bims-glecem 2023-03-26 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–03–26
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-b]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors.
Amnio acid substitution at position 298 of human glucose-6 phosphatase-α significantly impacts its stability in mammalian cells.
Hepatic Leucine Carboxyl Methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism.
Personalized Treatment of Periodontitis in a Patient with McArdle's Disease: The Benefits from Probiotics.
The hypoglycemic activities and underlying mechanisms of two saponins-rich components from fried Ziziphus jujuba Mill. kernel.
[Electroacupuncture regulates glucose metabolism disorder through PI3K/Akt/GSK3β signaling pathway in rats with depression].
Modeling structure-activity relationships with machine learning to identify GSK3-targeted small molecules as potential COVID-19 therapeutics.
Effects of glycogen synthase kinase-3β activity inhibition on cognitive, behavioral, and hippocampal ultrastructural deficits in adulthood associated with adolescent methamphetamine exposure.
TBC1D1 Ser237 phosphorylation, but not insulin sensitivity, is higher following a bout of high-intensity interval exercise in males as compared with females.
Intra-renal and urinary glycogen synthase kinase 3 beta levels in diabetic and non-diabetic chronic kidney disease.
Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats.
Does lithium attenuate the liver damage due to oxidative stress and liver glycogen depletion in experimental common bile duct obstruction?
Microtubule-associated protein 4 promotes epithelial mesenchymal transition in hepatocellular cancer cells via regulating GSK3β/β-catenin pathway.

J Med Chem. 2023 Mar 23. 66(6): 4231-4252

Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-b]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors.

Richard A Hartz, Vijay T Ahuja, Prasanna Sivaprakasam, Hong Xiao, Carol M Krause, Wendy J Clarke, Kevin Kish, Hal Lewis, Nicolas Szapiel, Ramu Ravirala, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R Burton, John E Macor, Gene M Dubowchik.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3β has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo[1,2-b]pyridazine derivatives that were evaluated as GSK-3β inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3β inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3β inhibitor that significantly lowered levels of phosphorylated tau.

DOI: https://doi.org/10.1021/acs.jmedchem.3c00133
Amino Acids. 2023 Mar 21.

Amnio acid substitution at position 298 of human glucose-6 phosphatase-α significantly impacts its stability in mammalian cells.

Jingsong Cao, Arianna Markel, Erin Hanahoe, Tatiana Ketova, Cosmin Mihai, Zach Zalinger, David Marquardt, Nicholas J Amato, Yi Min Cheng, David W Reid, Athanasios Dousis, Paloma H Giangrande, Joshua R Schultz, Paolo G V Martini, Patrick F Finn.

  Glucose-6-phosphatase-α (G6Pase-α) catalyzes the hydrolysis of glucose-6-phosphate to glucose and functions as a key regulator in maintaining blood glucose homeostasis. Deficiency in G6Pase-α causes glycogen storage disease 1a (GSD1a), an inherited disorder characterized by life-threatening hypoglycemia and other long-term complications. We have developed a potential mRNA-based therapy for GSD1a and demonstrated that a human G6Pase-α (hG6Pase-α) variant harboring a single serine (S) to cysteine (C) substitution at the amino acid site 298 (S298C) had > twofold increase in protein expression, resulting in improved in vivo efficacy. Here, we sought to investigate the mechanisms contributing to the increased expression of the S298C variant. Mutagenesis of hG6Pase-α identified distinct protein variants at the 298 amino acid position with substantial reduction in protein expression in cultured cells. Kinetic analysis of expression and subcellular localization in mammalian cells, combined with cell-free in vitro translation assays, revealed that altered protein expression stemmed from differences in cellular protein stability rather than biosynthetic rates. Site-specific mutagenesis studies targeting other cysteines of the hG6Pase-α S298C variant suggest the observed improvements in stability are not due to additional disulfide bond formation. The glycosylation at Asparagine (N)-96 is critical in maintaining enzymatic activity and mutations at position 298 mainly affected glycosylated forms of hG6Pase-α. Finally, proteasome inhibition by lactacystin improved expression levels of unstable hG6Pase-α variants. Taken together, these data uncover a critical role for a single amino acid substitution impacting the stability of G6Pase-α and provide insights into the molecular genetics of GSD1a and protein engineering for therapeutic development.

Keywords:  Degradation; Glucose metabolism; Glycogen storage disease; Glycosylation; Protein folding

DOI:  https://doi.org/10.1007/s00726-023-03263-8
J Nutr Biochem. 2023 Mar 22. pii: S0955-2863(23)00054-2. [Epub ahead of print] 109321

Hepatic Leucine Carboxyl Methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism.

Jiao Mo, Xinhang Wang, Ningjing Liang, Ning Zhang, Yunqing Li, Zhijian Zheng, Qingqing Ao, Yijie Wu, Tingting Tang, Simi Liao, Yu Lei, Huan Ding, Bingxin Du, Mei Feng, Chengying Chen, Qianqian Shi, Lancheng Wei, Yue Huang, Cailing Lu, Shen Tang, Xiyi Li.

  Impaired glucose regulation is one of the most important risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which have become a major public health issue worldwide. Dysregulation of carbohydrate metabolism in liver has been shown to play a critical role in the development of glucose intolerance but the molecular mechanism has not yet been fully understood. In this study, we investigated the role of hepatic LCMT1 in the regulation of glucose homeostasis using a liver-specific LCMT1 knockout mouse model. The hepatocyte-specific deletion of LCMT1 significantly upregulated the hepatic glycogen synthesis and glycogen accumulation in liver. We found that the liver-specific knockout of LCMT1 improved high fat diet-induced glucose intolerance and insulin resistance. Consistently, the high fat diet-induced downregulation of glucokinase (GCK) and other important glycogen synthesis genes were reversed in LCMT1 knockout liver. In addition, the expression of GCK was significantly upregulated in MIHA cells treated with siRNA targeting LCMT1 and improved glycogen synthesis. In this study, we provided evidences to support the role of hepatic LCMT1 in the development of glucose intolerance induced by high fat diet and demonstrated that inhibiting LCMT1 could be a novel therapeutic strategy for the treatment of glucose metabolism disorders.

Keywords:  HFD; LCMT1; glucokinase; glucose homeostasis; liver

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109321
Case Rep Dent. 2023 ;2023 5080384

Personalized Treatment of Periodontitis in a Patient with McArdle's Disease: The Benefits from Probiotics.

Salvatore Cannizzaro, Carolina Maiorani, Andrea Scribante, Andrea Butera.

Introduction: McArdle's disease is a severe glycogen storage disease characterized by intolerance to exercise; patients have a syndrome of muscle intolerance to stress, associated with myalgia, cramps, fatigue, and muscle weakness. Periodontal disease is a multifactorial pathology of the supporting tissues of the teeth: one of the main factors is the formation of bacterial biofilm; its control favors the prevention and the maintenance of good health of the oral cavity; and some systemic pathologies can worsen the periodontal disease and hinder its therapy. This case report concerns a woman with McArdle's disease diagnosed with periodontal disease. Material and Methods. A 54-year-old female patient with McArdle's disease has been diagnosed with Stage 3 generalized periodontitis, Grade B. At the baseline, the patient had 82 pockets with probing pocket depth (PPD) equal to or greater than 4 mm. The patient was instructed in the correct methods of oral hygiene and was advised toothpaste and mouthwash based on probiotics; subsequently, a debridement was performed to remove etiological factors using Dental-Biofilm Detection Topographic Technique (D-BioTECH).
Results: After 60 days, the number of pockets was reduced from 82 to 14 overall with PPD ≥ 4 mm and from 50 to 2 pockets with PPD ≥ 5 mm. Full mouth bleeding score (FMBS) increased from 48% to 15% and full mouth plaque score (FMPS) from 73% to 15%.
Conclusions: In this case, the use of a correct brushing method combined with the D-BioTECH has reduced the disease state, with the use of probiotics at home to restore and maintain a healthy oral microbiome.

DOI: https://doi.org/10.1155/2023/5080384
Mol Nutr Food Res. 2023 Mar 19. e2200364

The hypoglycemic activities and underlying mechanisms of two saponins-rich components from fried Ziziphus jujuba Mill. kernel.

Yi-Meng Li, Hong Xie, Jian-Guo Jiang.

  Dried Ziziphus jujuba Mill. kernel is a potential natural source of nutraceutical and therapeutic agents in China. Recent researches have shown that the saponins of dried Ziziphus jujuba Mill. Kernel (SZJs) had various biological effects. However, the hypoglycemic activities and underlying mechanisms of SZJs remain obscure. In the current study, two saponins SZJ-1 and SZJ-2 mainly composed of betulinic acid, spinosin, jujuboside A, jujuboside B were extracted and isolated from dried Z. jujuba Mill. kernel. The SZJ-1 and SZJ-2 could significantly inhibit the activities of digestion enzymes α-glucosidase and α-amylases. The hypoglycemic ability of SZJ-1 and SZJ-2 was further investigated and the results showed that SZJ-1 and SZJ-2 could improve the hyperglycemic by increasing the glucose consumption, improving the superoxide dismutase (SOD), hexokinase (HK), pyruvate kinase (PK) activities and decrease the MDA content of insulin resistant HepG2 cells. Furthermore, SZJ-1 and SZJ-2 could activate the phosphorated Adenosine 5'-monophosphate (AMP)-activated protein kinase α (p-AMPKα), phosphoinositide 3-kinase p110α (PI3K-p110α), and phosphorated glycogen synthase kinase-3β (Ser9) (p-GSK3β), indicating that the SZJ-1 and SZJ-2 might improve the insulin resistant symptoms by improving the energy metabolic level and increasing the glycogen synthase activity of HepG2 cells. This article is protected by copyright. All rights reserved.

Keywords:  Chemical composition; Hypoglycemic activities; Saponins; Ziziphus jujuba Mill. kernel

DOI:  https://doi.org/10.1002/mnfr.202200364
Zhen Ci Yan Jiu. 2023 Mar 25. 48(3): 247-52

[Electroacupuncture regulates glucose metabolism disorder through PI3K/Akt/GSK3β signaling pathway in rats with depression].

Yu-Jia Lu, Chen Shao, Shan Zhang, Wei Shi, Li Li, Jing-Jie Zhao.

   OBJECTIVE: To explore the mechanism of electroacupuncture (EA) at "Zusanli" (ST36) on improving glucose metabolism disorder in chronic restraint induced depressed rats.
METHODS: A total of 30 male SD rats were randomly divided into control, model and EA groups, with 10 rats in each group. The depression model was established by chronic restraint 2.5 h each day for 4 weeks. For rats in the EA group, EA stimulation (1 mA, 2 Hz, 30 min) was applied to bilateral ST36 during the modeling period, once a day for 4 weeks. The body weight of the rats was recorded before and after modeling. The behavior of rats was observed by sugar-water preference and forced swimming after modeling. The contents of glucose and glycosylated albumin in serum were determined by biochemical method. The histopathological morphology and liver glycogen content were observed by HE and PAS staining. The expression levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K (p-PI3K), protein kinase B (Akt), p-Akt, glycogen synthase kinase-3β (GSK3β) and p-GSK3β proteins in liver were determined by Western blot.
RESULTS: Compared with the control group, the weight increment and sugar-water preference index decreased (P<0.01), the immobile swimming time was prolonged (P<0.01), the glucose and glycosylated albumin contents in serum increased (P<0.05), the expression of p-Akt protein and the ratio of p-Akt/Akt in liver tissues decreased (P<0.001), the expression of p-GSK3β protein and the ratio of p-GSK3β/GSK3β in liver tissues increased (P<0.01,P<0.001) in the model group. Compared with the model group, the weight increment and sugar-water preference index increased (P<0.05), the immobile swimming time was shortened (P<0.05), the glucose and glycosylated albumin contents in serum decreased (P<0.05), the expressions of p-PI3K and p-Akt proteins and the ratio of p-PI3K/PI3K and p-Akt/Akt in liver tissues increased (P<0.05), the expression of p-GSK3β protein and the ratio of p-GSK3β/GSK3β in liver tissues decreased (P<0.01) in the EA group. HE staining showed that the structure of the hepatic lobule was intact, no obvious inflammatory cell infiltration or fibrosis was observed in the lobule and interstitium, and no abnormalities were observed in the small bile duct, portal vein and artery in the portal area. PAS staining showed that the intensity of staining from the center of the hepatic lobule to the periphery of the hepatic lobule was gradually enhanced in the blank group, that is, the glycogen-rich granules in the hepatic cells were gradually increased; most of the hepatocytes were light colored and glycogen was lost significantly in the model group; while the intensity of hepatocyte staining increased, the staining intensity of the perilobular zone was weaker than that in the blank group, and the glycogen particles partially recovered in the EA group.
CONCLUSION: EA intervention can regulate glucose metabolism disorder in chronic restraint induced depressed rats through PI3K/Akt/GSK3β signaling pathway.

Keywords:  Depression; Electroacupuncture; Hepatic glycogen; PI3K/Akt/GSK3β signaling pathway; Zusanli (ST36)

DOI:  https://doi.org/10.13702/j.1000-0607.20211353
Front Endocrinol (Lausanne). 2023 ;14 1084327

Modeling structure-activity relationships with machine learning to identify GSK3-targeted small molecules as potential COVID-19 therapeutics.

Rameez Hassan Pirzada, Bilal Ahmad, Naila Qayyum, Sangdun Choi.

  Coronaviruses induce severe upper respiratory tract infections, which can spread to the lungs. The nucleocapsid protein (N protein) plays an important role in genome replication, transcription, and virion assembly in SARS-CoV-2, the virus causing COVID-19, and in other coronaviruses. Glycogen synthase kinase 3 (GSK3) activation phosphorylates the viral N protein. To combat COVID-19 and future coronavirus outbreaks, interference with the dependence of N protein on GSK3 may be a viable strategy. Toward this end, this study aimed to construct robust machine learning models to identify GSK3 inhibitors from Food and Drug Administration-approved and investigational drug libraries using the quantitative structure-activity relationship approach. A non-redundant dataset consisting of 495 and 3070 compounds for GSK3α and GSK3β, respectively, was acquired from the ChEMBL database. Twelve sets of molecular descriptors were used to define these inhibitors, and machine learning algorithms were selected using the LazyPredict package. Histogram-based gradient boosting and light gradient boosting machine algorithms were used to develop predictive models that were evaluated based on the root mean square error and R-squared value. Finally, the top two drugs (selinexor and ruboxistaurin) were selected for molecular dynamics simulation based on the highest predicted activity (negative log of the half-maximal inhibitory concentration, pIC50 value) to further investigate the structural stability of the protein-ligand complexes. This artificial intelligence-based virtual high-throughput screening approach is an effective strategy for accelerating drug discovery and finding novel pharmacological targets while reducing the cost and time.

Keywords:  GSK3; QSAR; coronaviruses; machine learning; molecular descriptors

DOI:  https://doi.org/10.3389/fendo.2023.1084327
Front Mol Neurosci. 2023 ;16 1129553

Effects of glycogen synthase kinase-3β activity inhibition on cognitive, behavioral, and hippocampal ultrastructural deficits in adulthood associated with adolescent methamphetamine exposure.

Peng Yan, Jincen Liu, Haotian Ma, Yue Feng, Jingjing Cui, Yuying Bai, Xin Huang, Yongsheng Zhu, Shuguang Wei, Jianghua Lai.

   Objective: Glycogen synthase kinase-3β (GSK3β) has been implicated in the maintenance of synaptic plasticity, memory process, and psychostimulant-induced behavioral effects. Hyperactive GSK3β in the Cornu Ammonis 1 (CA1) subregion of the dorsal hippocampus (DHP) was associated with adolescent methamphetamine (METH) exposure-induced behavioral and cognitive deficits in adulthood. This study aimed to evaluate the possible therapeutic effects of GSK3β inhibition in adulthood on adolescent METH exposure-induced long-term neurobiological deficits.
Methods: Adolescent male mice were treated with METH from postnatal day (PND) 45-51. In adulthood, three intervention protocols (acute lithium chloride systemic administration, chronic lithium chloride systemic administration, and chronic SB216763 administration within CA1) were used for GSK3β activity inhibition. The effect of GSK3β intervention on cognition, behavior, and GSK3β activity and synaptic ultrastructure in the DHP CA1 subregion were detected in adulthood.
Results: In adulthood, all three interventions reduced adolescent METH exposure-induced hyperactivity (PND97), while only chronic systemic and chronic within CA1 administration ameliorated the induced impairments in spatial (PND99), social (PND101) and object (PND103) recognition memory. In addition, although three interventions reversed the aberrant GSK3β activity in the DHP CA1 subregion (PND104), only chronic systemic and chronic within CA1 administration rescued adolescent METH exposure-induced synaptic ultrastructure changes in the DHP CA1 subregion (PND104) in adulthood.
Conclusion: Rescuing synaptic ultrastructural abnormalities in the dHIP CA1 subregion by chronic administration of a GSK3β inhibitor may be a suitable therapeutic strategy for the treatment of behavioral and cognitive deficits in adulthood associated with adolescent METH abuse.

Keywords:  CA1 – Cornu ammonis region 1; adolescence; glycogen synthase kinase-3β (GSK3β); hyperactivity; methamphetamine; recognition memory

DOI:  https://doi.org/10.3389/fnmol.2023.1129553
Am J Physiol Regul Integr Comp Physiol. 2023 Mar 20.

TBC1D1 Ser237 phosphorylation, but not insulin sensitivity, is higher following a bout of high-intensity interval exercise in males as compared with females.

Kayleigh M Beaudry, Julian C Surdi, Jennifer A Wilkinson, Michaela C Devries.

  Interval training has been found to lower glucose concentrations and increase insulin sensitivity in males but not females, which may be due to inherent sex-based differences in metabolism. Twenty-four (12/sex) participants completed a bout of high-intensity interval exercise (HIIE, 10x1min at 90% HRmax) to evaluate whether sex influenced the physiological effects of HIIE on post-exercise glycemic control during an oral glucose tolerance test (OGTT). Given that body anthropometrics influence postprandial glucose, data were also expressed as a function of the normalized glucose dose. Additionally, we examined whether sex differences in post-exercise glycemic control were related to sex differences in muscle metabolism and/or insulin signaling proteins. HIIE increased insulin sensitivity in both sexes as characterized by the Matsuda (p=0.03, ηp2=0.20) and HOMA-IR (p=0.047, ηp2=0.17) indices. HIIE also lowered insulin concentration during the OGTT (p=0.04, ηp2=0.18) as compared with control. When normalized for glucose dose relative to lean mass, glucose AUC was lower in females than males (p=0.001, ηp2=0.42). TBC1D1 Ser237 phosphorylation increased in males, but not females, post-exercise (p=0.02, ηp2=0.22). There was no difference in total insulin signaling protein content, muscle glycogen utilization or AMPK activation during exercise between the sexes. These findings indicate that when the glucose dose is normalized for differences in body composition glycemic handling is better in females and that an acute bout of HIIE improves insulin sensitivity equally in healthy males and females.

Keywords:  TBC1D1; high intensity interval exercise; insulin sensitivity; muscle metabolism; sex-based differences

DOI:  https://doi.org/10.1152/ajpregu.00281.2021
Kidney Blood Press Res. 2023 Mar 20.

Intra-renal and urinary glycogen synthase kinase 3 beta levels in diabetic and non-diabetic chronic kidney disease.

Lingfeng Zeng, Jack Kit-Chung Ng, Winston Wing-Shing Fung, Gordon Chun-Kau Chan, Kai-Ming Chow, Cheuk-Chun Szeto.

Background Renal glycogen synthase kinase-3 beta (GSK3β) over-activity has been associated with a diverse range of kidney diseases. GSK3β activity in urinary exfoliated cells was reported to predict the progression of diabetic kidney disease (DKD). We compared the prognostic value of urinary and intra-renal GSK3β levels in DKD and non-diabetic chronic kidney disease (CKD). Methods We recruited 118 consecutive biopsy-proved DKD patients and 115 non-diabetic CKD patients. Their urinary and intra-renal GSK3β levels were measured. They were then followed for dialysis-free survival and rate of renal function decline. Results DKD group had higher intra-renal and urinary GSK3β levels than non-diabetic CKD (p<0.0001 for both), but their urinary GSK3β mRNA levels were similar. Urinary p-GSK3β level is statisticsly significantly corretated with the baseline estimated glomerular filtration rate (eGFR), but urinary GSK3β level by ELISA, it mRNA level, the p-GSK3β level, or the p-GSK3β/GSK3β ratio had no association with dialysis-free survival or the slope of eGFR decline. In contrast, intra-renal pY216-GSK3/total GSK3 ratio significantly correlated with the slope of eGFR decline (r = -0.335, p = 0.006), and remained an independent predictor after adjusting for other clinical factors. Conclusion Intra-renal and urinary GSK3β levels were increased in DKD. Intra-renal pY216-GSK3/total GSK3 ratio was associated with the rate of progression of DKD. The pathophysiological roles of GSK3β in kidney diseases deserve further studies.

DOI: https://doi.org/10.1159/000530210
Life Sci. 2023 Mar 20. pii: S0024-3205(23)00246-1. [Epub ahead of print] 121612

Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats.

Maisa Siddiq Abduh, Mohammed A Alzoghaibi, Abdullah M Alzoghaibi, Albandari Bin-Ammar, Mohammed F Alotaibi, Emadeldin M Kamel, Ayman M Mahmoud.

  Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg for 4 weeks). Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.

Keywords:  Arbutin; Diabetes; Glucose tolerance; Inflammation; Oxidative stress

DOI:  https://doi.org/10.1016/j.lfs.2023.121612
Toxicol Appl Pharmacol. 2023 Mar 22. pii: S0041-008X(23)00127-8. [Epub ahead of print] 116489

Does lithium attenuate the liver damage due to oxidative stress and liver glycogen depletion in experimental common bile duct obstruction?

Ayse Basak Engin, Atilla Engin, Evren Doruk Engin, Leyla Memis.

  In extrahepatic cholestasis, the molecular mechanisms of liver damage due to bile acid accumulation remain elusive. In this study, the activation of glutamatergic receptors was hypothesized to be responsible for bile acid-induced oxidative stress and liver damage. Recent evidence showed that lithium, as an N-methyl-d-aspartate receptor (NMDAR) GluN2B subunit inhibitor, may act on the glutamate/NMDAR signaling axis. Guinea pigs were assigned to four groups, as sham laparotomy (SL), bile duct ligated (BDL), lithium-treated SL (SL + Li) and lithium-treated BDL (BDL + Li) groups. Cholestasis-induced liver injury was evaluated by aspartate aminotransferase (AST), alanine transaminase (ALT), interleukin-6 (IL-6), tissue malondialdehyde (MDA), copper‑zinc superoxide dismutase and reduced glutathione levels. The liability of glutamate/NMDAR signaling axis was clarified by glutamate levels in both plasma and liver samples, with the production of nitric oxide (NO), as well as with the serum calcium concentrations. Blood glucose, glucagon, insulin levels and glucose consumption rates, in addition to tissue glycogen were measured to evaluate the liver glucose-glycogen metabolism. A high liver damage index (AST/ALT) was calculated in BDL animals in comparison to SL group. In the BDL animals, lithium reduced plasma NO and glutamate in addition to tissue glutamate concentrations, while serum calcium increased. The antioxidant capacities and liver glycogen contents significantly increased, whereas blood glucose levels unchanged and tissue MDA levels decreased 3-fold in lithium-treated cholestatic animals. It was concluded that lithium largely protects the cholestatic hepatocyte from bile acid-mediated damage by blocking the NMDAR-GluN2B subunit.

Keywords:  Extrahepatic cholestasis; Glutamate; Hydrophobic bile acids; Lithium; Liver glycogen; N-methyl-d-aspartate receptor

DOI:  https://doi.org/10.1016/j.taap.2023.116489
Heliyon. 2023 Mar;9(3): e14309

Microtubule-associated protein 4 promotes epithelial mesenchymal transition in hepatocellular cancer cells via regulating GSK3β/β-catenin pathway.

Pingping Hu, Bin Zong, Qian Chen, Rui Shao, Miao Chen, Yujie Yang, Genbao Shao.

  Metastasis is a major obstacle in the treatment of hepatocellular carcinoma (HCC). Microtubule-associated protein 4 (MAP4) plays an important role as a coordinator between microtubules and microfilaments. However, the role of MAP4 in HCC migration and epithelial mesenchymal transition (EMT) is unclear. We compared the protein and mRNA levels of MAP4 in human HCC and adjacent normal tissues using western blotting, immunohistochemistry and RT-qPCR. The migration and invasion abilities and the levels of EMT markers (E-Cadherin, N-Cadherin, Vimentin, and Snail) were compared between MAP4-knockdown and MAP4-overexpressed HCC cells. Finally, we examined whether β-catenin and glycogen synthase kinase 3β (GSK3β) are involved in the stimulatory effects of MAP4 on HCC migration, invasion and EMT. The results revealed that MAP4 levels were higher in the HCC tissues than in the normal hepatic tissues. More importantly, MAP4 knockdown suppressed migration and invasion abilities and EMT processes in HCC cells, which were confirmed by the stimulatory effects of MAP4 overexpression on EMT processes in HCC cells. Further evidence demonstrated that the up-regulation of β-catenin activity induced by the interaction between MAP4 and GSK3β possibly accounted for the pro-migration and pro-EMT effects of MAP4 on HCC cells. Taken together, these results suggest that MAP4 promotes migration, invasion, and EMT in HCC cells by regulating the GSK3β/β-catenin pathway.

Keywords:  EMT; EMT, epithelial mesenchymal transition; GSK3β; GSK3β, glycogen synthase kinase 3β; HCC; HCC, hepatocellular carcinoma; MAP4; MAP4, microtubule-associated protein 4; β-catenin

DOI:  https://doi.org/10.1016/j.heliyon.2023.e14309