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Nathan Goodyear

Dietary Strategy to Repair Plasma Membrane After Brain Trauma - 0 views

nnr.sagepub.com/...75.full

BDNF curcumin DHA TBI concussion brain injury traumatic brain injury

shared by Nathan Goodyear on 30 Aug 15 - No Cached
  • strategies directed to preserve phospholipids in the plasma membrane such as the use of dietary docosahexaenoic acid (C22:6n-3; DHA)5 can have beneficial effects for post-TBI recovery
  • DHA is the most abundant polyunsaturated fatty acid (PUFA) in the brain
  • Curcumin provided in the diet before TBI can reduce oxidative damage and counteract TBI-related cognitive dysfunction.
  • ...8 more annotations...
  • Our previous study indicated that n-3 fatty acids supplemented in the diet counteracted learning disability after TBI
  • There was a significant group effect on BDNF (F 4,25 = 5.229, P < .01 by ANOVA), and FPI reduced BDNF levels (50% of CTL, P < .01; Figure 1C), which was counteracted by DHA supplementation (90% of CTL, P < .05; Figure 1C). Curcumin also counteracted this reduction of BDNF
  • The combination of curcumin and DHA had a trend of greater effects in BDNF (117% of CTL; Figure 1C) compared with DHA or curcumin alone.
  • curcumin contributed to enhance the action of DHA, protecting against cognitive impairment, and these effects were associated with elevations in the BDNF receptor signaling
  • Our current results show that curcumin contributes to enhance the effects of DHA on TBI by promoting phosphorylation of the BDNF receptor TrkB in the hippocampus.
  • previous evidence indicates that curcumin10 and DHA5 counteract TBI-related learning disability by involving BDNF
  • The effects of the DHA diet and curcumin on cognitive enhancement were consistent with enhanced elevations in BDNF receptor signaling
  • effects of DHA and curcumin up to 2 weeks after TBI because this is the most critical period for the course of injury recovery because the brain is metabolically dysfunctional during this time
  • Nathan Goodyear on 30 Aug 15
     
    study that finds curcumin + DHA increased cognitive improvement after TBI within 2 weeks.  Good discussion of the proposed mechanism--increased BDNF.
Nathan Goodyear

Validation of Blood Spot Sampling for Gonadotropins and Ovarian Hormone Levels in Repro... - 0 views

www.fertstert.org/...fulltext

blood spot hormone testing hormones Estradiol Progesterone LH FSH

shared by Nathan Goodyear on 22 Jun 15 - No Cached
  • Nathan Goodyear on 22 Jun 15
     
    blood spot Estradiol, Progesterone, LH, and FSH levels shown to be comparable to plasma levels.
Nathan Goodyear

ScienceDirect - Journal of Steroid Biochemistry : Saliva testosterone time-course respo... - 0 views

www.sciencedirect.com/science

saliva salivary testosterone hormone hormones testing

shared by Nathan Goodyear on 18 Jan 11 - No Cached
  • Thus it was suggested to collect saliva instead of plasma for the evaluation of testicular secretion of testosterone after hCG administration
  • Nathan Goodyear on 18 Jan 11
     
    salivary testosterone testing validated
Nathan Goodyear

Salivary progesterone excellently reflects free and total progesterone in plasma during... - 0 views

www.clinchem.org/...168

salivary progesterone

shared by Nathan Goodyear on 18 Jan 11 - No Cached
  • Evidently salivary progesterone is a very good alternative to plasma as a sample for use in follow-up during pregnancy.
  • Nathan Goodyear on 18 Jan 11
     
    salivary progesterone validated during pregnancy
Nathan Goodyear

Replacement therapy for hypothyroidism with thyrox... [J Clin Invest. 1995] - PubMed re... - 0 views

www.ncbi.nlm.nih.gov/...8675653

hypothyroidism replacement therapy T4 T3

shared by Nathan Goodyear on 08 Mar 11 - No Cached
  • No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations.
  • Nathan Goodyear on 08 Mar 11
     
    replacement therapy for hypothyroidism must include both T4 and T3
Nathan Goodyear

Weight Regain after a Diet-Induced Loss Is Predicted by Higher Baseline Leptin and Lowe... - 0 views

jcem.endojournals.org/...5037.abstract

weight loss overweight obesity leptin ghrelin

shared by Nathan Goodyear on 31 May 11 - No Cached
  • Appetite-related hormones may play an important role in weight regain after obesity therapy.
  • Subjects with higher plasma leptin and lower ghrelin levels at baseline could be more prone to regain lost weight
  • Nathan Goodyear on 31 May 11
     
    leptin plays role in rebound weight gain after "diet" programs
Nathan Goodyear

ScienceDirect - American Heart Journal : Plasma total cysteine and total homocysteine a... - 0 views

www.sciencedirect.com/...S0002870310000815

elevated homocysteine MI risk cardiac

shared by Nathan Goodyear on 03 Aug 11 - No Cached
  • Fasting homocysteine was positively associated with MI risk
  • Fasting plasma concentration of total homocysteine, but not total cysteine, was positively associated with MI risk.
  • Nathan Goodyear on 03 Aug 11
     
    homocysteine associated with MI risk
Nathan Goodyear

Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease - NEJM - 0 views

www.nejm.org/...NEJM199707243370403

homocysteine mortality cardiovascular disease CAD risk

shared by Nathan Goodyear on 03 Aug 11 - No Cached
  • Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease
  • Nathan Goodyear on 03 Aug 11
     
    elevated homocysteine strong predictor of mortality
Nathan Goodyear

Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 dia... - 0 views

www.ajhp.org/...173.short

exenatide byetta diabetes overweight obesity pharmacodynamics pharmacokinetics

shared by Nathan Goodyear on 06 Apr 11 - No Cached
  • exenatide dose-dependently reduced postprandial plasma glucose excursion by insulinotropism
  • suppression of plasma glucagon, and slowing of gastric emptying.
  • Nathan Goodyear on 06 Apr 11
     
    exenatide improves insulin/glucose regulation
Nathan Goodyear

SpringerLink - Human Physiology, Volume 26, Number 4 - 0 views

www.springerlink.com/...5168320282711841

cortisol testing NASA

shared by Nathan Goodyear on 04 May 11 - No Cached
  • salivary cortisol were studied by Russian cosmonauts on board orbital station Mir during long-term space flights (SF)
  • After the long-term SF, individual ratios of salivary and plasma cortisol levels increased against the background of increased plasma content of the hormone, i.e., the fraction of free, physiologically active hormone in the total pool of circulating molecules decreased.
  • Nathan Goodyear on 04 May 11
     
    salivary cortisol testing and long-term space travel: conducted by NASA
Nathan Goodyear

Monitoring the circadian rhythm of se... [Domest Anim Endocrinol. 2013] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23688596

saliva salivary cortisol testing HPA hormone hormones

shared by Nathan Goodyear on 23 Aug 14 - No Cached
  • Nathan Goodyear on 23 Aug 14
     
    Animal study finds very good correlation of salivary cortisol and free plasma cortisol.
Nathan Goodyear

Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk - 0 views

jme.endocrinology-journals.org/...R51.full

metabolic endotoxemia obesity insulin resistance cardiovascular disease LPS inflammation

shared by Nathan Goodyear on 04 Aug 14 - No Cached
  • Weight gain has been associated with a higher gut permeability
  • a high-fat diet promotes LPS absorption
  • higher concentrations of fatty acids impair intestinal barrier integrity
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  • The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors
  • TLRs are PRRs that recognize microbe-associated molecular patterns
  • TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain
  • The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients
  • Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.
  • Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption
  • LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.
  • In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.
  • In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.
  • the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels
  • dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.
  • This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.
  • n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations
  • it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).
  • this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A
  • these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.
  • This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.
  • endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis
  • in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.
  • T2DM patients have mean values of LPS that are 76% higher than healthy controls
  • LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic
  • LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells
  • Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease
  • The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile
  • All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features
  • LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism
  • When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome
  • It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis
  • On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα
  • high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs
  • prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls
  • Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers
  • This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation
  • high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk
  • LPS has been shown to promote atherosclerosis
  • markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk
  • As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.
  • Nathan Goodyear on 04 Aug 14
     
    Very nice updated review on Metabolic endotoxemia
Nathan Goodyear

Hyperammonemia-induced depletion of glutamate and branched-chain am... - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...8938556

ammonia NH3 BCCA branched chain amino acids glutamine

shared by Nathan Goodyear on 18 Nov 14 - No Cached
  • Nathan Goodyear on 18 Nov 14
     
    Elevated ammonia depletes glutamate and BCCA in muscle and plasma.  A decrease in BCCA is through an up regulation of glutamine in an attempt to eliminate ammonia.
Nathan Goodyear

Comparisons of normal saline and lactated Ringer's resuscitation on hemodynamics, metab... - 0 views

www.ncbi.nlm.nih.gov/...PMC4029282

IV fluids lactated ringers normal saline LR NS

shared by Nathan Goodyear on 03 Jul 18 - No Cached
  • NS contains 154 mM Na+ and Cl-, with an average pH of 5.0 and osmolarity of 308 mOsm/L.
  • LR solution has an average pH of 6.5, is hypo-osmolar (272 mOsm/L), and has similar electrolytes (130 mM Na+, 109 mM Cl-, 28 mM lactate, etc.) to plasma
  • hyperchloremic acidosis
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  • LR’s acid base balance is superior to that of NS’s
  • There were no significant differences between LR and NS groups in fibrinogen concentrations or platelet count
  • Total protein dropped
  • no significant differences in Hct (Table  1) or total protein between LR and NS groups
  • Bicarbonate HCO3- levels were decreased by hemorrhage but returned to pre-hemorrhage values by 3 h after LR resuscitation, whereas no return was observed with NS resuscitation
  • Na+ was increased after NS resuscitation
  • No changes in Na+ or K+ were observed
  • K+ did not change initially after NS resuscitation but was elevated at 6 h afterwards
  • Ca++ was similarly decreased
  • Cl- was elevated for 6 h after NS resuscitation, with no changes shown after LR resuscitation
  • PT was similarly prolonged by resuscitation with LR (from 11.2 ± 0.2 sec at baseline to 12.1 ± 0.2 sec at 6 h) and NS
  • Plasma aPTT was also similarly prolonged by resuscitation with LR (from 17.1 ± 0.5 sec baseline to 20.1 ± 1.2 sec at 6 h) or NS
  • NS resuscitation resulted in better oxygen delivery and oxygen delivery-to-oxygen demand ratio as an index of oxygen debt
  • NS had better tissue perfusion and oxygen metabolism than LR
  • LR resuscitation returned BE and bicarbonate to pre-hemorrhage levels within 3 h, but no return of BE or bicarbonate was observed for 6 hr with NS resuscitation
  • current blood bank guidelines state that LR should not be mixed with blood to prevent the risk of clot formation from calcium included in LR
  • LR resuscitation should not be given with blood through the same iv-line and crystalloids should be avoided in patients with blood transfusion
  • PT and aPTT were prolonged for 6 h after hemorrhage and resuscitation, suggesting a hypocoagulable states
  • potential thrombotic risk from LR resuscitation is unlikely.
  • we suspected that the blood pressure after NS resuscitation would be lower than that of LR due to its vasodilator effects
  • NS required a larger resuscitation volume and was associated with poor acid base status and elevated serum potassium in this model
  • NS required 50% more volume and was associated with a higher cardiac output and lower peripheral resistance, as compared to LR resuscitation
  • These differences are possibly due to the vasodilator effects from NS
  • an elevation of K+ was observed at 6 h post NS resuscitation, while no change of K+ was observed after LR resuscitation
  • The mechanism for the increase of K+ from NS is not fully known
  • NS is associated with vasodilator effects and the risks of metabolic acidosis and hyperkalemia
  • Nathan Goodyear on 03 Jul 18
     
    LR vs NS crystalloid.
Nathan Goodyear

Clinical review: Specific aspects of acute renal failure in cancer patients - 0 views

www.ncbi.nlm.nih.gov/...PMC1550893

cancer renal failure

shared by Nathan Goodyear on 13 Aug 18 - No Cached
  • uric acid crystal formation in the renal tubules secondary to hyperuricaemia
  • calcium phosphate deposition related to hyperphosphataemia
  • usually develops shortly after the initiation of cytotoxic chemotherapy
  • ...18 more annotations...
  • Non-recombinant urate oxidase (Uricozyme®)
  • recombinant urate oxidase (Rasburicase®)
  • urine alkalisation may induce calcium phosphate deposition
  • renal replacement therapy should be started on an emergency basis when hydration fails to produce a prompt metabolic improvement or when ARF develops
  • Up to 50% of patients with newly diagnosed multiple myeloma have renal failure and up to 10% require dialysis
  • renal ultrasonography remains the method of choice for investigating extra-renal obstruction
  • The relief of the obstruction, either by percutaneous nephrostomy or through a ureteral stent, is the cornerstone of treatment
  • TMA may be associated with the cancer itself, with cancer chemotherapy, or with allogeneic BMT
  • thrombotic microangiopathy (TMA)
  • it may be as high as 5%
  • Most of the cases occur in patients with solid tumours, the most common type being adenocarcinoma (stomach, breast and lung)
  • The pathophysiology of the TMA-malignancy association remains controversial, although many studies suggest an insult to the vascular endothelium
  • mitomycin C. Subsequently, TMA has been reported with many anti-cancer agents, including gemcita-bine, bleomycin, cisplatin, CCNU, cytosine arabinoside, daunorubicin, deoxycoformycin, 5-FU, azathioprine and interferon α
  • Plasma exchanges have been shown to improve prognosis in the general population of patients with TMA
  • Causative factors should be looked for and antihypertensive treatment given. Lastly, in the absence of guidelines, we believe that plasma exchange should be proposed in patients with severe cancer treatment-associated TMA
  • The most widely used protective measure is saline infusion to induce solute diuresis
  • During methotrexate infusion and elimination, fluids should be given to maintain a high urinary output and urinary alkalisation should be performed to keep the urinary pH above 7.5. Rescue with folinic acid (50 mg four times a day) should be started 24 hours after each high-dose metho-trexate infusion and serum methotrexate concentrations should be measured every day
  • cyclophosphamide and ifosfamide
  • Nathan Goodyear on 13 Aug 18
     
    cancer and renal failure
Nathan Goodyear

The role of vitamin C in the treatment of pain: new insights - 0 views

www.ncbi.nlm.nih.gov/...PMC5391567

vitamin C pain arthritis

shared by Nathan Goodyear on 18 Sep 17 - No Cached
  • recommended that during illness one should be careful about the intake of vitamin C, keeping in mind that acute illness rapidly depletes stores of ascorbic acid
  • it is possible that other hospital-associated pain may be partly due to vitamin C deficiency, which is relatively prevalent in hospital settings
  • Vitamin C deficiency (defined as plasma vitamin C concentrations <11 µmol/L
  • ...5 more annotations...
  • Vitamin C is cost effective and appears to be a safe and effective adjunctive therapy for specific pain relief
  • it decreases the requirement for opioid analgesics, particularly post surgically and for bone metastasis
  • recent research has indicated a positive impact of high dose vitamin C on cancer- and chemotherapy-related quality of life, including pain
  • Cameron and Campbell [81] reported a number of cases of dramatic to complete amelioration of bone pain in patients with severe cancer-related pain given both high dose oral and intravenous vitamin C
  • hypovitaminosis C (defined as plasma vitamin C concentrations <23 µmol/L
  • Nathan Goodyear on 18 Sep 17
     
    vitamin C reduces pain; mechanism of action likely anti-inflammatory antioxidant, but yet inconclusive.
Nathan Goodyear

Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic... - 0 views

www.ebiomedicine.com/...fulltext

multiple myeloma vitamin C IV vitamin C smoldering myeloma cancer

shared by Nathan Goodyear on 25 Sep 17 - No Cached
  • Recent reports indicate that a certain ROS concentration is required for high-dose vitamin C to induce cytotoxicity in cancer cells.
  • The generation of ascorbyl- and H2O2 radicals by PAA increases ROS stress in cancer cells
  • In this study, we report that PAA is efficacious in killing MM cells in vitro and in vivo models, which generated levels of 20–40 mM ascorbate and 500 nM ascorbyl radicals after intraperitoneal administration of 4 g ascorbate per kilogram of body weight (Chen et al., 2008Chen et al., 2008), in xenograft MM mice
  • ...33 more annotations...
  • These data suggest that PAA may show a therapeutic advantage to blood cancers vs solid tumors because of the communication between tumor cells and blood plasma
  • These results strongly suggest that the mechanism of PAA killing of MM cells is indeed iron-dependent
  • These results suggest that PAA administration in SMM may be able to prevent progression to symtomatic MM
  • A recent study by Yun and colleagues demonstrated that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, but spares normal cells
  • RAS family genes show the most frequent mutations in MM. KRAS, NRAS and BRAF are mutated in 22%, 20% and 7% of MM samples
  • the disease stage rather than the mutation of RAS and/or BRAF is the major predictive factor for PAA sensitivity in MM treatment
  • Other molecular mechanisms including ATP depletion and ATM-AMPK signaling have been reported to explain PAA-induced cell death
  • our pilot study also suggested that PAA could overcome drug resistance to bortezomib in MM cells
  • Our findings complement reported studies and further address the mechanism of action using clinical samples in which we observed that PAA killed tumor cells with high iron content, suggesting that iron might be the initiator of PAA cytotoxicity
  • combination of PAA with standard therapeutic drugs, such as melphalan, may significantly reduce the dose of melphalan needed
  • Combined treatment of reduced dose melphalan with PAA achieved a significantly longer progression-free survival than the same dose of melphalan alone.
  • These data also suggest that the bone marrow suppression induced by high-dose melphalan can be ameliorated by the combination of PAA with lower dose of melphalan because of the lack of toxicity of PAA on normal cells with low iron content.
  • if creatinine clearance is <30 mL/min, high dose ascorbic acid should be not administrated.
  • In MM preclinical and clinical studies, ascorbate was used as an adjunct drug and showed controversial results (Harvey et al., 2009, Perrone et al., 2009, Held et al., 2013, Sharma et al., 2012, Nakano et al., 2011, Takahashi, 2010, Sharma et al., 2009, Qazilbash et al., 2008). However, none of these tests used pharmacological doses of ascorbate and intravenous administration
  • Multiple myeloma (MM) is a plasma cell neoplasm.
  • Cameron and Pauling reported that high doses of vitamin C increased survival of patients with cancer
  • pharmacologically dosed ascorbic acid (PAA) 50–100 g (Chen et al., 2008, Padayatty et al., 2004, Hoffer et al., 2008, Padayatty et al., 2006, Welsh et al., 2013), administered intravenously, has potent anti-cancer activity and its role as anti-cancer therapy is being studied at the University of Iowa and in other centers
  • In the presence of catalytic metal ions like iron, PAA administered intravenously exerts pro-oxidant effects leading to the formation of highly reactive oxygen species (ROS), resulting in cell death
  • the labile iron pool (LIP) is significantly elevated in MM cells
  • The survival of CD138+ cells in vitro was significantly decreased following PAA treatment in all 9 MM
  • In contrast, no significant change of cell viability was observed in CD138− BM cells from the same patients
  • The same effect of PAA was also observed in the SMM patients
  • no response to PAA was detected in CD138+ cells from the 2 MGUS patients
  • the combination of melphalan plus PAA showed greater tumor burden reduction than each drug alone, suggesting a synergistic activity between these two drugs
  • Both catalase and NAC protect cells from oxidative damage
  • cells pretreated with NAC and catalase became resistant to PAA even at high doses
  • adding deferoxamine (DFO), an iron chelator, to OCI-MY5 cells before PAA treatment was also sufficient to prevent PAA-induced cellular death
  • iron is essential for PAA to achieve its anti-cancer activity
  • PAA induced early necrosis (Fig. 3Fig. 3A, 60 min) followed by late apoptosis
  • results further indicated that PAA induced mitochondria-mediated apoptosis
  • PAA by reacting with LIP and generating ROS induces mitochondria-mediated apoptosis in which AIF1 cleavage is important for cell death.
  • ROS and H2O2 are well known factors mediating PAA-induced cancer cell death
  • PAA was sensitive to all 9 MMs and 2 SMMs
  • Nathan Goodyear on 25 Sep 17
     
    animal study finds high-dose, pharmacologic vitamin C found to kill multiple myeloma cells via pro-oxidant effect found in similar studies in dealing with different cancers.
Nathan Goodyear

Enhanced Human Neutrophil Vitamin C Status, Chemotaxis and Oxidant Generation Following... - 0 views

www.ncbi.nlm.nih.gov/...PMC4425162

immune system vitamin C neutrophils

shared by Nathan Goodyear on 11 Oct 17 - No Cached
  • Nathan Goodyear on 11 Oct 17
     
    Vitamin C enhances neutrophil function in study of 14 women.  The study found that their plasma vitamin C status was low.  No increase in new neutrophil generation was noted.  During the study, they only reached 70 micromol/L from the pre-study <50 micromol/L.  I wonder if the study had used higher doses and/or followed longer, they would have seen an increase in the neutrophil numbers?
Nathan Goodyear

Oncotarget | Vitamin C and Doxycycline: A synthetic lethal combination therapy targetin... - 0 views

www.impactjournals.com/...index.php

cancer doxycycline IV vitamin C vitamin C

shared by Nathan Goodyear on 14 Jun 17 - No Cached
  • These eight distinct cancer types included: DCIS, breast (ER(+) and ER(-)), ovarian, prostate, lung, and pancreatic carcinomas, as well as melanoma and glioblastoma. Doxycycline was also effective in halting the propagation of primary cultures of CSCs from breast cancer patients, with advanced metastatic disease (isolated from ascites fluid and/or pleural effusions)
  • Doxycycline behaves as a strong radio-sensitizer, successfully overcoming radio-resistance in breast CSCs
  • cancer cells can indeed escape the effects of Doxycycline, by reverting to a purely glycolytic phenotype. Fortunately, the metabolic inflexibility conferred by this escape mechanism allows Doxycycline-resistant (DoxyR) CSCs to be more effectively targeted with many other metabolic inhibitors, including Vitamin C, which functionally blocks aerobic glycolysis
  • ...36 more annotations...
  • Vitamin C inhibits GAPDH (a glycolytic enzyme) and depletes the cellular pool of glutathione, resulting in high ROS production and oxidative stress
  • DoxyR CSCs are between 4- to 10-fold more susceptible to the effects of Vitamin C
  • Doxycycline and Vitamin C may represent a new synthetic lethal drug combination for eradicating CSCs, by ultimately targeting both mitochondrial and glycolytic metabolism
  • inhibiting their propagation in the range of 100 to 250 µM
  • metabolic flexibility in cancer cells allows them to escape therapeutic eradication, leading to chemo- and radio-resistance
  • used doxycycline to pharmacologically induce metabolic inflexibility in CSCs, by chronically inhibiting mitochondrial biogenesis
  • This treatment resulted in a purely glycolytic population of surviving cancer cells
  • DoxyR cells are mainly glycolytic
  • MCF7 cells survive and develop Doxycycline-resistance, by adopting a purely glycolytic phenotype
  • Cancer stem cells (CSCs) are thought to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance
  • the conserved evolutionary similarities between aerobic bacteria and mitochondria, certain classes of antibiotics inhibit mitochondrial protein translation, as an off-target side-effect
  • Vitamin C was more potent than 2-DG; it inhibited DoxyR CSC propagation by &gt; 90% at 250 µM and 100% at 500 µM
  • IC-50
  • DoxyR CSCs are between 4- to 10-fold more sensitive to Vitamin C than control MCF7 CSCs
  • Berberine, which is a naturally occurring antibiotic that also behaves as an OXPHOS inhibitor
  • treatment with Berberine effectively inhibited the propagation of the DoxyR CSCs by &gt; 50% at 1 µM and &gt; 80% at 10 µM.
  • Doxycycline, a clinically approved antibiotic, induces metabolic stress in cancer cells. This allows the remaining cancer cells to be synchronized towards a purely glycolytic phenotype, driving a form of metabolic inflexibility
  • Doxycycline-driven aerobic glycolysis
  • new synthetic lethal strategy for eradicating CSCs, by employing i) Doxycycline (to target mitochondria) and ii) Vitamin C (to target glycolysis)
  • Doxycycline inhibits mitochondrial biogenesis and OXPHOS,
  • hibits glycolytic metabolism by targeting and inhibiting the enzyme GAPDH
  • CSCs act as the main promoter of tumor recurrence and patient relapse
  • a metabolic shift from oxidative to glycolytic metabolism represents an escape mechanism for breast cancer cells chronically-treated with a mitochondrial stressor like Doxycycline, as mitochondrial dys-function leads to a stronger dependence on glucose
  • Vitamin C has been demonstrated to selectively kill cancer cells in vitro and to inhibit tumor growth in experimental mouse models
  • many of these actions have been attributed to the ability of Vitamin C to act as a glycolysis inhibitor, by targeting GAPDH and depleting the NAD pool
  • here we show that DoxyR CSCs are more vulnerable to the inhibitory effects of Vitamin C, at 4- to 10-fold lower concentrations, between 100 to 250 μM
  • concurrent use of Vitamin C, with standard chemotherapy, reduces tumor recurrence and patient mortality
  • after oral administration, Vitamin C plasma levels reach concentrations of ~70-220 μM
  • intravenous administration results in 30- to 70- fold higher plasma concentrations of Vitamin C
  • pro-oxidant activity results from Vitamin C’s action on metal ions, which generates free radicals and hydrogen peroxide, and is associated with cell toxicity
  • it has been shown that high-dose Vitamin C is more cytotoxic to cancer cells than to normal cells
  • This selectivity appears to be due to the higher catalase content observed in normal cells (~10-100 fold greater), as compared to tumor cells. Hence, Vitamin C may be regarded as a safe agent that selectively targets cancer cells
  • the concurrent use of Doxycycline and Vitamin C, in the context of this infectious disease, appeared to be highly synergistic in patients
  • Goc et al., 2016, showed that Doxycycline is synergistic in vitro with certain phytochemicals and micronutrients, including Vitamin C, in the in vitro killing of the vegetative spirochete form of Borrelia spp., the causative agent underlying Lyme disease
  • Doxycycline, an FDA-approved antibiotic, behaves as an inhibitor of mitochondrial protein translation
  • CSCs successfully escape from the anti-mitochondrial effects of Doxycycline, by assuming a purely glycolytic phenotype. Therefore, DoxyR CSCs are then more susceptible to other metabolic perturbations, because of their metabolic inflexibility
  • Nathan Goodyear on 14 Jun 17
     
    Not especially new, but IV vitamin C + daily doxycycline found to kill cancer stem cells.
Nathan Goodyear

Vitamin C Status Correlates with Markers of Metabolic and Cognitive Health in 50-Year-O... - 0 views

www.ncbi.nlm.nih.gov/...PMC5579624

vitamin C health metabolism cognition

shared by Nathan Goodyear on 31 Jan 18 - No Cached
  • Nathan Goodyear on 31 Jan 18
     
    interesting cohort study: plasma vitamin C levels correlate with metabolic health i.e. insulin, HgbA1c and cognition.
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