phosphocreatine and Liver-Neoplasms

Diabetes mellitus (DM) associated liver damage is a major health burden. Hepatocellular-damage in DM characterized with elevated endoplasmic reticulum stress (ER) and may enhanced insulin-resistance. Phosphocreatine (PCr) a rapidly high-energy-reserve molecule of phosphates naturally occurs in liver, brain and skeletal muscle. This study aimed to investigate the protective effect of PCr on the liver-injury-associated with DM and to report the mechanism involved. Wistar rat's diabetes model was induced using streptozotocin (STZ), and the animals were treated with 20 mg/kg, or 50 mg/kg PCr injection. Blood glucose level, and body wt were recorded. Liver tissues homogenate were analyzed for liver damage markers alanine transaminase (ALT), aspartate transaminase (AST). Liver tissues proteins further evaluated for apoptosis, endoplasmic reticulum stress (ER), and insulin resistance biomarkers using western blotting. Our results revealed that PCr reduced blood glucose level, improved body wt, ameliorates liver function enzymes. Furthermore, PCr upregulates anti-apoptotic Bcl2 proteins expression, and down-regulates significantly pro-apoptotic casp3 and Bax proteins expression in vivo and invitro. Moreover, ER stress CHOP, GRP78 and ATF4 biomarkers level were significantly attenuated in PCr treated animals comparing to STZ diabetes associated liver-damage model with significant improving in insulin-resistance Akt and IRS-1. Our results revealed that treating with PCr in diabetes-associated liver injury models decreased blood glucose level and possess protective effect in-vitro and in-vivo, which could be suggested as potential therapeutic strategy for diabetes associated liver injury patients.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Blood Glucose; Body Weight; Carcinoma, Hepatocellular; Cell Shape; Cell Survival; Diabetes Mellitus, Experimental; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Hep G2 Cells; Humans; Insulin Resistance; Liver; Liver Neoplasms; Metabolome; Oxidative Stress; Phosphocreatine; Protective Agents; Rats, Wistar; Signal Transduction; Streptozocin

Levan productivity of Bacillus subtilis Natto was evaluated in submerged culture varying the pH, temperature and culture time, using factorial design and response surface methodology. The characterization of levan molecular weight was performed by HPSEC and its antitumor activity against HepG2 cells using metabolomic approach was also evaluated. At first, the variables investigated, as well as their interactions, demonstrated significant effect. Further, a second design using the same variables at different levels was developed. Thus, according to the model, an optimized value corresponding to 5.82 g.L⁻¹.h⁻¹ was achieved at pH 8, 39.5°C in 21 hours, the highest value reported so far. After analysis by HPSEC, two molecular weights were obtained corresponding to 72.37 and 4146 kDa. The levan promoted an increase of acetate, alanine, lactate and phosphocreatine in HepG2 cells suggesting an alteration in the bioenergetics pathways and cellular homeostasis by intracellular accumulation of lactate, justifying its antitumor activity.

Topics: Acetic Acid; Alanine; Antineoplastic Agents; Bacillus subtilis; Energy Metabolism; Fermentation; Fructans; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Lactic Acid; Liver Neoplasms; Metabolomics; Molecular Weight; Phosphocreatine; Temperature; Time Factors

(31)P MR spectroscopy (MRS) allows the noninvasive assessment of metabolic alterations in tumors. Due to physical as well as technical limitations, mostly large and single voxels are used. We used a spatially resolved (31)P MRS technique to characterize metabolic abnormalities inside and adjacent to liver metastases of patients with uvea melanoma.. Optimization of 3D chemical shift imaging (3D CSI) was performed in healthy volunteers (n = 19; voxel size 25 ml). Patients (n = 8) with liver metastases were then examined. Cross sectional imaging was available for all patients.. Compared to healthy volunteers, the PME/PDE ratios of patients with liver metastasis were significantly higher (0.56 +/- 0.30 vs. 0.39 +/- 0.21; p < 0.05). A trend towards increased PME/beta ATP ratios (2.07 +/- 1.83 vs. 1.02 +/- 0.45; p = 0.12) and decreased Pi/PME ratios (0.57 +/- 0.29 vs. 1.06 +/- 0.58; p = 0.06) was also observed. Patients with metastases > or = 5 cm showed significantly higher PME/PDE ratios (0.68 +/- 0.17 vs. 0.45 +/- 0.03; p < 0.05). Liver parenchyma adjacent to metastases did not show any significant changes compared to non-diseased tissue.. 3D CSI allows the simultaneous analysis of metabolic alterations in diseased as well as in healthy human liver. Metastases show significant metabolic alterations. Thus, (31)P MRS opens new possibilities for therapeutic monitoring.

Topics: Adenosine Triphosphate; Adult; Aged; Choroid Neoplasms; Energy Metabolism; Female; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Melanoma; Middle Aged; Observer Variation; Phosphocreatine; Phospholipids; Reference Values; Sensitivity and Specificity; Young Adult

Linear prediction algorithms are able to identify peaks in an NMR spectrum, but are not able to assign these peaks to components anticipated in the spectrum. We have developed an artificial-intelligence protocol which uses the output parameter list from an LPSVD algorithm, and automatically assigns the peaks on the basis of an anticipated list of components. To overcome the influence of experimental conditions on the absolute values of frequency, integrated area, and linewidth, the assignment routine performs an internal scaling of the data by comparing all possible pairs of peaks in the spectrum. Completely automated analysis of large numbers of in vivo FIDs is now possible.

Topics: Adenosine Triphosphate; Algorithms; Electronic Data Processing; Humans; Liver Neoplasms; Magnetic Resonance Spectroscopy; Muscles; Phosphates; Phosphocreatine; Phosphorus; Physical Exertion

In vivo and in vitro 31P-NMR spectroscopy was used to study the high energy phosphate metabolism of VX-2 tumors implanted into rabbit liver, kidney, and hind-limb muscle. Tumors, at various stages of growth, were first examined by in vivo 31P-NMR spectroscopy, then they were excised and underwent histologic examination and biochemical analysis; both in vitro 31P-NMR and standard enzymatic techniques were used. There was good correlation among the in vivo NMR spectra, the in vitro NMR data, and the biochemical analyses. Although the tumor spectra showed characteristics similar to those reported in the other tumor models, there was a striking variability in the spectra obtained from tumors implanted in the same site and from different sites. There was poor correlation between the degree of necrosis in the tumor and the tumor pH and between the Pi:ATP ratio and necrosis. This variability has important implications for the potential value of using 31P-NMR spectroscopy to monitor tumor growth and therapy in vivo.

Topics: Adenosine Triphosphate; Animals; Carcinoma; In Vitro Techniques; Kidney Neoplasms; Liver Neoplasms; Magnetic Resonance Spectroscopy; Muscular Diseases; Neoplasms, Experimental; Phosphocreatine; Phosphorus; Rabbits

Topics: Adrenal Gland Neoplasms; Biopsy; Ethanolamines; Female; Humans; Infant, Newborn; Liver; Liver Neoplasms; Magnetic Resonance Spectroscopy; Neuroblastoma; Phosphocreatine; Phosphorus Radioisotopes