bims-glecem 2022-09-25 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022‒09‒25
sixteen papers selected by
Dipsikha Biswas, Københavns Universitet

Crosstalk between Glycogen-Selective Autophagy, Autophagy and Apoptosis as a Road towards Modifier Gene Discovery and New Therapeutic Strategies for Glycogen Storage Diseases.
Novel mutation of SLC37A4 in a glycogen storage disease type Ib patient with neutropenia, horseshoe kidney, and arteriovenous malformation: a case report.
The Clinical Management of Pompe Disease: A Pediatric Perspective.
HM-Chromanone, a Major Homoisoflavonoid in Portulaca oleracea L., Improves Palmitate-Induced Insulin Resistance by Regulating Phosphorylation of IRS-1 Residues in L6 Skeletal Muscle Cells.
Potential new roles for glycogen in epilepsy.
Are the Bacteria and Their Metabolites Contributing for Gut Inflammation on GSD-Ia Patients?
Cdc42 Promotes Axonogenesis of Primary Hippocampal Neurons by Inhibiting Glycogen Synthase Kinase-3β.
Black Ginger (Kaempferia parviflora) Extract Enhances Endurance Capacity by Improving Energy Metabolism and Substrate Utilization in Mice.
Glycogen Synthase Kinase 3β inhibits BMSCs Chondrogenesis in Inflammation via the Cross-Reaction between NF-κB and β-Catenin in the Nucleus.
Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi-Bickel Syndrome.
Post-translational dysregulation of glucose uptake during exhaustive cycling exercise in vastus lateralis muscle of healthy homozygous carriers of the ACE deletion allele.
Enrichment of Hepatic Glycogen and Plasma Glucose from H₂¹8 O Informs Gluconeogenic and Indirect Pathway Fluxes in Naturally-feeding Mice.
Excellent long term oncological outcome in a patient with rare glycogen rich clear cell carcinoma of breast following breast conservation surgery.
Energy Consumption and Cold Hardiness of Diapausing Fall Webworm Pupae.
Notch3 Transactivates Glycogen Synthase Kinase-3-Beta and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer Cells.
AMPK: The key to ischemia-reperfusion injury.

Life (Basel). 2022 Sep 08. pii: 1396. [Epub ahead of print]12(9):

Crosstalk between Glycogen-Selective Autophagy, Autophagy and Apoptosis as a Road towards Modifier Gene Discovery and New Therapeutic Strategies for Glycogen Storage Diseases.

Marina Andjelkovic, Anita Skakic, Milena Ugrin, Vesna Spasovski, Kristel Klaassen, Sonja Pavlovic, Maja Stojiljkovic.

  Glycogen storage diseases (GSDs) are rare metabolic monogenic disorders characterized by an excessive accumulation of glycogen in the cell. However, monogenic disorders are not simple regarding genotype-phenotype correlation. Genes outside the major disease-causing locus could have modulatory effect on GSDs, and thus explain the genotype-phenotype inconsistencies observed in these patients. Nowadays, when the sequencing of all clinically relevant genes, whole human exomes, and even whole human genomes is fast, easily available and affordable, we have a scientific obligation to holistically analyze data and draw smarter connections between genotype and phenotype. Recently, the importance of glycogen-selective autophagy for the pathophysiology of disorders of glycogen metabolism have been described. Therefore, in this manuscript, we review the potential role of genes involved in glycogen-selective autophagy as modifiers of GSDs. Given the small number of genes associated with glycogen-selective autophagy, we also include genes, transcription factors, and non-coding RNAs involved in autophagy. A cross-link with apoptosis is addressed. All these genes could be analyzed in GSD patients with unusual discrepancies between genotype and phenotype in order to discover genetic variants potentially modifying their phenotype. The discovery of modifier genes related to glycogen-selective autophagy and autophagy will start a new chapter in understanding of GSDs and enable the usage of autophagy-inducing drugs for the treatment of this group of rare-disease patients.

Keywords:  apoptosis; autophagy; autophagy-inducing drugs; glycogen storage diseases; glycogen-selective autophagy; modifier genes

DOI:  https://doi.org/10.3390/life12091396
Immunol Res. 2022 Sep 21.

Novel mutation of SLC37A4 in a glycogen storage disease type Ib patient with neutropenia, horseshoe kidney, and arteriovenous malformation: a case report.

Sepideh Ebrahimi Meimand, Gholamreza Azizi, Reza Yazdani, Negin Sanadgol, Nima Rezaei.

  Glycogen storage disease type Ib (GSDIb) is an autosomal recessive disorder caused by mutations of SLC37A4 gene, which encodes glucose 6-phosphate translocase (G6PT). Malfunction of G6PT leads to excessive fat and glycogen in liver, kidney, and intestinal mucosa. The clinical manifestations of GSD1b include hepatomegaly, renomegaly, neutropenia, hypoglycemia, and lactic acidosis. Furthermore, the disorder may result in severe complications in long-term including inflammatory bowel disease (IBD), hepatocellular adenomas (HCA), short stature, and autoimmune disorders, which stem from neutropenia and neutrophil dysfunction. Here, we represent a novel mutation of SLC37A4 in a 5-month girl who has a history of hospitalizations several times due to recurrent infection and her early presentations were failure to thrive and tachypnea. Further investigations revealed mild atrial septal defect, mild arteriovenous malformation from left lung, esophageal reflux, Horseshoe kidney, and urinary reflux in this patient. Moreover, the lab tests showed neutropenia, immunoglobulin (Ig) G and IgA deficiency, as well as thrombocytosis. Whole exome sequencing revealed c.1245G > A P.W415 homozygous mutation in SLC37A4 gene and c.580G > A p.V1941 heterozygous mutation in PIK3CD gene. This study shows that manifestations of GSD1b may not be limited to what was previously known and it should be considered in a wider range of patients.

Keywords:  Cardiovascular; Gastrointestinal; Immunodeficiency; Lymphocyte

DOI:  https://doi.org/10.1007/s12026-022-09320-w
Children (Basel). 2022 Sep 16. pii: 1404. [Epub ahead of print]9(9):

The Clinical Management of Pompe Disease: A Pediatric Perspective.

Jorge Sales Marques.

  Pompe disease (PD) is an inherited metabolic disorder caused by a deficiency of acid α-glucosidase (GAA), leading to lysosomal accumulation of glycogen, mainly in skeletal and cardiac muscles as well as the nervous system. Patients with PD develop cellular dysfunction and muscle damage. PD can be classified into two classic forms, namely infantile-onset PD (IOPD) and late-onset PD (LOPD). Delayed treatment, particularly in IOPD, would result in significant organ damage and early death. Nonetheless, early diagnosis and timely treatment are often hampered by the rarity of PD and its wide variety of, but overlapping, symptoms. This article reviews the common clinical presentations of PD and outlines the essentials of PD management. In particular, the implications of newborn screening (NBS) and clinical performance of enzyme replacement therapy (ERT) are highlighted.

Keywords:  Pompe disease; alglucosidase alpha; clinical management; enzyme replacement therapy; newborn screening

DOI:  https://doi.org/10.3390/children9091404
Nutrients. 2022 Sep 15. pii: 3815. [Epub ahead of print]14(18):

HM-Chromanone, a Major Homoisoflavonoid in Portulaca oleracea L., Improves Palmitate-Induced Insulin Resistance by Regulating Phosphorylation of IRS-1 Residues in L6 Skeletal Muscle Cells.

Jae-Eun Park, Ji-Sook Han.

  This study investigated the effect of (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone) on palmitate-induced insulin resistance and elucidated the underlying mechanism in L6 skeletal muscle cells. Glucose uptake was markedly decreased due to palmitate-induced insulin resistance in these cells; however, 10, 25, and 50 µM HM-chromanone remarkably improved glucose uptake in a concentration-dependent manner. HM-chromanone treatment downregulated protein tyrosine phosphatase 1B (PTP1B) and phosphorylation of c-Jun N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ), which increased because of palmitate mediating the insulin-resistance status in cells. HM-chromanone promoted insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and suppressed palmitate-induced phosphorylation of IRS-1 serine. This activated phosphoinositide 3-kinase (PI3K) and stimulated protein kinase B (AKT) phosphorylation. Phosphorylated AKT promoted the translocation of Glucose transporter type 4 to the plasma membrane and significantly enhanced glucose uptake into muscle cells. Additionally, HM-chromanone increased glycogen synthesis through phosphorylating glycogen synthase kinase 3 alpha/beta (GSK3 α/β) via AKT. Consequently, HM-chromanone may improve insulin resistance by downregulating the phosphorylation of IRS-1 serine through inhibition of negative regulators of insulin signaling and inflammation-activated protein kinases in L6 skeletal muscle cells.

Keywords:  HM-chromanone; L6 skeletal muscle cells; glycogen synthesis; insulin resistance

DOI:  https://doi.org/10.3390/nu14183815
Epilepsia. 2022 Sep 19.

Potential new roles for glycogen in epilepsy.

Gerald A Dienel, Lisa Gillinder, Aileen McGonigal, Karin Borges.

  Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue, often show low signals with 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in many epileptic patients, even when there are no radiologically detectable structural abnormalities. Low FDG-PET signals are thought to reflect glucose hypometabolism. Here we review knowledge about metabolism of glucose and glycogen and oxidative stress in people with epilepsy and acute and chronic rodent seizure models. Interictal brain glucose levels are normal and do not cause apparent glucose hypometabolism that remains unexplained. During seizures, high amounts of fuel are needed to satisfy the energy demands. Astrocytes consume glycogen as an additional emergency fuel to supplement glucose during high metabolic demand, such as during brain stimulation, stress, and seizures. In rodents, brain glycogen levels drop during induced seizures and increase to higher levels thereafter. Interictally, in people with epilepsy and chronic epilepsy models, normal glucose but high glycogen levels have been found in the presumed brain areas involved in seizure generation. We present our new hypothesis that as an adaptive response to repeated episodes of high metabolic demand, high interictal glycogen levels in epileptogenic brain areas are used to support energy metabolism and potentially interictal neuronal activity. Glycogenolysis, which can be triggered by stress or oxidative stress, leads to decreased utilisation of plasma glucose in epileptogenic brain areas resulting in low FDG signals that are related to functional changes underlying seizure onset and propagation. This is (partially) reversible after successful surgery. Last, we propose that potential interictal glycogen depletion in epileptogenic and surrounding areas may cause energy shortages in astrocytes, which may impair potassium buffering and contribute to seizure generation. Based on these hypotheses, auxiliary fuels or treatments that support glycogen metabolism may be useful to treat epilepsy.

Keywords:  FDG-PET; glucose utilization; glycogen; interictal epileptic hyperactivity

DOI:  https://doi.org/10.1111/epi.17412
Metabolites. 2022 Sep 16. pii: 873. [Epub ahead of print]12(9):

Are the Bacteria and Their Metabolites Contributing for Gut Inflammation on GSD-Ia Patients?

Karina Colonetti, Evelise Leis de Carvalho, Darlene Lopes Rangel, Paulo Marcos Pinto, Luiz Fernando Wurdig Roesch, Franciele Cabral Pinheiro, Ida Vanessa Doederlein Schwartz.

  Recently, patients with glycogen storage disease (GSD) have been described as having gut dysbiosis, lower fecal pH, and an imbalance in SCFAs due to an increase in acetate and propionate levels. Here, we report the fecal measurement of bacterial-related metabolites formic, acetic, lactic, propionic, and succinic acid, a key metabolite of both host and microbiota, on a previously described cohort of 24 patients (GSD Ia = 15, GSD Ib = 5, 1 GSD III = 1 and GSD IX = 3) and 16 healthy controls, with similar sex and age, using the high-performance liquid chromatography technique. The succinic acid levels were higher in the GSD patients than in the controls (patients = 38.02; controls = 27.53; p = 0.045), without differences between the groups for other metabolites. Fecal pH present inverse correlation with lactic acid (R = -0.54; p = 0.0085), while OTUs were inversely correlated with both lactic (R = -0.46; p = 0.026) and formic (R = -0.54; p = 0.026) acids. Using two distinct metrics of diversity, borderline significance was obtained for propionic acid, affecting the microbial structure on Euclidean basis in 8% (r2 = 0.081; p = 0.079), and for lactic acid, affecting 6% of microbial structure using Bray-Curtis distance (r2 = 0.065; p = 0.060). No correlation was found between SCFAs and total carbohydrate consumption among the participants or uncooked cornstarch consumption among the patients.

Keywords:  dysbiosis; fecal pH; glycogen storage disease; gut microbiota; inflammation; short-chain fatty acids

DOI:  https://doi.org/10.3390/metabo12090873
J Integr Neurosci. 2022 Jul 22. 21(5): 133

Cdc42 Promotes Axonogenesis of Primary Hippocampal Neurons by Inhibiting Glycogen Synthase Kinase-3β.

Yu-Ting Li, Fang-Zheng Chen, Wei Chen, Hui-Ming Zhu, Yu Chen, Zhen-Lin Li, Fang Yan, Zhong-Ying Liu, Wei-Ren Dong, Lin Zhang, Hai-Hong Wang.

  BACKGROUND: Progressive axon degeneration is a common pathological feature of neurodegenerative diseases. Cdc42 is a member of the Rho GTPase family that participates in axonogenesis. GSK-3β is a serine/threonine kinase highly implicated in neuronal development and neurodegeneration. This study aimed to examine whether cdc42 promotes axonogenesis by regulating GSK-3β activity.METHODS: Hippocampal neurons were isolated from neonatal Sprague-Dawley rats and transfected with designated plasmid vectors to alter the activities of cdc42 and GSK-3β. LiCl treatment was used to inhibit the GSK-3β activity in primary neurons. GSK-3β activity was determined by an enzyme activity assay kit. Immunofluorescence staining was used to detect axons stained with anti-Tau-1 antibody and dendrites stained with anti-MAP2 antibody.
RESULTS: Transfection with an active cdc42 mutant (cdc42F28L) decreased the activity of GSK-3β and induced axonogenesis in primary rat hippocampal neurons, while transfection with a negative cdc42 mutant (cdc42N17) resulted an opposite effect. Moreover, transfection with plasmid vectors carrying wild-type GSK-3β or a constitutively active GSK3β mutant (GSK-3β S9A) increased the activity of GSK-3β and attenuated axonogenesis of primary hippocampal neurons with excessive cdc42 activity, whereas inhibition of GSK-3β by LiCl abolished the inhibitory effect of the negative cdc42 mutant on axonogenesis.
CONCLUSIONS: This study suggests that cdc42 induces axonogenesis of primary rat hippocampal neurons via inhibiting GSK-3β activity. These findings support further investigation into the mechanisms of cdc42/GSK-3β-mediated axonogenesis.

Keywords:  CRMP-2; GSK-3β; axonogenesis; cdc42; hippocampal neurons

DOI:  https://doi.org/10.31083/j.jin2105133
Nutrients. 2022 Sep 17. pii: 3845. [Epub ahead of print]14(18):

Black Ginger (Kaempferia parviflora) Extract Enhances Endurance Capacity by Improving Energy Metabolism and Substrate Utilization in Mice.

Jiapeng Huang, Takashi Tagawa, Sihui Ma, Katsuhiko Suzuki.

  Black ginger (Kaempferia parviflora) extract (KPE), extracted from KP, a member of the ginger family that grows in Thailand, has a good promotion effect on cellular energy metabolism and therefore has been used to enhance exercise performance and treatment of obesity in previous studies. However, the effect of single-dose administration of KPE on endurance capacity has not been thoroughly studied, and whether the positive effect of KPE on cellular energy metabolism can have a positive effect on exercise capacity in a single dose is unknown. In the present study, we used a mouse model to study the effects of acute KPE administration 1 h before exercise on endurance capacity and the underlying mechanisms. The purpose of our study was to determine whether a single administration of KPE could affect endurance performance in mice and whether the effect was produced through a pro-cellular energy metabolic pathway. We found that a single administration of KPE (62.5 mg/kg·bodyweight) can significantly prolong the exercise time to exhaustion. By measuring the mRNA expression of Hk2, Slc2a4 (Glut4), Mct1, Ldh, Cd36, Cpt1β, Cpt2, Lpl, Pnpla2 (Atgl), Aco, Acadm (Mcad), Hadh, Acacb (Acc2), Mlycd (Mcd), Pparg, Ppargc1a (Pgc-1α), Tfam, Gp, Gs, Pfkm, Pck1 (Pepck), G6pc (G6pase), Cs, and Pfkl in skeletal muscle and liver, we found that acute high-concentration KPE administration significantly changed the soleus muscle gene expression levels (p < 0.05) related to lipid, lactate, and glycogen metabolism and mitochondrial function. In gastrocnemius muscle and liver, glycogen metabolism-related gene expression is significantly changed by a single-dose administration of KPE. These results suggest that KPE has the potential to improve endurance capacity by enhancing energy metabolism and substrate utilization in muscles and liver.

Keywords:  Kaempferia parviflora; energy metabolism; exercise tolerance; lactate acid; lipid metabolism

DOI:  https://doi.org/10.3390/nu14183845
Stem Cells Int. 2022 ;2022 5670403

Glycogen Synthase Kinase 3β inhibits BMSCs Chondrogenesis in Inflammation via the Cross-Reaction between NF-κB and β-Catenin in the Nucleus.

Zhenggang Wang, Zhiyi He, Weikai Zhang, Shuang Liang, Kun Chen, Shimeng Xu, Ying Zhang, Peng Cheng.

Inflammation can influence the pluripotency and self-renewal of mesenchymal stem cells (MSCs), thereby altering their cartilage regeneration ability. Sprague-Dawley (SD) rat bone marrow mesenchymal stem cells (BMSCs) were isolated and found to be defective in differentiation potential in the interleukin-1β- (IL-1β-) induced inflammatory microenvironment. Glycogen synthase kinase-3β (GSK-3β) is an evolutionarily conserved serine/threonine kinase that plays a role in numerous cellular processes. The role of GSK-3β in inflammation may be related to the nuclear factor-κB (NF-κB) signaling pathway and the Wnt/β-catenin signaling pathway, whose mechanism remains unclear. In this study, we found that GSK-3β can inhibit chondrogenesis of IL-1β-impaired BMSCs by disrupting metabolic balance and promoting cell apoptosis. By using the inhibitors LiCl and SN50, we demonstrated that GSK-3β regulates the chondrogenesis via the NF-κB and Wnt/β-catenin signaling pathways and possibly mediates the cross-reaction between NF-κB and β-catenin in the nucleus. Given the molecular mechanisms of GSK-3β in chondrogenic differentiation in inflammation, GSK-3β is a crucial target for the treatment of inflammation-induced cartilage disease.

DOI: https://doi.org/10.1155/2022/5670403
Biomedicines. 2022 Aug 29. pii: 2114. [Epub ahead of print]10(9):

Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi-Bickel Syndrome.

Sanaa Sharari, Basirudeen Kabeer, Idris Mohammed, Basma Haris, Igor Pavlovski, Iman Hawari, Ajaz Ahmad Bhat, Mohammed Toufiq, Sara Tomei, Rebecca Mathew, Najeeb Syed, Sabah Nisar, Selma Maacha, Jean-Charles Grivel, Damien Chaussabel, Johan Ericsson, Khalid Hussain.

  Fanconi-Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.

Keywords:  Fanconi–Bickel syndrome (FBS); PBMCs (peripheral blood mononuclear cells); dysglycemia; glucose transporter 2 (GLUT2); miRNAs

DOI:  https://doi.org/10.3390/biomedicines10092114
Front Physiol. 2022 ;13 933792

Post-translational dysregulation of glucose uptake during exhaustive cycling exercise in vastus lateralis muscle of healthy homozygous carriers of the ACE deletion allele.

Martin Flück, David Vaughan, Jörn Rittweger, Marie-Noëlle Giraud.

  Homozygous carriers of the deletion allele in the gene for angiotensin-converting enzyme (ACE-DD) demonstrate an elevated risk to develop inactivity-related type II diabetes and show an overshoot of blood glucose concentration with enduring exercise compared to insertion allele carriers. We hypothesized that ACE-DD genotypes exhibit a perturbed activity of signaling processes governing capillary-dependent glucose uptake in vastus lateralis muscle during exhaustive cycling exercise, which is associated with the aerobic fitness state. 27 healthy, male white Caucasian subjects (26.8 ± 1.1 years; BMI 23.6 +/- 0.6 kg m-2) were characterized for their aerobic fitness based on a threshold of 50 ml O2 min-1 kg-1 and the ACE-I/D genotype. Subjects completed a session of exhaustive one-legged exercise in the fasted state under concomitant measurement of cardiorespiratory function. Capillary blood and biopsies were collected before, and ½ and 8 h after exercise to quantify glucose and lipid metabolism-related compounds (lipoproteins, total cholesterol, ketones) in blood, the phosphorylation of 45 signaling proteins, muscle glycogen and capillaries. Effects of aerobic fitness, ACE-I/D genotype, and exercise were assessed with analysis of variance (ANOVA) under the hypothesis of a dominant effect of the insertion allele. Exertion with one-legged exercise manifested in a reduction of glycogen concentration ½ h after exercise (-0.046 mg glycogen mg-1 protein). Blood glucose concentration rose immediately after exercise in association with the ACE-I/D genotype (ACE-DD: +26%, ACE-ID/II: +6%) and independent of the fitness state (p = 0.452). Variability in total cholesterol was associated with exercise and fitness. In fit subjects, the phosphorylation levels of glucose uptake-regulating kinases [AKT-pT308 (+156%), SRC-pY419, p38α-pT180/T182, HCK-pY411], as well as cytokine/angiotensin 1-7 signaling factors [(STAT5A-pY694, STAT5B-pY699, FYN-pY420, EGFR-pY1086] were higher in angiotensin converting enzyme I-allele carriers than ACE-DD genotypes after exercise. Conversely, the AKT-S473 phosphorylation level (+117%) and angiotensin 2's blood concentration (+191%) were higher in ACE-DD genotypes. AKT-S473 phosphorylation levels post-exercise correlated to anatomical parameters of muscle performance and metabolic parameters (p < 0.05 and │r│>0.70). The observations identify reciprocal alterations of S473 and T308 phosphorylation of AKT as gatekeeper of a post-translational dysregulation of transcapillary glucose uptake in ACE-DD genotypes which may be targeted in personalized approaches to mitigate type II diabetes.

Keywords:  angiotensin; diabetes; exercise; genotype; signalling

DOI:  https://doi.org/10.3389/fphys.2022.933792
NMR Biomed. 2022 Sep 23. e4837

Enrichment of Hepatic Glycogen and Plasma Glucose from H₂¹8 O Informs Gluconeogenic and Indirect Pathway Fluxes in Naturally-feeding Mice.

Margarida Coelho, Rohit Mahar, Getachew D Belew, Alejandra Torres, Cristina Barosa, Fernando Cabral, Ivan Viegas, Amalia Gastaldelli, Vera M Mendes, Bruno Manadas, John G Jones, Matthew E Merritt.

  Deuterated water (2 H2 O) is a widely used tracer of carbohydrate biosynthesis in both pre-clinical and clinical settings, but the significant kinetic isotope effects (KIE) of 2 H can distort metabolic information and mediate toxicity. 18 O-water (H2 18 O) has no significant KIE and is incorporated into specific carbohydrate oxygens via well-defined mechanisms, but to date it has not been evaluated in any animal model. Mice were given H2 18 O during overnight feeding and 18 O-enrichments of liver glycogen, triglyceride glycerol and blood glucose was quantified by 13 C NMR and mass spectrometry (MS). Enrichment of oxygens 5 and 6 relative to body water informed indirect pathway contributions from Krebs cycle and triose phosphate sources. Compared to normal chow-fed mice (NC), mice whose chow was supplemented with a fructose/glucose mix (HS) had significantly higher indirect pathway contributions from triose phosphate sources, consistent with fructose glycogenesis. Blood glucose and liver triglyceride glycerol (TG) 18 O-enrichments were quantified by MS. Blood glucose 18 O-enrichment was significantly higher for HS versus NC and consistent with gluconeogenic fructose metabolism. TG 18 O-enrichment was extensive for both NC and HS mice indicating high turnover of liver triglyceride independently of diet. Thus, H2 18 O informs hepatic carbohydrate biosynthesis in similar detail to 2 H2 O but without KIE-associated risks.

Keywords:  fructose; gluconeogenesis; glycogenesis; isotope shift; triose phosphates

DOI:  https://doi.org/10.1002/nbm.4837
Int J Surg Case Rep. 2022 Sep 15. pii: S2210-2612(22)00886-0. [Epub ahead of print]99 107640

Excellent long term oncological outcome in a patient with rare glycogen rich clear cell carcinoma of breast following breast conservation surgery.

Ravinder Chowrappa Sanjeeviah, Mahesh Bandimegal, Veena Ramaswamy, Kanmani Govindrao Telkar, Drishti Patil.

  INTRODUCTION: We present a case report of excellent oncological outcome after 7-year follow up in a female Indian patient with pT2N3aM0 rare GRCC of the breast following breast conservation surgery and appropriate adjuvant treatment. Glycogen rich cell carcinoma (GRCC) is a rare subtype of primary malignant neoplasm of the breast which is not commonly discussed. Only approximately 288 cases have been reported since its first description globally with reports of varying prognosis. Even less (4 patients), which have been reported from India have described only clinic pathological features. This is first case report of patient from India discussing long term oncological outcome of a patient with rare GRCC (pT2N3aMO) of the breast following breast conservation surgery and appropriate adjuvant treatment. A 41-year-old lady presented to us with history of 2 × 2 cm right breast lump for 2 weeks. A BIRAD IV hypo echoic lesion with slightly irregular margins in the upper outer quadrant of the right breast and right axillary lymphadenopathy was reported in mammogram. PET CT showed metabolically active lesion 2.3 × 1.3 cm enhancing nodule with spiculated margins at the same site (SUV-10.8) with metabolically active right axillary metastatic lymphadenopathy (SUV-11) with no distant metastases. Core biopsy indicated Ductal carcinoma. Patient underwent right breast conservation surgery (Wide local excision and oncoplasty with axillary clearance) uneventfully followed by appropriate adjuvant treatment (Chemotherapy, Targeted treatment, Radiotherapy). The final pathological stage was Glycogen rich clear cell carcinoma, pT2N3a M0 with Her2 positive but negative for ER and PR with Ki 67-50 %. The patient had excellent outcome and was alive and cancer free even after 7 years follow up.CONCLUSION: The purpose of reporting this case is to increase the knowledge about this rare subtype of breast cancer which underwent organ preservation. This case report reveals that clinical behavior and oncological outcome of GRCC breast can be unexpected, unusual, varied and even good, contrary to recent 2019 SEER data (Zhou Z, Kinslow CJ, Hibshoosh H, et al. Clinical features, survival and prognostic factors of glycogen-rich clear cell carcinoma (GRCC) of the breast in the US population. J Clin Med. 2019; 8: pii: E246).

Keywords:  Breast conservation surgery; Case report; Glycogen rich cell carcinoma (GRCC) of breast; Surgical outcome

DOI:  https://doi.org/10.1016/j.ijscr.2022.107640
Insects. 2022 Sep 19. pii: 853. [Epub ahead of print]13(9):

Energy Consumption and Cold Hardiness of Diapausing Fall Webworm Pupae.

Lvquan Zhao, Xinmei Wang, Zheng Liu, Alex S Torson.

  Diapause and cold hardiness are essential components of winter survival for most insects in temperate zones. The fall webworm, Hyphantria cunea, overwinters in a pupal diapause. In this study, we investigated the energy consumption and cold hardiness of diapausing pupae. We found that lipid content decreased from October to November and stabilized from November to March. Glycogen content decreased by 61.3% and 52.2% for females and males, respectively, from October to November, and decreased slowly from November to March. We also observed a significant increase in trehalose concentrations as ambient temperatures decreased from October to November and a decrease in trehalose as temperatures increased again in March. We did not observe substantial changes in pupal supercooling points among the dates sampled. In addition, prolonged pupal development time reduced their survival rate and had no significant effect on post-diapause adult body mass and fecundity but reduced egg diameter in females. These results suggest that the energy consumption of H. cunea pupae during early diapause depends on lipid and glycogen, while it shifts to depend on glycogen or other energy stores in the mid- and late diapause stages. Our results also suggest that the prolonged development time of diapausing pupae had a negative effect on post-diapause fitness.

Keywords:  Hyphantria cunea; diapause; energy consumption; post-diapause fitness; supercooling point

DOI:  https://doi.org/10.3390/insects13090853
Cells. 2022 Sep 14. pii: 2872. [Epub ahead of print]11(18):

Notch3 Transactivates Glycogen Synthase Kinase-3-Beta and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer Cells.

Weiling Chen, Yongqu Zhang, Ronghui Li, Wenhe Huang, Xiaolong Wei, De Zeng, Yuanke Liang, Yunzhu Zeng, Min Chen, Lixin Zhang, Wenliang Gao, Yuanyuan Zhu, Yaochen Li, Guojun Zhang.

  As a critical transformational process in the attributes of epithelial cells, epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion, metastasis, and resistance to treatment, which contributes to the ultimate death of some patients with breast cancer. Glycogen synthase kinase-3-beta (GSK3β) is thought to be an EMT suppressor that down-regulates the protein, snail, a zinc finger transcription inhibitor, and regulates E-cadherin expression and the Wnt signaling pathway. Our previous studies have shown that Notch3 also inhibits EMT in breast cancer. In mammary gland cells, GSK3β physically bound and phosphorylated the intracellular domain of two Notch paralogs: N1ICD was positively regulated, but N2ICD was negatively regulated; however, the relationship between Notch3, GSK3β, and EMT in breast cancer is still unclear and crosstalk between Notch3 and GSK3β has not been widely investigated. In this study, we revealed that Notch3 was an essential antagonist of EMT in breast cancer cells by transcriptionally upregulating GSK3β. In breast cancer, MCF-7 and MDA-MB-231 cell lines, the silencing of Notch3 reduced GSK3β expression, which is sufficient to induce EMT. Conversely, ectopic Notch3 expression re-activated GSK3β and E-cadherin. Mechanistically, Notch3 can bind to the GSK3β promoter directly and activate GSK3β transcription. In human breast cancer samples, Notch3 expression is positively associated with GSK3β (r = 0.416, p = 0.001); moreover, high expressions of Notch3 and GSK3β mRNA are correlated to better relapse-free survival in all breast cancer patients via analysis in "the Kaplan-Meier plotter" database. In summary, our preliminary results suggested that Notch3 might inhibit EMT by trans-activating GSK3β in breast cancer cells. The suppression of Notch3 expression may contribute to EMT by transcriptionally downregulating GSK3β in breast cancer.

Keywords:  GSK3β; Notch3; breast cancer; epithelial-to-mesenchymal transition; prognosis

DOI:  https://doi.org/10.3390/cells11182872
J Cell Physiol. 2022 Sep 22.

AMPK: The key to ischemia-reperfusion injury.

Jie Cai, Xinyue Chen, Xingyu Liu, Zhangwang Li, Ao Shi, Xiaoyi Tang, Panpan Xia, Jing Zhang, Peng Yu.

  Ischemia-reperfusion injury (IRI) refers to a syndrome in which tissue damage is further aggravated and organ function further deteriorates when blood flow is restored after a period of tissue ischemia. Acute myocardial infarction, stress ulcer, pancreatitis, intestinal ischemia, intermittent claudication, acute tubular necrosis, postshock liver failure, and multisystem organ failure are all related to reperfusion injury. AMP-activated protein kinase (AMPK) has been identified in multiple catabolic and anabolic signaling pathways. The functions of AMPK during health and diseases are intriguing but still need further research. Except for its conventional roles as an intracellular energy switch, emerging evidence reveals the critical role of AMPK in IRI as an energy-sensing signal molecule by regulating metabolism, autophagy, oxidative stress, inflammation, and other progressions. At the same time, drugs based on AMPK for the treatment of IRI are constantly being researched and applied in clinics. In this review, we summarize the mechanisms underlying the effects of AMPK in IRI and describe the AMPK-targeting drugs in treatment, hoping to increase the understanding of AMPK in IRI and provide new insights into future clinical treatment.

Keywords:  AMPK; glycolysis and glycogen synthesis; ischemia-reperfusion injury; lipid metabolism; programmed cell death

DOI:  https://doi.org/10.1002/jcp.30875