scholarly journals A systems-level analysis of dynamic total-body PET data reveals complex skeletal energy metabolism networks in vivo

2021 ◽  
Author(s):  
Karla J. Suchacki ◽  
Carlos J. Alcaide-Corral ◽  
Samah Nimale ◽  
Mark G. Macaskill ◽  
Roland H. Stimson ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Metabolic Network ◽  
Mineral Metabolism ◽  
Integrative Approach ◽  
Therapeutic Implications ◽  
The Metabolic Syndrome ◽  
Metabolic Interactions ◽  
Total Body

AbstractBone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary, limiting our ability to assess systemic mechanisms underlying diseases and develop novel therapeutics. In vitro molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism signature in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network. These data could have important therapeutic implications in the management of the metabolic syndrome and skeletal disease. The application of our approach to clinical and preclinical total-body PET studies promises to reveal further physiological and pathological tissue interactions, which simplistic PET standard uptake values analysis fail to interrogate, extending beyond skeletal metabolism, due to the diversity of PET radiotracers available and under development as well as the advent of clinical total-body PET systems.One Sentence SummaryBones form a complex metabolic network.

scholarly journals A Systems-Level Analysis of Total-Body PET Data Reveals Complex Skeletal Metabolism Networks in vivo

2021 ◽  
Vol 8 ◽  
Author(s):  
Karla J. Suchacki ◽  
Carlos J. Alcaide-Corral ◽  
Samah Nimale ◽  
Mark G. Macaskill ◽  
Roland H. Stimson ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Mineral Metabolism ◽  
Underlying Disease ◽  
Integrative Approach ◽  
Tissue Interactions ◽  
Positron Emission ◽  
Metabolic Interactions ◽  
Total Body

Bone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary. in vitro molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network, which could not be identified using single tissue simplistic PET standard uptake values analysis. The application of our approach could reveal new physiological and pathological tissue interactions beyond skeletal metabolism, due to PET radiotracers diversity and the advent of clinical total-body PET systems.

scholarly journals ETMM-06. ELEVATED MITOCHONDRIAL TOM20 EXPRESSION SUPPRESSES GLIOMA MALIGNANCY BY ENHANCING OXIDATIVE PHOSPHORYLATION

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i15-i15
Author(s):  
Mao Li ◽  
Shuxin Zhang ◽  
Wanchun Yang ◽  
Yuan Yang ◽  
Dejiang Pang ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Aerobic Glycolysis ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Integrative Approach ◽  
Mitochondrial Outer Membrane ◽  
Metabolic Switch ◽  
Therapeutic Implications

Abstract BACKGROUND Malignant glioma display a metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation (OXPHOs). However, the underlying mechanism for this metabolic switch in glioma is not well elucidated. Mitochondrial translocases of the outer/inner membrane (TOMs/TIMs) import proteins into mitochondria, and could thereby regulate OXPHOs. The objective of this study is to investigate the expression of TOM/TIM members in glioma, as well as their functional and therapeutic implications. METHODS Transcriptome sequencing (RNA-seq), real-time PCR, Western blot, and immunohistochemistry were used to identify Tom20 as a significantly downregulated TOM/TIM protein in 20 paired glioma/Peritumoral tissues. To study the biological function of Tom20 in glioma, we interrogated metabolic alterations in Tom20 overexpressed glioma cells by GC-MS metabolomics, acetyl-CoA assay, and Seahorse assay. We compared the cell proliferation and viability profiles between Tom20 overexpressed and control cells in vitro and in vivo. To investigate the therapeutic implication of Tom20 expression, we tested OXPHOs inhibitor metformin in Tom20 overexpressed cells and xenograft mouse models. RESULTS We find that Tom20, a critical component of the mitochondrial outer membrane translocases, is downregulated in malignant gliomas. Using an integrative approach spanning bioinformatic analysis, metabolomics, and functional approaches, we reveal that Tom20 elevation activates mitochondrial OXPHOs in glioma cells and reduces tumor malignancy. We also find that Tom20 upregulation sensitizes glioma cells to metformin in vitro, and improves the therapeutic efficacy of metformin in glioma in vivo. CONCLUSION Our work defines Tom20 as a glioma suppressor and an indicator of metformin treatment in glioma.

scholarly journals The phytochemical constituents and therapeutic uses of genus Aloe: A review

2021 ◽  
Vol 49 (2) ◽  
pp. 12332
Author(s):  
Aida PUIA ◽  
Cosmin PUIA ◽  
Emil MOIȘ ◽  
Florin GRAUR ◽  
Alin FETTI ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
In Vivo Studies ◽  
The Metabolic Syndrome ◽  
Therapeutic Uses ◽  
Conventional Drug ◽  
Closed Canopy ◽  
Phytochemical Constituents ◽  
Total Body

Aloe, the largest genus in the Asphodelaceae family, comprises 548 species, with A. vera, A. arborescens and A. ferox being among the most widely studied species. Aloe species originated in arid climates and cover various habitats, from sea level up to 2700 m, and from desert to closed-canopy forests. For human health, Aloe species are the richest natural sources. The biological activity of Aloe sp. constituents covers a wide spectrum. Most of the indications come from traditional, folkloric use and several have been verified by in vitro or in vivo studies. Emodin, the main phenolic component, has showed anti-neoplastic, anti-inflammatory, anti-angiogenic and toxicological potential for use in pharmacology. Polysaccharides, with acemannan being the most important, are present in high abundance in Aloe gels. Acemannan has been reported to have applications in oral, metabolic and cardiovascular diseases, oncology, dentistry and wound healing. The effectiveness of Aloe sp. constituents on colon, liver, duodenum, skin, pancreas, intestine, lungs and kidneys cancers was highly studied with remarkable findings. Regarding the metabolic syndrome, Aloe sp. can be used as an antidiabetic and reduces cholesterol and total body fat. Constituents of Aloe sp. are nontoxic in experimental acute oral studies and are widely used in cosmetology and as bitter agents or consistence modifiers in food and beverages. Traditional Aloe remedies cover most human diseases; however, in order to gain legitimacy, the Aloe-derived drugs must have a well-established composition, with thoroughly investigated adverse effects and conventional drug interactions.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

Total body fat content and fat topography are associated differently with in vivo glucose metabolism in nonobese and obese nondiabetic women

Diabetes ◽  
1992 ◽  
Vol 41 (9) ◽  
pp. 1151-1159 ◽  
Author(s):  
E. Bonora ◽  
S. Del Prato ◽  
R. C. Bonadonna ◽  
G. Gulli ◽  
A. Solini ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Body Fat ◽  
Fat Content ◽  
Body Fat Content ◽  
Total Body Fat ◽  
Total Body

ACIS, A Novel KepTide™, Binds to ACE-2 Receptor and Inhibits the Infection of SARS-CoV2 Virus in vitro in Primate Kidney Cells: Therapeutic Implications for COVID-19 (Preprint)

2020 ◽  
Author(s):  
Avik Sotira Scientific
Keyword(s):  
Social Life ◽  
Plaque Assay ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
Crystallographic Structure ◽  
Therapeutic Implications ◽  
Biochemical Assays ◽  
Targeted Medicine

UNSTRUCTURED Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by a virus known as SARS-Coronavirus 2 (SARS-CoV2). Without a targeted-medicine, this disease has been causing a massive humanitarian crisis not only in terms of mortality, but also imposing a lasting damage to social life and economic progress of humankind. Therefore, an immediate therapeutic strategy needs to be intervened to mitigate this global crisis. Here, we report a novel KepTide™ (Knock-End Peptide) therapy that nullifies SARS-CoV2 infection. SARS-CoV2 employs its surface glycoprotein “spike” (S-glycoprotein) to interact with angiotensin converting enzyme-2 (ACE-2) receptor for its infection in host cells. Based on our in-silico-based homology modeling study validated with a recent X-ray crystallographic structure (PDB ID:6M0J), we have identified that a conserved motif of S-glycoprotein that intimately engages multiple hydrogen-bond (H-bond) interactions with ACE-2 enzyme. Accordingly, we designed a peptide, termed as ACIS (ACE-2 Inhibitory motif of Spike), that displayed significant affinity towards ACE-2 enzyme as confirmed by biochemical assays such as BLItz and fluorescence polarization assays. Interestingly, more than one biochemical modifications were adopted in ACIS in order to enhance the inhibitory action of ACIS and hence called as KEpTide™. Consequently, a monolayer invasion assay, plaque assay and dual immunofluorescence analysis further revealed that KEpTide™ efficiently mitigated the infection of SARS-CoV2 in vitro in VERO E6 cells. Finally, evaluating the relative abundance of ACIS in lungs and the potential side-effects in vivo in mice, our current study discovers a novel KepTide™ therapy that is safe, stable, and robust to attenuate the infection of SARS-CoV2 virus if administered intranasally. INTERNATIONAL REGISTERED REPORT RR2-https://doi.org/10.1101/2020.10.13.337584

scholarly journals Glucose Transporter 8 (GLUT8) Regulates Enterocyte Fructose Transport and Global Mammalian Fructose Utilization

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4181-4191 ◽  
Author(s):  
Brian J. DeBosch ◽  
Maggie Chi ◽  
Kelle H. Moley
Keyword(s):  
Glucose Transporter ◽  
Serum Insulin ◽  
Density Lipoprotein ◽  
Wild Type ◽  
In Vivo Models ◽  
The Metabolic Syndrome ◽  
High Fructose

Enterocyte fructose absorption is a tightly regulated process that precedes the deleterious effects of excess dietary fructose in mammals. Glucose transporter (GLUT)8 is a glucose/fructose transporter previously shown to be expressed in murine intestine. The in vivo function of GLUT8, however, remains unclear. Here, we demonstrate enhanced fructose-induced fructose transport in both in vitro and in vivo models of enterocyte GLUT8 deficiency. Fructose exposure stimulated [14C]-fructose uptake and decreased GLUT8 protein abundance in Caco2 colonocytes, whereas direct short hairpin RNA-mediated GLUT8 knockdown also stimulated fructose uptake. To assess GLUT8 function in vivo, we generated GLUT8-deficient (GLUT8KO) mice. GLUT8KO mice exhibited significantly greater jejunal fructose uptake at baseline and after high-fructose diet (HFrD) feeding vs. wild-type mice. Strikingly, long-term HFrD feeding in GLUT8KO mice exacerbated fructose-induced increases in blood pressure, serum insulin, low-density lipoprotein and total cholesterol vs. wild-type controls. Enhanced fructose uptake paralleled with increased abundance of the fructose and glucose transporter, GLUT12, in HFrD-fed GLUT8KO mouse enterocytes and in Caco2 cultures exposed to high-fructose medium. We conclude that GLUT8 regulates enterocyte fructose transport by regulating GLUT12, and that disrupted GLUT8 function has deleterious long-term metabolic sequelae. GLUT8 may thus represent a modifiable target in the prevention and treatment of malnutrition or the metabolic syndrome.

Abstract 18060: TRAIL Promotes Angiogenesis and Ischemia-Induced Neovascularisation via NOX4, H2O2 and Nitric Oxide-Dependent Mechanisms

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Belinda A Di Bartolo ◽  
Sian P Cartland ◽  
Leonel Prado-Lourenco ◽  
Nor Saadah M Azahri ◽  
Thuan Thai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiogenic Factor ◽  
Tubule Formation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Therapeutic Implications ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
First Time

Background: Angiogenesis and neovascularization are essential processes that follow ischemia insults. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) not only induces endothelial cell (EC) death and inhibits angiogenesis, but also promotes EC migration, invasion and proliferation in vitro . These seemingly opposite effects make its role in angiogenesis in vivo unclear. Using TRAIL -/- and wild-type mice, we sought to determine the role of TRAIL in angiogenesis and neovascularisation. We also sought mechanisms in vitro . Methods and Results: Reduced vascularisation assessed by real-time in vivo 3D Vevo ultrasound imaging and CD31 staining was observed in TRAIL -/- mice 28 d after hindlimb ischemia. Moreover, reduced capillary formation and increased apoptosis was evident in TRAIL -/- muscles even at 3 d after ischemic surgery. We have previously shown that fibroblast growth factor-2 (FGF-2), a potent angiogenic factor, regulates TRAIL gene expression in vascular smooth muscle cells. Indeed, FGF-2 also regulates TRAIL expression in ECs, and FGF-2-inducible proliferation, migration and tubule formation was inhibited with siRNA targeting TRAIL. Notably, both FGF-2 and TRAIL significantly increased NOX4 expression. TRAIL-inducible angiogenic activity in ECs was inhibited with siRNAs targeting NOX4, and consistent with these, NOX4 mRNA was reduced in 3 d ischemic hindlimbs of TRAIL -/- mice. TRAIL stimulated intracellular H 2 O 2 levels in ECs, and TRAIL-inducible proliferation, migration and tubule formation was inhibited with not only PEG-catalase, a H 2 O 2 scavenger, but also blocked with L-NAME, a nitric oxide synthase inhibitor. Conclusions: This is the first demonstration showing that TRAIL promotes angiogenesis in vivo . We show for the first time that the TRAIL stimulates NOX4 expression to mediate nitric oxide-dependent angiogenic effects. This has significant therapeutic implications such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with CVD and diabetes.

scholarly journals Enhanced phosphorylation of Na+–Cl− co-transporter in experimental metabolic syndrome: role of insulin

2012 ◽  
Vol 123 (11) ◽  
pp. 635-647 ◽  
Author(s):  
Radko Komers ◽  
Shaunessy Rogers ◽  
Terry T. Oyama ◽  
Bei Xu ◽  
Chao-Ling Yang ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Time Course ◽  
Kinase Inhibitor ◽  
Endogenous Expression ◽  
The Metabolic Syndrome ◽  
Mammalian Cell Lines ◽  
Phosphoinositide 3 Kinase

In the present study, we investigated the activity of the thiazide-sensitive NCC (Na+–Cl− co-transporter) in experimental metabolic syndrome and the role of insulin in NCC activation. Renal responses to the NCC inhibitor HCTZ (hydrochlorothiazide), as a measure of NCC activity in vivo, were studied in 12-week-old ZO (Zucker obese) rats, a model of the metabolic syndrome, and in ZL (Zucker lean) control animals, together with renal NCC expression and molecular markers of NCC activity, such as localization and phosphorylation. Effects of insulin were studied further in mammalian cell lines with inducible and endogenous expression of this molecule. ZO rats displayed marked hyperinsulinaemia, but no differences in plasma aldosterone, compared with ZL rats. In ZO rats, natriuretic and diuretic responses to NCC inhibition with HCTZ were enhanced compared with ZL rats, and were associated with a decrease in BP (blood pressure). ZO rats displayed enhanced Thr53 NCC phosphorylation and predominant membrane localization of both total and phosphorylated NCC, together with a different profile in expression of SPAK (Ste20-related proline/alanine-rich kinase) isoforms, and lower expression of WNK4. In vitro, insulin induced NCC phosphorylation, which was blocked by a PI3K (phosphoinositide 3-kinase) inhibitor. Insulin-induced reduction in WNK4 expression was also observed, but delayed compared with the time course of NCC phosphorylation. In summary, we report increased NCC activity in hyperinsulinaemic rodents in conjunction with the SPAK expression profile consistent with NCC activation and reduced WNK4, as well as an ability of insulin to induce NCC stimulatory phosphorylation in vitro. Together, these findings indicate that hyperinsulinaemia is an important driving force of NCC activity in the metabolic syndrome with possible consequences for BP regulation.

scholarly journals Dangguijakyak-San Protects against 1-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-Induced Neuronal Damage via Anti-Inflammatory Action

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Deok-Sang Hwang ◽  
Hyo Geun Kim ◽  
Jun-Bock Jang ◽  
Myung Sook Oh
Keyword(s):  
Neuronal Damage ◽  
Cell Damage ◽  
Substantia Nigra Pars Compacta ◽  
Inflammatory Factors ◽  
Dopaminergic Cell ◽  
Therapeutic Implications ◽  
Anti Inflammatory ◽  
Inflammatory Action

Dangguijakyak-san (DJS), a famous traditional Korean multiherbal medicine, has been used to treat gynecological and neuro-associated disease. Recent studies demonstrated that DJS has multiple bioactivities including neuroprotection. In the present study, we were to investigate the effect of DJS and its mechanism in anin vitroandin vivomodel of Parkinson’s disease (PD). In primary mesencephalic culture system, DJS attenuated the dopaminergic cell damage induced by 1-methyl-4-phenylpyridine toxicity, and it inhibited production of inflammatory factors such as tumor necrosis factorα(TNF-α), nitric oxide (NO), and activation of microglial cells. Then, we confirmed the effect of DJS in a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the pole test, DJS at 50 mg/kg/day for 5 days showed increase of motor activity showing shortened time to turn and locomotor activity compared with the MPTP only treated mice. In addition, DJS significantly protected nigrostriatal dopaminergic neuron from MPTP stress. Moreover, DJS showed inhibition of gliosis in the substantia nigra pars compacta. These results have therapeutic implications for DJS in the treatment of PD via anti-inflammatory effects.

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