bims-glecem 2023-01-22 papers

Issue of 2023‒01‒22
four papers selected by
Dipsikha Biswas, Københavns Universitet

Bioorg Med Chem Lett. 2023 Jan 17. pii: S0960-894X(23)00021-5. [Epub ahead of print] 129143

Structure-Activity Relationship (SAR) Studies on Substituted N-(Pyridin-3-yl)-2-amino-isonicotinamides as Highly Potent and Selective Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.

Guanglin Luo, Ling Chen, Swanee Jacutin-Porte, Ying Han, Catherine R Burton, Hong Xiao, Carol M Krause, Yang Cao, Nengyin Liu, Kevin Kish, Hal A Lewis, John E Macor, Gene M Dubowchik.

In our continuing efforts to explore structure-activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer's disease model. In general, these 2-pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.

Keywords: Alzheimer’s Disease; GSK-3 inhibitor; SAR studies; isonicotinamide

DOI: https://doi.org/10.1016/j.bmcl.2023.129143

Ecotoxicol Environ Saf. 2023 Jan 18. pii: S0147-6513(23)00063-5. [Epub ahead of print]251 114559

Sediment pollutant exposures caused hepatotoxicity and disturbed glycogenesis.

Meng-Wei Lin, Xin-Ru Yu, Jai-Yu Chen, Yu-Shan Wei, Hsin-Yi Chen, Yi-Ting Tsai, Li-Hsun Lin, En-Chi Liao, Hsiang-Yu Kung, Shuh-Sen Young, Hong-Lin Chan, Hsiu-Chuan Chou.

Liver metabolic syndrome, which involves impaired hepatic glycogen synthesis, is persistently increased by exposure to environmental pollutants. Most studies have investigated the pathogenesis of liver damage caused by single metal species or pure organics. However, under normal circumstances, the pollutants that we are exposed to are usually chemical mixtures that accumulate over time. Sediments are long-term repositories for environmental pollutants due to their environmental cycles, which make them good samples for evaluating the effect of environmental pollutants on the liver via bioaccumulation. This study aimed to clarify the effects of sediment pollutants on liver damage. Our results indicate that industrial wastewater sediment (downstream) is more cytotoxic than sediments from other zones. Downstream sediment extract (DSE) causes hepatotoxicity, stimulates reactive oxygen species (ROS) generation, triggers mitochondrial dysfunction, induces cell apoptosis, and results in the release of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) proteins. Additionally, to elucidate the underlying mechanism by which sediment pollutants disturb hepatic glycogen synthesis, we investigated the effects of different sediment samples from different pollution situations on glycogen synthesis in liver cell lines. It was found that DSE induced multiple severe impairments in liver cells, and disturbed glycogen synthesis more than under other conditions. These impairments include decreased hepatic glycogen synthesis via inhibition and insulin receptor substrate 1 (IRS-1) /AKT /glycogen synthase kinase3β (GSK3β)-mediated glycogen synthase (GYS) inactivation. To our knowledge, this study provides the first detailed evidence of in vitro sediment-accumulated toxicity that interferes with liver glycogen synthesis, leading to hepatic cell damage through apoptosis.

Keywords: Apoptosis; Environmental pollution; Glycogenesis; Liver damage; Sediment

DOI: https://doi.org/10.1016/j.ecoenv.2023.114559

J Pediatr Endocrinol Metab. 2023 Jan 23.

Identification of a novel mutation in the ALDOB gene in hereditary fructose intolerance.

Zahra Beyzaei, Fatih Ezgu, Mohammad Hadi Imanieh, Mahmoud Haghighat, Seyed Mohsen Dehghani, Naser Honar, Bita Geramizadeh.

OBJECTIVES: Hereditary fructose intolerance (HFI) is caused by aldolase B enzyme deficiency. There has been no report about HFI from Iran and the type of mutations has not been reported in the Iranian population so far.CASE PRESENTATION: Herein we report a 2 year old girl presented with failure to thrive, hepatomegaly, and liver dysfunction. The primary impression has been hepatic glycogen storage disease type 1 or 6. This diagnosis was not confirmed by laboratory data and liver biopsy. Therefore, targeted-gene sequencing (TGS) covering 450 genes involved in inborn errors in metabolic diseases was performed. The results of TGS showed a rare novel homozygous pathogenic variant c.944del (p.Gly315ValfsTer15) in the ALDOB gene.
CONCLUSIONS: This report introduces a novel variant that expands the mutational spectrum of the ALDOB gene in patients with HFI.

Keywords: hereditary fructose intolerance; targeted gene sequencing; variant ALDOB

DOI: https://doi.org/10.1515/jpem-2022-0566

Life Sci. 2023 Jan 11. pii: S0024-3205(23)00015-2. [Epub ahead of print] 121381

Nutritional geometry framework of sleep.

Mei-Ling Lai, An-Qi Li, Alistair Senior, G Gregory Neely, Stephen J Simpson, Qiao-Ping Wang.

AIMS: Sleep is a fundamental physiological function and is essential for all animals. Sleep is affected by diet compositions including protein (P) and carbohydrates (C), but there has not been a systematic investigation on the effect of dietary macronutrient balance on sleep.MAIN METHODS: We used the nutritional geometry framework (NGF) to explore the interactive effects on sleep of protein (P) and carbohydrates (C) in the model organism Drosophila. Both female and male flies were fed various diets containing seven ratios of protein-to-carbohydrates at different energetic levels for 5 days and sleep was monitored by the Drosophila Activity Monitor (DAM) system.
KEY FINDINGS: Our results showed that the combination of low protein and high carbohydrates (LPHC) prolonged sleep time and sleep quality, with fewer sleep episodes and longer sleep duration. We further found that the effects of macronutrients on sleep mirrored levels of hemolymph glucose and whole-body glycogen. Moreover, transcriptomic analyses revealed that a high-protein, low-carbohydrate (HPLC) diet significantly elevated the gene expression of metabolic pathways when compared to the LPHC diet, with the glycine, serine, and threonine metabolism pathway being most strongly elevated. Further studies confirmed that the contents of glycine, serine, and threonine affected sleep.
SIGNIFICANCE: Our results demonstrate that sleep is affected by the dietary balance of protein and carbohydrates possibly mediated by the change in glucose, glycogen, glycine, serine, and threonine.

Keywords: Carbohydrates; Dietary balance; Drosophila; Nutritional geometry framework; Protein; Sleep

DOI: https://doi.org/10.1016/j.lfs.2023.121381