altered glucose
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2022 ◽  
Vol 12 ◽  
Author(s):  
Rajtilak Majumdar ◽  
Paul J. Galewski ◽  
Imad Eujayl ◽  
Rakesh Minocha ◽  
Eric Vincill ◽  
...  

Beet curly top virus (BCTV) mediated yield loss in sugar beets is a major problem worldwide. The circular single-stranded DNA virus is transmitted by the beet leafhopper. Genetic sources of BCTV resistance in sugar beet are limited and commercial cultivars rely on chemical treatments versus durable genetic resistance. Phenotypic selection and double haploid production have resulted in sugar beet germplasm (KDH13; 13 and KDH4-9; 4) that are highly resistant to BCTV. The molecular mechanism of resistance to the virus is unknown, especially the role of small non-coding RNAs (sncRNAs) during early plant–viral interaction. Using the resistant lines along with a susceptible line (KDH19-17; 19), we demonstrate the role of sugar beet microRNAs (miRNAs) in BCTV resistance during early infection stages when symptoms are not yet visible. The differentially expressed miRNAs altered the expression of their corresponding target genes such as pyruvate dehydrogenase (EL10Ac1g02046), carboxylesterase (EL10Ac1g01087), serine/threonine protein phosphatase (EL10Ac1g01374), and leucine-rich repeats (LRR) receptor-like (EL10Ac7g17778), that were highly expressed in the resistant lines versus susceptible lines. Pathway enrichment analysis of the miRNA target genes showed an enrichment of genes involved in glycolysis/gluconeogenesis, galactose metabolism, starch, and sucrose metabolism to name a few. Carbohydrate analysis revealed altered glucose, galactose, fructose, and sucrose concentrations in the infected leaves of resistant versus susceptible lines. We also demonstrate differential regulation of BCTV derived sncRNAs in the resistant versus susceptible lines that target sugar beet genes such as LRR (EL10Ac1g01206), 7-deoxyloganetic acid glucosyltransferase (EL10Ac5g12605), and transmembrane emp24 domain containing (EL10Ac6g14074) and altered their expression. In response to viral infection, we found that plant derived miRNAs targeted BCTV capsid protein/replication related genes and showed differences in expression among resistant and susceptible lines. The data presented here demonstrate the contribution of miRNA mediated regulation of metabolic pathways and cross-kingdom RNA interference (RNAi) in sugar beet BCTV resistance.


2021 ◽  
Author(s):  
Chung-Yen Huang ◽  
Yu-Chen Pai ◽  
Linda Chia-Hui Yu

Abstract Background: Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). The aim of this study was to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Methods: Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of high concentrations of glucose, pyruvate or ATP-encapsulated liposomes. Cell apoptosis was measured by DNA fragmentation and caspase activities, and necroptosis was evaluated by immunoprecipitation of receptor-interacting protein kinase (RIP) 1/3 complex. Cell cycles were assessed by flow cytometric analysis.Results: Human CRC cell lines treated with irinotecan in the presence of high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in the presence of normal glucose. Irinotecan induced apoptosis and necroptosis, both of which were mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it had no effect on necroptosis. In contrast, pyruvate attenuated the RIP1/3-dependent necroptosis via free radical scavenging, without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated irinotecan-induced G0/G1 shift whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere sizes while pyruvate prevented the deformation of spheroid mass. Conclusions: Glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, which might contribute to tumor recurrence.


2021 ◽  
Vol 12 ◽  
Author(s):  
Tian-Tian Jiang ◽  
Chao-Fan Ji ◽  
Xiu-Ping Cheng ◽  
Shao-Fei Gu ◽  
Rui Wang ◽  
...  

A previously validated anti-rheumatic compound α-mangostin (MAN) shows significant metabolism regulatory effects. The current study aimed to clarify whether this property contributed to its inhibition on synovial angiogenesis. Male wistar rats with adjuvant-induced arthritis (AIA) were orally treated by MAN for 32 days. Afterwards, biochemical parameters and cytokines in plasma were determined by corresponding kits, and glycometabolism-related metabolites were further accurately quantified by LC-MS method. Anti-angiogenic effects of MAN were preliminarily assessed by joints based-immunohistochemical examination and matrigel plug assay. Obtained results were then validated by experiments in vitro. AIA-caused increase in circulating transforming growth factor beta, interleukin 6, hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in blood and local HIF-1α/VEGF expression in joints was abrogated by MAN treatment, and pannus formation within matrigel plugs implanted in AIA rats was inhibited too. Scratch and transwell assays revealed the inhibitory effects of MAN on human umbilical vein endothelial cells (HUVECs) migration. Furthermore, MAN inhibited tubule formation capability of HUVECs and growth potential of rat arterial ring-derived endothelial cells in vitro. Meanwhile, MAN eased oxidative stress, and altered glucose metabolism in vivo. Glycolysis-related metabolites including glucose 6-phosphate, fructose 6-phosphate, 3-phosphoglyceric acid and phosphoenolpyruvic acid in AIA rats were decreased by MAN, while the impaired pyruvate-synthesizing capability of lactate dehydrogenase (LDH) was recovered. Consistently, MAN restored lipopolysaccharide-elicited changes on levels of glucose and LDH in HUVECs culture system, and exerted similar effects with LDH inhibitor stiripentol on glycometabolism and VEGF production as well as tubule formation capability of HUVECs. These evidences show that MAN treatment inhibited aerobic glycolysis in AIA rats, which consequently eased inflammation-related hypoxia, and hampered pathological neovascularization.


Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1332
Author(s):  
Aleksandra A. Stefaniak ◽  
Piotr K. Krajewski ◽  
Dorota Bednarska-Chabowska ◽  
Marek Bolanowski ◽  
Grzegorz Mazur ◽  
...  

Background: Despite growing interest in itch, data regarding itch in type 2 diabetes mellitus (DM2) are still limited, and mostly based on outdated studies. This study aimed to evaluate the clinical characteristics of itch in the adult population with DM2 and explore potential underlying causes. Methods: The study group consisted of 109 adult patients with DM2. Standardized questionnaires were completed in order to assess the itch intensity [Numerical Rating Scale (three days, 24hours) (NRS)] and the Four-item Itch Questionnaire (4IIQ) and to assess the psychological impact of itch [ItchyQoL, Six-Item Stigmatization Scale (6-ISS), Hospital Anxiety and Depression Scale (HADS)]. Skin dryness was evaluated clinically and by non-invasive assessment of epidermis moisturizing. Neuropathy was assessed using the clinical Katzenwadel neuropathy scale. Results: Itch occurred in 35.8% of adult patients with DM2, with NRSmax three days 6.31 ± 2.16 and 8.1 ± 3.5 points in 4IIQ. Itchy patients have had significantly higher FPG levels compared with the non-itchy population (p = 0.01). Patients with itch had a significantly higher possibility of neuropathy compared with non-itchy subjects (p < 0.01). Skin xerosis was significantly more advanced in patients with itch compared to those without (p < 0.01). The mean ItchyQol score was assessed as 41.2 ± 13.4 points, indicating mild life quality impairment and correlated positively with itch intensity. Itchy subjects had significantly higher scores in both anxiety and depression dimensions of HADS (in each p < 0.01). Conclusions: We suggest that the primary cause of itch is prolonged poor diabetes control with altered glucose and insulin levels, subsequently causing skin dryness and neuropathy in long-lasting DM2.


Author(s):  
Brianna L Bourgeois ◽  
Hui-Yi Lin ◽  
Alice Y Yeh ◽  
Danielle E. Levitt ◽  
Stefany DePrato Primeaux ◽  
...  

People living with HIV (PLWH) have increased prevalence of comorbid conditions including insulin resistance and at-risk alcohol use. Circulating microRNAs (miRs) may serve as minimally invasive indicators of pathophysiological states. We aimed to identify whether alcohol modulates circulating miR associations with measures of glucose/insulin dynamics in PLWH. PLWH (N=96; 69.8% male) enrolled in the Alcohol & Metabolic Comorbidities in PLWH: Evidence-Driven Interventions (ALIVE-Ex) study were stratified into negative phosphatidylethanol (PEth<8ng/ml, N=42) and positive PEth (PEth≥8ng/ml, N=54) groups. An oral glucose tolerance test (OGTT) was administered, and total RNA was isolated from fasting plasma to determine absolute miR expression. Circulating miRs were selected based on their role in skeletal muscle (miR-133a, miR-206), pancreatic β-cell (miR-375), liver (miR-20a), and adipose tissue (miR-let-7b, miR-146a, miR-221) function. Correlation and multiple regression analyses between miR expression and adiponectin, 2h glucose, insulin, and C-peptide values were performed adjusting for BMI category, age, sex, and viral load. miR-133a was negatively associated with adiponectin (p=0.002) in the negative PEth group, and miR-20a was positively associated with 2h glucose (p=0.013) in the positive PEth group. Regression analyses combining miRs demonstrated that miR-133a (p<0.001) and miR-221 (p=0.010) together predicted adiponectin in the negative PEth group. miR-20a (p<0.001) and miR-375 (p=0.002) together predicted 2h glucose in the positive PEth group. Our results indicate that associations between miRs and measures of glucose/insulin dynamics differed between PEth groups suggesting that the pathophysiological mechanisms contributing to altered glucose homeostasis in PLWH are potentially modulated by alcohol use.


Author(s):  
Matteo Vecellio ◽  
Elvezia Maria Paraboschi ◽  
Angela Ceribelli ◽  
Natasa Isailovic ◽  
Francesca Motta ◽  
...  

Background: Psoriatic disease is a multifactorial inflammatory condition spanning from skin and nail psoriasis (Pso) to spine and joint involvement characterizing psoriatic arthritis (PsA). Monozygotic twins provide a model to investigate genetic, early life environmental exposure and stochastic influences to complex diseases, mainly mediated by epigenetics.Methods: We performed a genome-wide DNA methylation study on whole blood of monozygotic twins from 7 pairs discordant for Pso/PsA using the Infinium Methylation EPIC array (Illumina). MeDiP—qPCR was used to confirm specific signals. Data were replicated in an independent cohort of seven patients with Pso/PsA and 3 healthy controls. Transcriptomic profiling was performed by RNAsequence on the same 7 monozygotic twin pairs.Results: We identified 2,564 differentially methylated positions between psoriatic disease and controls, corresponding to 1,703 genes, 59% within gene bodies. There were 19 regions with at least two DMPs within 1 kb of distance and significant within-pair Δβ-values (p &lt; 0.005), among them SNX25, BRG1 and SMAD3 genes, all involved in TGF-β signaling pathway, were identified. Co-expression analyses on transcriptome data identified IL-6/JAK/STAT3 and TNF-α pathways as important signaling axes involved in the disease, and they also suggested an altered glucose metabolism in patients’ immune cells, characteristic of pro-inflammatory T lymphocytes.Conclusion: The study suggests the presence of an epigenetic signature in affected individuals, pointing to genes involved in immunological and inflammatory responses. This result is also supported by transcriptome data, that altogether suggest a higher activation state of the immune system, that could promote the disease status.


2021 ◽  
Vol 105 (12S1) ◽  
pp. S43-S43
Author(s):  
Anja Steffen ◽  
Natascha de Graaf ◽  
Marten Engelse ◽  
Eelco de Koning

2021 ◽  
Author(s):  
Qifei Wang ◽  
Xin Yang ◽  
Jianxun Ma ◽  
Xiang Xie ◽  
Yimou Sun ◽  
...  

Abstract Background Keloids are disfiguring fibro-proliferative disorders characterized by glucose metabolism reprogramming, namely elevated glycolysis and compromised oxidative phosphorylation. Our previous study demonstrated altered glucose metabolism and enhanced phosphorylation of the PI3K/AKT pathway in keloid fibroblasts (KFb) under hypoxic conditions. However, whether the PI3K/AKT pathway influences KFb cell function by regulating glucose metabolism under hypoxic conditions remains unclear. Results Our findings revealed that when the PI3K/AKT pathway was inactivated with LY294002 under hypoxia, the protein expression of glycolytic enzymes GLUT1, HK2, PFKFB3, PGK1, ENO1, PKM2, and LDHA decreased under hypoxia, while the amount of mitochondria and mitochondrial membrane potential (MMP) increased, and mitochondrial ultrastructure in KFb remained unchanged. The key parameters of extracellular acidification rate (ECAR) markedly diminished, and those of oxygen consumption rate (OCR) significantly increased after inhibition of the PI3K/AKT pathway. When the PI3K/AKT pathway was suppressed, the levels of ROS and mitochondrial ROS were significantly increased. Meanwhile, cell proliferation, migration, and invasion were inhibited, and apoptosis was increased when the PI3K/AKT pathway was blocked. Additionally, cell proliferation was compromised when KFb were treated with both SC79 (an activator of the PI3K/AKT pathway) and 2-DG (an inhibitor of glycolysis), compared to the SC79 group. Moreover, a positive feedback mechanism was demonstrated in the PI3K/AKT pathway and HIF-1α. Conclusions Our data collectively demonstrated that the PI3K/AKT pathway promotes proliferation and inhibits apoptosis in KFb under hypoxia by regulating glycolysis, indicating that the PI3K/AKT signaling pathway could be a therapeutic target for keloids.


2021 ◽  
Vol 12 ◽  
Author(s):  
Miira M. Klemetti ◽  
Kari Teramo ◽  
Hannu Kautiainen ◽  
Niko Wasenius ◽  
Johan G. Eriksson ◽  
...  

ObjectiveTo investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D).Methods156 OT1D born between 7/1995 and 12/2000 at Helsinki University Hospital, Finland, were invited for follow-up between 3/2019 and 11/2019. A control group of 442 adults born from non-diabetic pregnancies, matched for date and place of birth, was obtained from the Finnish Medical Birth Register. In total, 58 OT1D and 86 controls agreed to participate. All OT1D had amniotic fluid (AF) sampled for erythropoietin (EPO) measurement within two days before delivery in order to diagnose fetal hypoxia. In total, 29 OTID had an AF EPO concentration &lt;14.0 mU/l, defined as normal, and were categorized into the low EPO (L-EPO) group. The remaining 29 OT1D had AF EPO ≥14.0 mU/ml, defined as fetal hypoxia, and were categorized into the high EPO (H-EPO) group. At the age of 18-23 years, participants underwent a 2-h 75g oral glucose tolerance test (OGTT) in addition to height, weight, waist circumference, body composition, blood pressure, HbA1c, cholesterol, triglyceride, high-sensitivity CRP and leisure-time physical activity measurements.ResultsTwo OT1D were diagnosed with diabetes and excluded from further analyses. At young adult age, OT1D in the H-EPO group had a higher BMI than those in the L-EPO group. In addition, among female participants, waist circumference and body fat percentage were highest in the H-EPO group. In the OGTTs, the mean (SD) 2-h post-load plasma glucose (mmol/L) was higher in the H-EPO [6.50 (2.11)] than in the L-EPO [5.21 (1.10)] or control [5.67 (1.48)] offspring (p=0.009). AF EPO concentrations correlated positively with 2-h post-load plasma glucose [r=0.35 (95% CI: 0.07 to 0.62)] and serum insulin [r=0.44 (95% CI: 0.14 to 0.69)] concentrations, even after adjusting for maternal BMI, birth weight z-score, gestational age at birth and adult BMI. Control, L-EPO and H-EPO groups did not differ with regards to other assessed parameters.ConclusionsHigh AF EPO concentrations in late pregnancy, indicating fetal hypoxia, are associated with increased adiposity and elevated post-load glucose and insulin concentrations in young adult OT1D.


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