Combined Supplementation with Vitamin B-6 and Curcumin is Superior to Either Agent Alone in Suppressing Obesity-Promoted Colorectal Tumorigenesis in Mice

2021 ◽  
Author(s):  
Xian Wu ◽  
Per M Ueland ◽  
Jatin Roper ◽  
Gar Yee Koh ◽  
Xu Liang ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Fold Increase ◽  
Fecal Calprotectin ◽  
Tumor Burden ◽  
Colorectal Carcinogenesis ◽  
Vitamin B ◽  
Colonic Inflammation ◽  
Tumor Multiplicity ◽  
Supplemental Vitamin ◽  
The Individual

ABSTRACT Background Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation. Objectives We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis. Methods Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids. Results HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%–80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%–47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%–93% (P < 0.03), demonstrating relevance to humans. Conclusions In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.

Arterial Thrombosis in Cancer Patients: An Update

2021 ◽  
Author(s):  
Massimo Franchini ◽  
Antonella Tufano ◽  
Aniello Casoria ◽  
Antonio Coppola
Keyword(s):  
Cancer Patients ◽  
Arterial Thrombosis ◽  
Cardiovascular Events ◽  
Tumor Burden ◽  
Vascular Events ◽  
Time Period ◽  
Treatment Considerations ◽  
Arterial Thromboembolic Events ◽  
The Individual ◽  
Patients Experience

AbstractCancer is associated with an increased incidence of both venous thromboembolism (VTE) and arterial thrombosis (cardiovascular events and ischemic stroke). Cancer-associated arterial thrombotic events are less well studied than VTE, but increasingly recognized, particularly in specific malignancies and in association with specific anticancer therapies. The pathogenesis of arterial thrombotic events in cancer is complex and involves generation of tumor-associated procoagulant factors and a variety of alterations in platelet function as well as in the coagulation and fibrinolytic systems, and endothelial injury and dysfunction, that combine to produce hypercoagulability. The multifactorial interaction between this prothrombotic state, the individual cardiovascular risk, advanced age and presence of comorbidities, and the specific neoplasm characteristics and therapy, may induce the vascular events. Recent studies based on population databases and prospective or retrospective analyses with prolonged follow-up highlight that cancer patients experience an increased (approximately 1.5–2-fold) risk of both cerebrovascular and cardiovascular events compared with noncancer individuals, which peaks in the time period of the diagnosis of cancer but may persist for years. Beyond the type of cancer, the risk reflects the tumor burden, being higher in advanced stages and metastatic cancers. The occurrence of arterial thromboembolic events is also associated with increased overall mortality. We here present an update of the pathophysiology, risk factors, clinical evidence, and treatment considerations on cancer-associated arterial thrombosis, in the light of the need for specific multidisciplinary prevention and surveillance strategies in this setting, in the frame of cardio-oncology approaches.

EXCRETION OF 4(5)-AMINO-5(4)-IMIDAZOLECARBOXAMIDE AND FORMIMINO-L-GLUTAMIC ACID IN FOLIC ACID AND VITAMIN B12 DEFICIENT RATS

1965 ◽  
Vol 43 (8) ◽  
pp. 1367-1374 ◽  
Author(s):  
P. L. McGeer ◽  
N. P. Sen ◽  
D. A. Grant
Keyword(s):  
Folic Acid ◽  
Glutamic Acid ◽  
Fold Increase ◽  
Urocanic Acid ◽  
Vitamin B ◽  
Deficient Diet ◽  
Intraperitoneal Dose ◽  
Group A ◽  
Acid Load ◽  
Deficient Group

The excretion of 4(5)-amino-5(4)-imidazolecarboxamide (AIC) in the urines of normal rats, rats raised on a folic acid deficient diet, and rats raised on a vitamin B12 deficient diet was measured. The AIC excretion was elevated 3-fold above normal in the B12 deficient group and 1.5-fold above normal in the folic acid deficient group.No evidence could be found that the raised AIC excretion was associated with a block in the conversion of AIC to purines. The recovery of radioactive AIC in the urine after an intraperitoneal dose of 2 μmoles AIC per kg was not increased over normal in any of the deficient groups, and was significantly less than normal in the B12-deficient group. Most of the urinary radioactivity in all groups was in allantoin, uric acid, and purines.When a load of 220 μmoles of AIC per kg was administered there was no difference between the vitamin B12 deficient and the normal groups in AIC recovery in the urine. When a load of 220 μmoles of urocanic acid per kg was administered, however, the B12-deficient group had an 18-fold increase over normal in Figlu excretion, and the folic acid deficient group a 17-fold increase. Thus, a substantial block in formimino-L-glutamic acid (Figlu) metabolism, but not in AIC metabolism, existed in the vitamin-deficient groups.Feeding a B12-deficient group a 2% methionine supplement reduced the Figlu excretion after a urocanic acid load to less than half that observed in B12-deficient groups without methionine supplementation, but had no influence on the AIC excretion.

scholarly journals Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography

2015 ◽  
Vol 8s1 ◽  
pp. CGM.S21216 ◽  
Author(s):  
Susan LeGendre-McGhee ◽  
Photini S. Rice ◽  
R. Andrew Wall ◽  
Kyle J. Sprute ◽  
Ramireddy Bommireddy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Rate ◽  
Optical Coherence Tomography ◽  
Mouse Model ◽  
Tumor Burden ◽  
Colorectal Carcinogenesis ◽  
Optical Coherence ◽  
Ki 67 ◽  
Tumor Number ◽  
Cox 2

Optical coherence tomography (OCT) is a high-resolution, nondestructive imaging modality that enables time-serial assessment of adenoma development in the mouse model of colorectal cancer. In this study, OCT was utilized to evaluate the effectiveness of interventions with the experimental antitumor agent α-difluoromethylornithine (DFMO) and a nonsteroidal anti-inflammatory drug sulindac during early [chemoprevention (CP)] and late stages [chemotherapy (CT)] of colon tumorigenesis. Biological endpoints for drug interventions included OCT-generated tumor number and tumor burden. Immunochistochemistry was used to evaluate biochemical endpoints [Ki-67, cleaved caspase-3, cyclooxygenase (COX)-2, β-catenin]. K-Ras codon 12 mutations were studied with polymerase chain reaction-based technique. We demonstrated that OCT imaging significantly correlated with histological analysis of both tumor number and tumor burden for all experimental groups ( P < 0.0001), but allows more accurate and full characterization of tumor number and burden growth rate because of its time-serial, nondestructive nature. DFMO alone or in combination with sulindac suppressed both the tumor number and tumor burden growth rate in the CP setting because of DFMO-mediated decrease in cell proliferation (Ki-67, P < 0.001) and K-RAS mutations frequency ( P = 0.04). In the CT setting, sulindac alone and DFMO/sulindac combination were effective in reducing tumor number, but not tumor burden growth rate. A decrease in COX-2 staining in DFMO/sulindac CT groups (COX-2, P < 0.01) confirmed the treatment effect. Use of nondestructive OCT enabled repeated, quantitative evaluation of tumor number and burden, allowing changes in these parameters to be measured during CP and as a result of CT. In conclusion, OCT is a robust minimally invasive method for monitoring colorectal cancer disease and effectiveness of therapies in mouse models.

scholarly journals Measuring vitamin B-12 bioavailability with [13C]-cyanocobalamin in humans

2020 ◽  
Vol 112 (6) ◽  
pp. 1504-1515 ◽  
Author(s):  
Sarita Devi ◽  
Roshni M Pasanna ◽  
Zeeshan Shamshuddin ◽  
Kishor Bhat ◽  
Ambily Sivadas ◽  
...  
Keyword(s):  
Stable Isotope ◽  
Low Dose ◽  
Age Groups ◽  
Fold Increase ◽  
Compartment Model ◽  
Radioactive Isotopes ◽  
Vitamin B ◽  
Before And After ◽  
Vitamin B 12 ◽  
The Mean

ABSTRACT Background Vitamin B-12 deficiency is widespread in many parts of the world, affecting all age groups and increasing with age. It is primarily due to a low intake of animal source foods or malabsorption. The measurement of bioavailability of vitamin B-12 is etiologically important in deficiency but is limited due to the use of radioactive isotopes like [57Co]- or [14C]-cyanocobalamin. Objectives The aim of this study was to measure the bioavailability of [13C]-cyanocobalamin in humans and to assess the effect of parenteral replenishment of vitamin B-12 on the bioavailability. Methods We synthesized a stable isotope-labeled vitamin B-12, [13C]-cyanocobalamin, using Salmonella enterica by providing [13C2]-ethanolamine as a sole carbon source. After purification and mass spectrometry–based characterization, its oral bioavailability was measured in the fasted state with high and low oral doses, before and after parenteral replenishment of vitamin B-12 stores, from the kinetics of its plasma appearance in a 2-compartment model. Results [13C]-cyanocobalamin was completely decyanated to [13C]-methylcobalamin describing metabolic utilization, and its plasma appearance showed early and late absorption phases. At a low dose of 2.3 µg, the mean bioavailability was 46.2 ± 12.8 (%, mean ± SD, n = 11). At a higher dose of 18.3 µg, the mean bioavailability was 7.6 ± 1.7 (%, mean ± SD, n = 4). Parenteral replenishment of the vitamin B-12 store in deficient individuals prior to the measurement resulted in a 1.9-fold increase in bioavailability. Conclusions Vitamin B-12 bioavailability is dose dependent and at a low dose that approximates the normal daily requirement (46%). The stable isotope method described here could be used to define the etiology of deficiency and to inform the dietary requirement in different physiologic states as well as the dose required for supplementation and food fortification. This trial was registered at the Clinical Trials Registry of India as CTRI/2018/04/012957.

scholarly journals Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6206-6214 ◽  
Author(s):  
Bruno Nervi ◽  
Pablo Ramirez ◽  
Michael P. Rettig ◽  
Geoffrey L. Uy ◽  
Matthew S. Holt ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Fold Increase ◽  
Firefly Luciferase ◽  
Tumor Burden ◽  
Cathepsin G ◽  
Cxcr4 Antagonist ◽  
Competitive Antagonist ◽  
Induced Apoptosis ◽  
Knockin Mouse

Abstract The CXCR4–SDF-1 axis plays a central role in the trafficking and retention of normal and malignant stem cells in the bone marrow (BM) microenvironment. Here, we used a mouse model of acute promyelocytic leukemia (APL) and a small molecule competitive antagonist of CXCR4, AMD3100, to examine the interaction of mouse APL cells with the BM microenvironment. APL cells from a murine cathepsin G-PML-RARα knockin mouse were genetically modified with firefly luciferase (APLluc) to allow tracking by bioluminescence imaging. Coculture of APLluc cells with M2-10B4 stromal cells protected the leukemia cells from chemotherapy-induced apoptosis in vitro. Upon injection into syngeneic recipients, APLluc cells rapidly migrated to the BM followed by egress to the spleen then to the peripheral blood with death due to leukostasis by day 15. Administration of AMD3100 to leukemic mice induced a 1.6-fold increase in total leukocytes and a 9-fold increase of circulating APL blast counts, which peak at 3 hours and return to baseline by 12 hours. Treatment of leukemic mice with chemotherapy plus AMD3100 resulted in decreased tumor burden and improved overall survival compared with mice treated with chemotherapy alone. These studies provide a proof-of-principle for directing therapy to the critical tethers that promote AML-niche interactions.

Leptin enhances feeding suppression and neural activation produced by systemically administered bombesin

2005 ◽  
Vol 289 (2) ◽  
pp. R473-R477 ◽  
Author(s):  
Ellen E. Ladenheim ◽  
M. Emond ◽  
T. H. Moran
Keyword(s):  
Food Intake ◽  
Fold Increase ◽  
Liquid Diet ◽  
Individual Response ◽  
Neural Activation ◽  
Solitary Tract ◽  
Significant Suppression ◽  
Feeding Inhibition ◽  
Feeding Suppression ◽  
The Individual

Leptin amplifies feeding inhibition and neural activation produced by either cholecystokinin or intragastric preloads, suggesting that leptin may increase the efficacy of gastrointestinal meal-related signals. To determine whether leptin would similarly potentiate the feeding inhibitory actions of another putative satiety peptide, we evaluated the effects of third ventricular leptin administration on food intake and c-Fos activation in response to systemically administered bombesin (BN). Leptin (3.5 μg) was administered 1 h before either 0.9% saline or BN (0.32 and 1.0 nmol/kg) followed by 30-min access to Ensure liquid diet. Although neither leptin nor 0.32 nmol/kg BN alone suppressed Ensure intake, the combination reduced intake by 28%. The higher BN dose (1.0 nmol/kg) produced a significant suppression by itself but was further enhanced in the presence of leptin. Consistent with the behavioral results, c-Fos activation in the nucleus of the solitary tract was increased by combined dosages of leptin and 0.32 nmol/kg BN beyond the individual response to either peptide. In the presence of leptin, BN produced a 3.4- to 5.2-fold increase in the number of c-Fos-positive cells in the nucleus of the solitary tract compared with when BN was given alone. These data provide further support for the hypothesis that the effect of leptin on food intake may be mediated, in part, by modulating meal-related satiety signals.

scholarly journals A new method for the assay of tissue. S-adenosylhomocysteine and S-adenosylmethione. Effect of pyridoxine deficiency on the metabolism of S-adenosylhomocysteine, S-adenosylmethionine and polyamines in rat liver

1976 ◽  
Vol 160 (2) ◽  
pp. 287-294 ◽  
Author(s):  
T O Eloranta ◽  
E O Kajander ◽  
A M Raina
Keyword(s):  
Fold Increase ◽  
Major Effect ◽  
Albino Rats ◽  
Vitamin B ◽  
Deficient Diet ◽  
Tissue Samples ◽  
Adenosylmethionine Decarboxylase ◽  
Pyridoxine Deficiency ◽  
Hepatic Synthesis

The hepatic synthesis and accumulation of S-adenosylhomocysteine, S-adenosylmethionine and polyamines were studied in normal and vitamin B-6-deficient male albino rats. A method involving a single chromatography on a phosphocellulose column was developed for the determination of S-adenosylhomocysteine and S-adenosylmethionine from tissue samples. Feeding the rat with pyridoxine-deficient diet for 3 or 6 weeks resulted in a four- to five-fold increase in the concentration of S-adenosylhomocysteine, whereas that of S-adenosylmethionine was only slighly elevated. The concentration of putrescine was decreased to half, that of spermidine was somewhat decreased and that of spermine remained fairly constant. The activities of L-ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, L-methionine adenosyltransferase and S-adenosyl-L-homocysteine hydrolase were moderately increased. S-Adenosylmethionine decarboxylase showed no requirement for pyridoxal 5′-phosphate. The major effect of pyridoxine deficiency of S-adenosylmethionine metabolism seems to be a block in the utilization of S-adenosylhomocysteine, resulting in the accumulation of this metabolite to a concentration that may inhibit biological methylation reactions.

scholarly journals High excess mortality during the COVID-19 outbreak in Stockholm Region areas with young and socially vulnerable populations

2020 ◽  
Author(s):  
Amaia Calderón-Larrañaga ◽  
Davide L Vetrano ◽  
Debora Rizzuto ◽  
Tom Bellander ◽  
Laura Fratiglioni ◽  
...  
Keyword(s):  
Socioeconomic Status ◽  
Excess Mortality ◽  
Age Distribution ◽  
Fold Increase ◽  
Mortality Rates ◽  
Individual Risk ◽  
Mortality Data ◽  
Gainful Employment ◽  
Viral Spread ◽  
The Individual

AbstractBackgroundWe aimed to describe the distribution of excess mortality (EM) during the first weeks of the COVID-19 outbreak in the Stockholm Region, Sweden, according to individual age and sex, and the sociodemographic contextMethodsWeekly all-cause mortality data were obtained from Statistics Sweden for the period 01/01/2015 to 17/05/2020. EM during the first 20 weeks of 2020 was estimated by comparing observed mortality rates with expected mortality rates during the five previous years (N=2,379,792). EM variation by socioeconomic status (tertiles of income, education, Swedish-born, gainful employment) and age distribution (share of 70+ year-old persons) was explored based on Demographic Statistics Area (DeSO) data.FindingsAn EM was first detected during the week of March 23-29 2020. During the peaking week of the epidemic (6-12 April 2020), an EM of 160% was observed: 211% in 80+ year-old women; 179% in 80+ year-old men. During the same week, the highest EM was observed for DeSOs with lowest income (171%), lowest education (162%), lowest share of Swedish-born (178%), and lowest share of gainfully employed (174%). There was a 1.2 to 1.7-fold increase in EM between those areas with a higher vs. lower proportion of young people.InterpretationLiving in areas with lower socioeconomic status and younger populations is linked to COVID-19 EM. These conditions might have facilitated the viral spread. Our findings add to the well-known biological vulnerability linked to increasing age, the relevance of the sociodemographic context when estimating the individual risk to COVID-19.FundingNone.

scholarly journals How Mathematical Modeling Could Contribute to the Quantification of Metastatic Tumor Burden Under Therapy: Insights in Immunotherapeutic Treatment of Non-Small Cell Lung Cancer

2020 ◽  
Author(s):  
Pirmin Schlicke ◽  
Christina Kuttler ◽  
Christian Schumann
Keyword(s):  
Metastatic Tumor ◽  
Clinical History ◽  
Primary Diagnosis ◽  
Tumor Burden ◽  
Primary Tumors ◽  
Prognostic Features ◽  
Therapeutic Decisions ◽  
Platinum Based Chemotherapy ◽  
The Individual ◽  
The Mathematical Model

Abstract Background: Cancer is one of the leading death causes globally with about 8.2 million deaths per year and an increase in numbers in recent years. About 90% of cancer deaths do not occur due to primary tumors but due to metastases, of which most are not clinically identifiable because of their relatively small size at primary diagnosis and limited technical possibilities. However, therapeutic decisions are formed depending on the existence of metastases and their properties. Therefore non-identified metastases might have huge influence in the treatment outcome. The quantification of clinically visible and invisible metastases is important for the choice of an optimal treatment of the individual patient as it could clarify the burden of non-identifiable tumors as well as the future behavior of the cancerous disease. Results: The mathematical model presented in this study gives insights in how this could be achieved, taking into account different treatment possibilities and therefore being able to compare therapy schedules for individual patients with different clinical parameters. The framework was tested on three patients with NSCLC, one of the deadliest types of cancer worldwide, and clinical history including platinum-based chemotherapy and PD-L1-targeted immunotherapy. Results yield promising insights into the framework to establish methods to quantify effects of different therapy methods and prognostic features for individual patients already at stage of primary diagnosis.

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