWe prospectively recruited consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018. Serial measurements of CK-18 and CAP were recorded. NAFLD and NASH were diagnosed by CAP ≥ 270 dB/m, and a combination of CAP ≥ 270 dB/m with CK-18 > 130.5 U/L, respectively. Incidences and predictors of NAFLD and NASH were investigated using survival analysis and Cox proportional hazards.RESULTSOverall, 40 liver transplant recipients (mean age 57 years; 70% males) were included. During a median follow-up of 16.8 mo (interquartile range 15.6-18.0), 63.0% and 48.5% of patients developed NAFLD and NASH, respectively. On multivariable analysis, after adjusting for sex and alanine aminotransferase, body mass index was an independent predictor of development of NAFLD [adjusted hazard ratio (aHR): 1.21, 95% confidence interval (CI): 1.04-1.41; P = 0.01] and NASH (aHR: 1.26, 95%CI: 1.06-1.49; P < 0.01). Compared to liver histology, CAP had a 76% accuracy to diagnose NAFLD, while the accuracy of CAP plus CK-18 to diagnose NASH was 82%.CONCLUSIONNAFLD and NASH diagnosed non-invasively are frequent in liver transplant recipients within the first 18 mo. Close follow-up and nutritional counselling should be planned in overweight patients.     

Clinical and socio‐demographic factors associated with diabetic ketoacidosis hospitalization in adults with Type 1 diabetes

Aim

To identify the clinical and socio‐demographic factors associated with hospitalization for diabetic ketoacidosis in adults with Type 1 diabetes.

Methods

We combined clinical and administrative health data from a large urban diabetes clinic to perform a data linkage study. We identified adults (aged ≥ 18 years old) with Type 1 diabetes and linked to hospital discharge abstracts to assess for diabetic ketoacidosis hospitalization. The study period was between 1 January 2004 and 31 December 2009, with all individuals living in the same geographic area. Multivariate logistic regression was used to identify potential predictors of diabetic ketoacidosis hospitalization.

Results

We identified 255 individuals with a diabetic ketoacidosis hospitalization and 1739 without a diabetic ketoacidosis hospitalization. Mean (standard deviation) age was 40.0 (15.8) years, 51.7% were men and mean duration of diabetes was 17.8 (12.9) years. Diabetic ketoacidosis hospitalization was associated with shorter duration of diabetes (odds ratio 0.96 per year; 95% confidence interval 0.95–0.98), gastroparesis (odds ratio 4.13; 95% confidence interval 1.82–9.35), psychiatric diagnosis (odds ratio 1.98; 95% confidence interval 1.22–3.19), and higher HbA_1c (odds ratio 1.25 per 1% increase; 95% confidence interval 1.16–1.35).

Conclusions

This study identifies specific clinical factors associated with diabetic ketoacidosis hospitalization in adults with Type 1 diabetes. This information can help to inform the detection of high‐risk patients, for whom special attention and interventions may be warranted to prevent diabetic ketoacidosis.     

Evaluation of the genotoxic potential of 3-monochloropropane-1,2-diol (3-MCPD) and its metabolites, glycidol and beta-chlorolactic acid, using the single cell gel/comet assay.

3-monochloropropane-1,2-diol (3-MCPD) is a member of a group of chemicals known as chloropropanols. It is found in many foods and food ingredients as a result of food processing. 3-MCPD is regarded as a rat carcinogen known to induce Leydig-cell and mammary gland tumours in males and kidney tumours in both genders. The aim of our study was to clarify the possible involvement of genotoxic mechanisms in 3-MCPD induced carcinogenicity at the target organ level. For that purpose, we evaluated DNA damages in selected target (kidneys and testes) and non-target (blood leukocytes, liver and bone marrow) male rat organs by the in vivo alkaline single cell gel electrophoresis (comet) assay, 3 and 24 h after 3-MCPD oral administration to Sprague-Dawley and Fisher 344 adult rats. 3-MCPD may be metabolised to a genotoxic intermediate, glycidol, whereas the predominant urinary metabolite in rats following 3-MCPD administration is beta-chlorolactic acid. Therefore, we also studied the DNA damaging effects of 3-MCPD and its metabolites, glycidol and beta-chlorolactic acid, in the in vitro comet assay on CHO cells. Our results show the absence of genotoxic potential of 3-MCPD in vivo in the target as well as in the non-target organs. Glycidol, the epoxide metabolite, induced DNA damages in CHO cells. beta-Chlorolactic acid, the main metabolite of 3-MCPD in rats, was shown to be devoid of DNA-damaging effects in vitro in mammalian cells.