bims-glecem Biomed News
on Glycogen metabolism in exercise, cancer and energy metabolism
Issue of 2022–02–13
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet
  1. A Dioxidovanadium Complex cis-[VO2 (obz) py] Attenuates Hyperglycemia in Streptozotocin (STZ)-Induced Diabetic Male Sprague-Dawley Rats via Increased GLUT4 and Glycogen Synthase Expression in the Skeletal Muscle.
  2. No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease and healthy controls: a randomized placebo-controlled cross-over study.
  3. Brain-Type Glycogen Phosphorylase Is Crucial for Astrocytic Glycogen Accumulation in Chronic Social Defeat Stress-Induced Depression in Mice.
  4. Lung adenocarcinoma-derived vWF promotes tumor metastasis by regulating PHKG1-mediated glycogen metabolism.
  5. Sevoflurane induced neurotoxicity in neonatal mice links to a GSK3β/Drp1-dependent mitochondrial fission and apoptosis.
  6. NAD+ ameliorates endotoxin-induced acute kidney injury in a sirtuin1-dependent manner via GSK-3β/Nrf2 signalling pathway.
  7. Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward.
  8. The Gender-Specific Interaction of DVL3 and GSK3β Polymorphisms on Major Depressive Disorder Susceptibility in a Chinese Han Population: A Case-Control Study.
  9. Diagnosis and follow-up of Glycogen Storage Disease (GSD) Type VI from the largest GSD center in China.
  10. Erratum to ``Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group'' [Neuromuscular Disorders 31 (2021) 1296-1310].
  11. Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a.
  12. Sex differences in endurance exercise capacity and skeletal muscle lipid metabolism in mice.
  13. Reposition of the anti-inflammatory drug diacerein in an in-vivo colorectal cancer model.
  1. Evid Based Complement Alternat Med. 2022 ;2022 5372103
    A Dioxidovanadium Complex cis-[VO2 (obz) py] Attenuates Hyperglycemia in Streptozotocin (STZ)-Induced Diabetic Male Sprague-Dawley Rats via Increased GLUT4 and Glycogen Synthase Expression in the Skeletal Muscle.
    Bonisiwe Mbatha, Andile Khathi, Ntethelelo Sibiya, Irvin Booysen, Phikelelani Ngubane.
      Vanadium has demonstrated antihyperglycemic effects in diabetes mellitus (DM) but is, however, associated with toxicity. Therefore, new vanadium complexes envisaged to possess heightened therapeutic potency while rendering less toxicity are being explored. Accordingly, the aim of the study was to investigate the effects of a dioxidovanadium (V) complex, cis-[VO2 (obz) py], on selected glucose metabolism markers in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were treated orally with cis-[VO2 (obz) py] (10, 20, and 40 mg/kg) twice every 3rd day for 5 weeks. Blood glucose concentrations, body weight, and food and water intake were monitored weekly, for 5 weeks. Rats were then euthanized after which blood, liver, and muscle tissues were collected for biochemical analysis. The administration of dioxidovanadium complex significantly decreased blood glucose concentrations throughout the 5-week period in comparison with the diabetic control (DC). The attenuation of hyperglycemia was accompanied by an increased glycogen concentration in both liver and muscle tissues in the treated groups. Furthermore, a significant increase was observed in the expression of glucose transporter type 4 (GLUT4) in the skeletal muscle tissues and glycogen synthase in the liver tissues. These findings indicate that our vanadium complex cis-[VO2 (obz) py] may exert antihyperglycemic effects through increased glucose uptake, glycogen synthesis, and increased GLUT4 and glycogen synthase expression.
    DOI:  https://doi.org/10.1155/2022/5372103
  2. J Inherit Metab Dis. 2022 Feb 12.
    No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease and healthy controls: a randomized placebo-controlled cross-over study.
    Nicoline Løkken, Jesper H Storgaard, Karoline L Revsbech, Nicol C Voermans, Gerrit Van Hall, John Vissing, Mette C Ørngreen.
      Patients with glycogen storage disease type V (GSDV), also known as McArdle disease, have blocked glycogen breakdown due to myophosphorylase-deficiency, leading to exercise intolerance, muscle pain and risk of muscle damage. Blood-derived ketone-bodies (KBs) constitute an alternative energy source that could fuel the muscle independent of glycogenolysis. However, except for long-time fasting or ketogenic dieting, KBs are present in low quantities. This led us to explore the effects of a drink containing exogenously-produced KBs in the form of poly-D-b-hydroxybutyrate (KE) on exercise capacity and metabolism in patients with GSDV. Eight GSDV-patients and four healthy controls (HC) were included in this placebo-controlled, cross-over-study where subjects were randomized to receive a KE-drink with 395mgKE/kg or placebo-drink on two separate days 25-minutes before a submaximal cycle exercise test. The primary outcome was exercise capacity as indicated by heart rate response (HR) to exercise. Secondary outcomes included perceived exertion (PE) and measures of KB-, carbohydrate- and fat-metabolism during exercise. In GSDV, the KE-drink vs. placebo increased plasma-KBs and KB-oxidation (p ≤ 0.0001) but did not improve exercise capacity as judged from HR (p = 0.120) and PE (p = 0.109). In addition, the KE-drink lowered plasma-glucose, free-fatty-acids and lowered lipolytic-rate and glucose rate of appearance compared to placebo. Similar results were found in the HC-group. The present study indicates that an increase in KB-oxidation by oral KE-supplementation does not improve exercise capacity in GSDV, possibly because of KB-induced inhibition of lipolysis and liver glucose output. Thus, oral KE-supplementation alone cannot be recommended as a treatment option for patients with GSDV. This article is protected by copyright. All rights reserved.
    Keywords:  McArdle disease; exercise capacity; exogenous ketone bodies; glycogen storage disease type V; ketone ester
    DOI:  https://doi.org/10.1002/jimd.12484
  3. Front Mol Neurosci. 2021 ;14 819440
    Brain-Type Glycogen Phosphorylase Is Crucial for Astrocytic Glycogen Accumulation in Chronic Social Defeat Stress-Induced Depression in Mice.
    Yuanyuan Zhu, Ze Fan, Qiuying Zhao, Jiaqi Li, Guohong Cai, Rui Wang, Yi Liang, Naining Lu, Junjun Kang, Danlei Luo, Huiren Tao, Yan Li, Jing Huang, Shengxi Wu.
      Astrocytic glycogen plays an important role in brain energy metabolism. However, the contribution of glycogen metabolism to stress-induced depression remains unclear. Chronic social defeat stress was used to induce depression-like behaviors in mice, assessed with behavioral tests. Glycogen concentration in the medial prefrontal cortex (mPFC) and the expression of key enzymes of the glycogen metabolism were investigated using Western blots, immunofluorescent staining, electron microscopy, and biochemical assays. Stereotaxic surgery and viral-mediated gene transfer were applied to knockdown or overexpress brain-type glycogen phosphorylase (PYGB) in the mPFC. The glycogen content increased in the mPFC after stress. Glycogenolytic dysfunction due to inactivation of PYGB was responsible for glycogen accumulation. Behavioral tests on astrocyte-specific PYGB overexpression mice showed that augmenting astrocytic PYGB reduces susceptibility to depression when compared with stress-susceptible mice. Conversely, PYGB genetic down-regulation in the mPFC was sufficient to induce glycogen accumulation and depression-like behaviors. Furthermore, PYGB overexpression in the mPFC decreases susceptibility to depression, at least partially by rescuing glycogen phosphorylase activity to maintain glycogen metabolism homeostasis during stress. These findings indicate that (1) glycogen accumulation occurs in mice following stress and (2) glycogenolysis reprogramming leads to glycogen accumulation in astrocytes and PYGB contributes to stress-induced depression-like behaviors. Pharmacological tools acting on glycogenolysis might constitute a promising therapy for depression.
    Keywords:  astrocyte; brain type glycogen phosphorylase; depression; glycogen; medial prefrontal cortex
    DOI:  https://doi.org/10.3389/fnmol.2021.819440
  4. Cancer Sci. 2022 Feb 12.
    Lung adenocarcinoma-derived vWF promotes tumor metastasis by regulating PHKG1-mediated glycogen metabolism.
    Jiayi Gu, Yingxue Qi, Yuxin Lu, Qianying Tao, Die Yu, Chunchun Jiang, Jianwen Liu, Xin Liang.
      Tumor metastasis is a series of complicated biological events. Hematogenous metastasis mediated by von Willebrand factor (vWF) is critical in tumor metastasis. However, the source of vWF and its role in tumor metastasis are controversial, and the further mechanism involved in mediating tumor metastasis is still unclear. In this study, we first demonstrated that lung adenocarcinoma cells could express vWF de novo and promotes tumor metastasis. Through the analysis of transcriptome sequencing, metastasis promotion effect of vWF may be related to phosphorylase kinase subunit G1 (PHKG1), a catalytic subtype of phosphorylase kinase PhK. PHKG1 was highly expressed in lung adenocarcinoma patients and led to poor prognosis. Further experiments found that lung adenocarcinoma-derived vWF induced the up-regulation of PHKG1 through the PI3K/AKT pathway to promote glycogenolysis. Glycogen was funneled into glycolysis, leading to increased metastasis. Tumor metastasis assayed in vitro and in vivo showed that knockdown of PHKG1 or synergistic injection of phosphorylase inhibition based on the overexpression of vWF could inhibit metastasis. In summary, our research proved that lung adenocarcinoma-derived vWF may mediate tumor metastasis by regulating PHKG1 to promote glycogen metabolism, and suggested potential targets for inhibition of lung adenocarcinoma metastasis.
    Keywords:  PHKG1; glycogen; metabolism; tumor metastasis; vWF
    DOI:  https://doi.org/10.1111/cas.15298
  5. Free Radic Biol Med. 2022 Feb 02. pii: S0891-5849(22)00042-9. [Epub ahead of print]181 72-81
    Sevoflurane induced neurotoxicity in neonatal mice links to a GSK3β/Drp1-dependent mitochondrial fission and apoptosis.
    Jinsheng Liu, Li Li, Ping Xie, Xiaoyan Zhao, Dongjing Shi, Yan Zhang, Chuxiong Pan, Tianzuo Li.
      Mitochondria damage and apoptosis were found associated with sevoflurane induced neurotoxicity in developing brains of rodent and neuro cell lines. The detailed upstream mechanism remains unclear. This study explored whether sevoflurane induces neurotoxicity by activating a GSK3β (glycogen synthase kinase 3β)/Drp1 (dynamin-related protein-1)-dependent mitochondrial fission and apoptosis. Our results showed that sevoflurane exposure promoted mitochondria fission in hippocampus of neonatal mice, resulted in a prolonged escape latency from P32 (32-day-postnatal) to P35, and decreased platform crossing times on P36 as compared to the control treatment. Additionally, sevoflurane upregulated GSK3β stability and activation, promoted phosphorylation of Drp1 at Ser616 along with its translocation to mitochondria and resulted in increasing cytochrome c and cleaved casepase-3 in hippocampus of neonatal mice and in human SK-N-SH cells. Simultaneously, sevoflurane promoted the interaction between Drp1 and GSK3β. Furthermore, GSK3β activated phosphorylation of Drp1 at Ser616, induced mitochondrial fission, loss of mitochondrial membrane potential (MMP) and apoptosis in SK-N-SH cells, which was attenuated by TDZD-8, an inhibitor of GSK3β. In conclusion, sevoflurane induced neurotoxicity links to a GSK3β/Drp1 dependent mitochondrial fission and apoptosis.
    Keywords:  Apoptosis; Drp1 protein; Glycogen Synthase Kinase 3 beta; Mitochondria; Mitochondrial fission; Neurotoxicity; Sevoflurane
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.031
  6. J Cell Mol Med. 2022 Feb 09.
    NAD+ ameliorates endotoxin-induced acute kidney injury in a sirtuin1-dependent manner via GSK-3β/Nrf2 signalling pathway.
    Simeng He, Qiaoying Gao, Xiaoyang Wu, Jia Shi, Yuan Zhang, Jing Yang, Xiangyun Li, Shihan Du, Yanfang Zhang, Jianbo Yu.
      Acute kidney injury (AKI) is a substantial worldwide public health concern with no specific and effective therapies in clinic. NAD+ is a pivotal determinant of cellular energy metabolism involved in the progression of AKI; however, its mechanism in kidney injury remains poorly understood. Sirtuin 1 (SIRT1) is an NAD+ -dependent deacetylase associated with renal protection and acute stress resistance. In this study, we have investigated the role of NAD+ in AKI and the potential mechanism(s) involved in its renoprotective effect. NAD+ was notably decreased and negatively correlated with kidney dysfunction in AKI, restoring NAD+ with NMN significantly ameliorates LPS-induced oxidative stress and apoptosis and attenuates renal damage. We also found that the protection of NAD+ is associated with SIRT1 expressions and performs in a SIRT1-dependent manner. Inhibition of SIRT1 blunted the protective effect of NAD+ and up-regulated the activity of glycogen synthase kinase-3β (GSK-3β) that was concomitant with mitigated Nrf2 nuclear accumulation, thereby exacerbates AKI. These findings suggest that NAD+ /SIRT1/GSK-3β/Nrf2 axis is an important mechanism that can protect against AKI which might be a potential therapeutic target for the treatment of AKI.
    Keywords:  NAD+; acute kidney injury; renal tubular injury; sepsis; sirtuins
    DOI:  https://doi.org/10.1111/jcmm.17222
  7. Front Mol Neurosci. 2021 ;14 792364
    Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward.
    Sara Melisa Arciniegas Ruiz, Hagit Eldar-Finkelman.
      The protein kinase, GSK-3, participates in diverse biological processes and is now recognized a promising drug discovery target in treating multiple pathological conditions. Over the last decade, a range of newly developed GSK-3 inhibitors of diverse chemotypes and inhibition modes has been developed. Even more conspicuous is the dramatic increase in the indications that were tested from mood and behavior disorders, autism and cognitive disabilities, to neurodegeneration, brain injury and pain. Indeed, clinical and pre-clinical studies were largely expanded uncovering new mechanisms and novel insights into the contribution of GSK-3 to neurodegeneration and central nerve system (CNS)-related disorders. In this review we summarize new developments in the field and describe the use of GSK-3 inhibitors in the variety of CNS disorders. This remarkable volume of information being generated undoubtedly reflects the great interest, as well as the intense hope, in developing potent and safe GSK-3 inhibitors in clinical practice.
    Keywords:  CNS; GSK-3; drug development; inhibitors; neurodegeneration
    DOI:  https://doi.org/10.3389/fnmol.2021.792364
  8. Oxid Med Cell Longev. 2022 ;2022 2633127
    The Gender-Specific Interaction of DVL3 and GSK3β Polymorphisms on Major Depressive Disorder Susceptibility in a Chinese Han Population: A Case-Control Study.
    Siyuan Ke, Jiarui Li, Lu Zhao, Jiarun Yang, Xueyan Zhao, Wenxin Zhang, Xiaohui Qiu, Xiuxian Yang, Jiawei Zhou, Yuying Tong, Xiongzhao Zhu, Xuan Liu, Yanjie Yang, Zhengxue Qiao, Tianyi Bu.
      Based on the "oxidative stress hypothesis" of major depressive disorder (MDD), cells regulate their structure through the Wnt pathway. Little is known regarding the interactions of dishevelled 3 (DVL3) and glycogen synthase kinase 3 beta (GSK3β) polymorphisms with MDD. The aim of the current study was to verify the relationship between DVL3 and GSK3β genetic variants in a Chinese Han population and further to evaluate whether these interactions exhibit gender-specificity. A total of 1136 participants, consisting of 541 MDD patients and 595 healthy subjects, were recruited. Five single-nucleotide polymorphisms (SNPs) of DVL3/GSK3β were selected to assess their interaction by use of a generalized multifactor dimensionality reduction method. The genotype and haplotype frequencies of DVL3/GSK3β polymorphisms were significantly different between patients and controls for DVL3 rs1709642 (P < 0.01) and GSK3β rs334558, rs6438552, and rs2199503 (P < 0.01). In addition, our results also showed that there were significant interaction effects between DVL3 and GSK3β polymorphisms and the risk of developing MDD, particularly in women. The interaction between DVL3 (rs1709642) and GSK3β (rs334558, rs6438552) showed a cross-validation (CV) consistency of 10/10, a P value of 0.001, and a testing accuracy of 59.22%, which was considered as the best generalized multifactor dimensionality reduction (GMDR) model. This study reveals the interaction between DVL3 and GSK3β polymorphisms on MDD susceptibility in a female Chinese Han population. The effect of gender should be taken into account in future studies that seek to explore the genetic predisposition to MDD relative to the DVL3 and GSK3β genes.
    DOI:  https://doi.org/10.1155/2022/2633127
  9. Hum Mutat. 2022 Feb 10.
    Diagnosis and follow-up of Glycogen Storage Disease (GSD) Type VI from the largest GSD center in China.
    Xiaomei Luo, Ying Duan, Di Fang, Yu Sun, Bing Xiao, Huiwen Zhang, Lianshu Han, Lili Liang, Zhuwen Gong, Xuefan Gu, Yongguo Yu, Wenjuan Qiu.
      Glycogen storage disease (GSD) type VI is a glycogenolysis disorder caused by variants of PYGL. Knowledge about this disease is limited because only approximately 50 cases have been reported. we investigated the clinical profiles, molecular diagnosis, and treatment outcomes in patients with gsd VI from 2000 to 2021. The main initial clinical features of this cohort include hepatomegaly, short stature, elevated liver transaminases, hypertriglyceridemia, fasting hypoglycemia, and hyperuricemia. After uncooked cornstarch treatment, the stature and biochemical parameters improved significantly (P < 0.05). However, hyperuricemia recurred in most patients during adolescence. Among the 56 GSD VI patients, 54 biallelic variants and two single allelic variants of PYGL were identified, of which 43 were novel. There were two hotspot variants, c.1621-258_2178-23del and c.2467C>T p.(Gln823*), mainly in patients from Southwest and South China. c.1621-258_2178-23del is a 3.6 kb deletion that results in an out-of-frame deletion r.1621_2177del and an in-frame deletion r.1621_2265del. Our data show for the first time that long-term monitoring of uric acid is recommended for older GSD VI patients. This study also broadens the variant spectrum of PYGL and indicates that there are two hot-spot variants in China. This article is protected by copyright. All rights reserved.
    Keywords:   PYGL ; Glycogen storage disease type VI; Hyperuricemia; Molecular diagnosis; Uncooked cornstarch treatment
    DOI:  https://doi.org/10.1002/humu.24345
  10. Neuromuscul Disord. 2022 Feb 06. pii: S0960-8966(22)00020-7. [Epub ahead of print]
    Erratum to ``Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group'' [Neuromuscular Disorders 31 (2021) 1296-1310].
    International Association for Muscle Glycogen Storage Disease study group
      
    DOI:  https://doi.org/10.1016/j.nmd.2022.01.004
  11. J Endocrinol Invest. 2022 Feb 07.
    Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a.
    P I H G Simons, O Valkenburg, I Telgenkamp, K M van der Waaij, D M de Groot, P Veeraiah, J A P Bons, T G J Derks, C G Schalkwijk, V B Schrauwen-Hinderling, C D A Stehouwer, M C G J Brouwers.
       PURPOSE: De novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels.
    METHODS: A case-control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy.
    RESULTS: Serum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction-a marker of de novo lipogenesis-were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (β: - 0.28, 95% CI: - 0.47;- 0.09 and β: - 0.02, 95% CI: - 0.04;- 0.01, respectively).
    CONCLUSION: Patients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls.
    Keywords:  De novo lipogenesis; Glycogen storage disease type 1a; Intrahepatic lipid content; Sex hormone-binding globulin
    DOI:  https://doi.org/10.1007/s40618-022-01753-2
  12. Physiol Rep. 2022 Feb;10(3): e15174
    Sex differences in endurance exercise capacity and skeletal muscle lipid metabolism in mice.
    Lola E Holcomb, Patrick Rowe, Caitlin C O'Neill, Elizabeth A DeWitt, Stephen C Kolwicz.
      Previous studies suggest that sex differences in lipid metabolism exist with females demonstrating a higher utilization of lipids during exercise, which is mediated partly by increased utilization of muscle triglycerides. However, whether these changes in lipid metabolism contribute directly to endurance exercise performance is unclear. Therefore, the objective of this study was to investigate the contribution of exercise substrate metabolism to sex differences in endurance exercise capacity (EEC) in mice. Male and female C57BL/6-NCrl mice were subjected to an EEC test until exhaustion on a motorized treadmill. The treadmill was set at a 10% incline, and the speed gradually increased from 10.2 m/min to 22.2 m/min at fixed intervals for up to 2.5 h. Tissues and blood were harvested in mice immediately following the EEC. A cohort of sedentary, non-exercised male and female mice were used as controls. Females outperformed males by ~25% on the EEC. Serum levels of both fatty acids and ketone bodies were ~50% higher in females at the end of the EEC. In sedentary female mice, skeletal muscle triglyceride content was significantly greater compared to sedentary males. Gene expression analysis demonstrated that genes involved in skeletal muscle fatty acid oxidation were significantly higher in females with no changes in genes associated with glucose uptake or ketone body oxidation. The findings suggest that female mice have a higher endurance exercise capacity and a greater ability to mobilize and utilize fatty acids for energy.
    Keywords:  exercise metabolism; exercise physiology; fatty acid oxidation; ketosis; triglyceride metabolism
    DOI:  https://doi.org/10.14814/phy2.15174
  13. Saudi Pharm J. 2022 Jan;30(1): 72-90
    Reposition of the anti-inflammatory drug diacerein in an in-vivo colorectal cancer model.
    Raghda T Abdel-Latif, Walaa Wadie, Yousra Abdel-Mottaleb, Dalaal M Abdallah, Nabila N El-Maraghy, Hanan S El-Abhar.
      Excessive interleukin (IL)-6 production is a driver for malignancy and drug resistance in colorectal cancer (CRC). Our study investigated a seven-week post-treatment with the anti-inflammatory drug, Diacerein (Diac), alone or in combination with 5-fluorouracil (5-FU), using a 1,2-dimethylhydrazine (DMH) rat model of CRC. Diac alone and 5-FU+Diac reduced serum levels of carcino-embryonic antigen (CEA), while all regimens decreased serum levels of colon cancer-specific antigen (CCSA), a more specific CRC biomarker. Additionally, Diac, 5-FU and their combination suppressed colonic content/gene expression of IL-6, its downstream oncogene, Kirsten rat sarcoma viral oncogene homolog (K-Ras), and consequently Notch intracellular domain and nuclear factor-kappa B (NF-κB) p65. In turn, NF-κB downstream factors, viz., matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), c-Myc, and B-cell lymphoma-2 (Bcl-2) were also downregulated, while E-cadherin was elevated. Additionally, the drugs reduced the immunoreactivity of CD31 to prove their anti-angiogenic effect, while the TUNEL assay confirmed the apoptotic effect. The apoptotic effect was confirmed by transferase dUTP nick-end labeling assay. Moreover, these drugs inhibited colon content of p-Akt, β-catenin, and cyclin D1 immunoreactivity. The drugs also activated the tumor suppressor glycogen synthase kinase 3- β (GSK3-β) and upregulated the expression of the Nur77 gene, which represents the second arm of IL-6 signaling. However, only 5-FU upregulated miR-200a, another K-Ras downstream factor. The in-vitro cytotoxic and migration/invasion assays verified the molecular trajectories. Accordingly, we evaluated the antineoplastic effect of Diac alone and its possible chemosensitization effect when added to 5-FU. This combination may target critical oncogenic pathways, including the IL-6/K-Ras/Notch/NF-κB p65 axis, p-Akt/GSK3-β/β-catenin/cyclin D-1 hub, and Nur77.
    Keywords:  5-FU, 5-flurouracil; 5-fluorouracil; ANOVA, analysis of variance; Akt, protein kinase B; BSA, bovine serum albumin; Bcl-2, B-cell lymphoma-2; CCSA-2, colon cancer specific antigen; CD 31, cluster of differentiation 31; CDK, cyclin dependent kinase; CEA, carcino-embryonic antigen; CRC, colorectal cancer; Colorectal cancer; Ct, cycle threshold; DAB, 3, 3'- Diaminobenzidine; DMH, di-methylhydrazine; Diac, diacerein; Diacerein; Dll-1, Delta-like 1; ELISA, Enzyme-Linked immunosorbent Assay; EMT, epithelial mesenchymal transition; GSK3-β, glycogen synthase kinase 3- β; H&E, hematoxylin & eosin; HRP, horse-radish peroxidase; Hes-1, hairy enhance of split-1; IL-6; Notch; VEGF, vascular endothelial growth factor; gp130, glycoprotein 130; β-catenin
    DOI:  https://doi.org/10.1016/j.jsps.2021.12.009
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