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Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. | A Tale of Two Medicines | Scoop.it
Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein–coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.
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A Tale of Two Medicines
Natural Medicine, Pharmaceuticals and GMO’s, the Good, the Bad and the OMG! - (The information provided is not intended to be a substitute for professional medical advice, diagnosis or treatment.  Never disregard professional medical advice, or delay in seeking it, because of something you have read on this scoopit page.)
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Mistletoe extract doubles survival time of pancreatic cancer patients

Mistletoe extract doubles survival time of pancreatic cancer patients | A Tale of Two Medicines | Scoop.it

This new Phase III clinical trial was randomized, open-label and carried out in Serbia on 220 patients. All patients received Best Supportive Care. Patients in the treatment group also received subcutaneous injections of mistletoe extract three times weekly with dosages escalating from 0.01 mg up to a constant 10 mg after the twenty-second dose. Patients who started the study with a ‘good prognosis’ saw their survival times more than double from 3.2 months (if untreated) to 6.6 months if treated with mistletoe. Likewise, patients with a ‘poor prognosis’ averaged 2.0 months survival if untreated, but 3.4 months if treated with mistletoe. Remarkably, the group treated with mistletoe experienced only 16 adverse events compared to 53 adverse events in the untreated group. Rather than carrying negative side effects as chemo drugs do, the mistletoe treatment actually decreased the likelihood of painful or undesirable effects (adverse events) by 75 percent. And none of the adverse events in the mistletoe group were caused by the mistletoe itself.

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Pasquale Valente's curator insight, December 18, 9:39 AM

VaL therapy showed a significant and clinically relevant prolongation of OS. The study findings suggest VaL to be a non-toxic and effective second-line therapy that offers a prolongation of OS as well as less disease-related symptoms for patients with locally advanced or metastatic pancreatic cancer. http://www.ncbi.nlm.nih.gov/pubmed/23890767

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Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention.

The growing interest in cancer epigenetics is largely due to the reversible nature of epigenetic changes which tend to alter during the course of carcinogenesis. Major epigenetic changes including DNA methylation, chromatin modifications and miRNA regulation play important roles in tumorigenic process. There are several epigenetically active synthetic molecules such as DNA methyltransferase (DNMTs) and histone deacetylases (HDACs) inhibitors, which are either approved or, are under clinical trials for the treatment of various cancers. However, most of the synthetic inhibitors have shown adverse side effects, narrow in their specificity and also expensive. Hence, bioactive phytochemicals, which are widely available with lesser toxic effects, have been tested for their role in epigenetic modulatory activities in gene regulation for cancer prevention and therapy. Encouragingly, many bioactive phytochemicals potentially altered the expression of key tumor suppressor genes, tumor promoter genes and oncogenes through modulation of DNA methylation and chromatin modification in cancer. These bioactive phytochemicals either alone or in combination with other phytochemicals showed promising results against various cancers. Here, we summarize and discuss the role of some commonly investigated phytochemicals and their epigenetic targets that are of particular interest in cancer prevention and cancer therapy.

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Aged garlic extract protects against doxorubicin-induced cardiotoxicity in rats.

Clinical uses of doxorubicin (DOX), a highly active anticancer agent, are limited by its severe cardiotoxic side effects associated with increased oxidative stress and apoptosis. In this study we investigated whether aged garlic has protective effects against doxorubicin-induced free radical production and cardiotoxicity in male rats. A single dose of doxorubicin (25mg/kg) caused increased both serum cardiac enzymes LDH and CPK activities and a significant increase malonyldialdehyde (MDA) in plasma. However, pretreatment of rats with aged garlic extract (250 mg/kg) for 27 days before doxorubicin therapy, reduced the activity of both enzymes, and significantly decreased of MDA production in plasma. Total antioxidant activity was increased after aged garlic extract administration. Histopathological examination of heart tissue showed that DOX treatment resulted in alteration of cardiac tissue structure in the form of peri arterial fibrosis and apoptotic changes in cardiomyocytes. Pretreatment with aged garlic extract for 27 days ameliorated the effect of DOX administration on cardiac tissue; cardiomyocytes looked more or less similar to those of control. However, still vascular dilatation, mild congestion and interstitial edemas were observed. Our results suggest that aged garlic extract is potentially protective against doxorubicin-induced cardiotoxicity.

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Curcumin Combined with Oxaliplatin Effectively Suppress Colorectal Carcinoma in vivo Through Inducing Apoptosis.

Studies have shown chemopreventive and/or chemotherapeutic effects of several curcumin-based combinatorial treatments on colorectal cancer cells. However, their in vivo effects remain unclear. This study has demonstrated the therapeutic effect of curcumin and oxaliplatin, alone or in combination, on subcutaneously xenografted LoVo human colorectal cancer cells in immunodeficient (nu/nu) mice in vivo. Combinatorial administration of curcumin and oxaliplatin evidently inhibited the growth of colorectal cancer in nude mice, which was significantly more effective than either agent alone. Curcumin combined with oxaliplatin treatment induced apoptosis, accompanied by ultrastructural changes and cell cycle arrest in S and G2/M phases. Further mechanism analysis indicated that while the number of apoptotic tumor cells and the expression of Bax, caspase-3, and poly (ADP-ribose) polymerase (PARP) increased significantly, the expression of Bcl-2, survivin, HSP70, pro-caspase-3, and pro-PARP were dramatically suppressed in tumor cells after the treatment with combinatorial curcumin and oxaliplatin for 22 days. Taken together, the present study has demonstrated that administration of combined curcumin and oxaliplatin effectively suppressed colorectal carcinoma in vivo through inducing apoptosis and thus may provide an effective treatment for colorectal carcinoma.

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Antioxidant capacity of orange juice is multiplied tenfold

Antioxidant capacity of orange juice is multiplied tenfold | A Tale of Two Medicines | Scoop.it

The antioxidant activity of citrus juices and other foods is undervalued. A new technique developed by researchers from the University of Granada for measuring this property generates values that are ten times higher than those indicated by current analysis methods. The results suggest that tables on the antioxidant capacities of food products that dieticians and health authorities use must be revised.

 

Orange juice and juices from other citrus fruits are considered healthy due to their high content of antioxidants, which help to reduce harmful free radicals in our body, but a new investigation shows that their benefits are greater than previously thought.

 

In order to study these compounds in the laboratory, techniques that simulate the digestion of food in the digestive tract are used, which analyse only the antioxidant capacities of those substances that can potentially be absorbed in the small intestine: the liquid fraction of what we eat.

 

"The problem is that the antioxidant activity of the solid fraction (the fibre) isn't measured, as it's assumed that it isn't beneficial. However, this insoluble fraction arrives at the large intestine and the intestinal microbiota can also ferment it and extract even more antioxidant substances, which we can assess with our new methodology," José Ángel Rufián Henares, professor at the University of Granada, explains.

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Nutrients and their role in host resistance to infection

Almost all nutrients in the diet play a crucial role in maintaining an “optimal” immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens. Iron and vitamin A deficiencies and protein-energy malnutrition are highly prevalent worldwide and are important to the public health in terms of immunocompetence. There are also nutrients (i.e., glutamine, arginine, fatty acids, vitamin E) that provide additional benefits to immunocompromised persons or patients who suffer from various infections. The remarkable advances in immunology of recent decades have provided insights into the mechanisms responsible for the effects of various nutrients in the diet on specific functions in immune cells. In this review, we will present evidence and proposed mechanisms for the importance of a small group of nutrients that have been demonstrated to affect host resistance to infection will be presented. An inadequate status of some of these nutrients occurs in many populations in the world (i.e., vitamin A, iron, and zinc) where infectious disease is a major health concern. We will also review nutrients that may specifically modulate host defense to infectious pathogens (long-chain polyunsaturated n-3 fatty acids, vitamin E, vitamin C, selenium, and nucleotides). A detailed review of the effect of long-chain polyunsaturated n-3 fatty acids on host defense is provided as an example of how the disciplines of nutrition and immunology have been combined to identify key mechanisms and propose nutrient-directed management of immune-related syndromes.

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Enzyme may be key to cancer progression in many tumors

Enzyme may be key to cancer progression in many tumors | A Tale of Two Medicines | Scoop.it

Mutations in the KRAS gene have long been known to cause cancer, and about one third of solid tumors have KRAS mutations or mutations in the KRAS pathway. KRAS promotes cancer formation not only by driving cell growth and division, but also by turning off protective tumor suppressor genes, which normally limit uncontrolled cell growth and cause damaged cells to self-destruct.

 

A new University of Iowa study provided a deeper understanding of how KRAS turns off tumor suppressor genes and identifies a key enzyme in the process. The findings, published online Nov. 26 in the journal Cell Reports, suggest that this enzyme, known as TET1, may be an important target for cancer diagnostics and treatment.

 

In KRAS-driven cancers, tumor suppressor genes are turned off, or silenced, because the DNA that controls their expression is modified by methylation. The UI study shows that KRAS promotes this methylation-associated gene silencing by turning off the TET1 enzyme, which can remove methyl marks from DNA.

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L-glutamine decreases the severity of mucositis induced by chemoradiotherapy in patients with locally advanced head and neck cancer: A double-blind, randomized, placebo-controlled trial

L-glutamine decreases the severity of mucositis induced by chemoradiotherapy in patients with locally advanced head and neck cancer: A double-blind, randomized, placebo-controlled trial | A Tale of Two Medicines | Scoop.it

The incidence of severe mucositis in the oral cavity, pharynx and larynx is high among patients with head and neck cancer (HNC) receiving chemoradiotherapy (CRT), resulting in significant pain and impairment of quality of life. The present study investigated whether L-glutamine (glutamine) decreases the severity of mucositis in the oral cavity, pharynx and larynx induced by CRT. This double-blind, randomized, placebo-controlled trial included 40 untreated patients with squamous cell carcinoma of the nasopharynx, oropharynx, hypopharynx or larynx. Patients received 66 or 70 Gy of total radiation at the rate of 2 Gy/fraction daily and 5 fractions/week. Cisplatin (20 mg/m2) and docetaxel (10 mg/m2) were intravenously co-administered once a week for 6 weeks. Patients were randomized to orally receive either glutamine (group G) or placebo (group P) at a dose of 10 g 3 times a day throughout the CRT course. Mucositis was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The primary end point was mucositis severity. Mucositis developed in all patients. A maximal mucositis grade of G4 was observed in 0 and 25% group G and P patients, respectively, while that of G2 was observed in 10 and 0% group G and P patients, respectively (p=0.023). Glutamine significantly decreased the maximal mucositis grade (group G, 2.9±0.3; group P, 3.3±0.4; p=0.005) and pain score at weeks 4, 5 and 6. Glutamine significantly decreased mucositis severity in the oral cavity, pharynx and larynx induced by CRT in patients with HNC.

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Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer

Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer | A Tale of Two Medicines | Scoop.it

Curcumin has attracted increasing interest as an anti-cancer drug for decades. The mechanisms of action involve multiple cancer-related signaling pathways. Recent studies highlighted curcumin has epigenetic regulatory effects on miRNA in cancers. In the present study, we demonstrated the proapoptotic effects of curcumin in vitro and in vivo. miRNA microarray and qPCR indicated miR-192-5p and miR-215 were the most responsive miRNAs upon curcumin treatment in H460 and A427 cells. Functional studies showed miR-192-5p/215 were putative tumor suppressors in non-small cell lung cancer. Curcumin also promoted miR-192-5p/215 expressions in A549 cells (p53 wild type) but not in H1299 cells (p53-null). Conditional knockdown of p53 by tetracycline inducible expression system significantly abrogated curcumin-induced miR-192-5p/215 upregulation in the p53 wild-type H460, A427 and A549 cells. Conversely, ectopic expression of exogenous wild-type but not R273H mutant p53 in the p53-null H1299 cells enabled miR-192-5p/215 response to curcumin treatment. The proapoptotic effects of curcumin also depended on miR-192-5p/215 induction, and antagonizing miR-192-5p/215 expression attenuated curcumin-induced apoptosis in H460, A427 and A549 cells, but not in H1299 cells. Finally, X-linked inhibitor of apoptosis (XIAP) is proved to be a novel transcriptional target of miR-192-5p/215. Taken together, this study highlights the proapoptotic effects of curcumin depend on miR-192-5p/215 induction and the p53-miR-192-5p/215-XIAP pathway is an important therapeutic target for non-small cell lung cancer.

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Black tea in chemo-prevention of cancer and other human diseases

In summary, black tea and its extracts possess many health promoting properties supported by a myriad of data from in vitro and in vivo experiments as well as human clinical trials. The major black tea polyphenols, theaflavins and catechins should be recognized as biomolecular markers of black tea and its extract. Delineating biological mechanisms that are associated with a well-characterized chemical profile will provide crucial information for product development in targeting specific conditions.

 

The key molecular action of black tea polyphenols include the activation of Nrf2 transcription factor that up-regulates detoxifying and antioxidant enzymes. This action may also contribute to the inhibition of NF-κB, the master transcription factor that regulates inflammation. Black tea polyphenols also activate AMPK the key cellular energy sensor that regulates glucose and lipid metabolisms. All these diverse actions provide the scientific foundation in supporting the consumption of black tea or its extract for the prevention of cancer and treatment of many inflammatory and metabolic diseases.

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The Glutathione System: A New Drug Target in Neuroimmune Disorders - Springer

The Glutathione System: A New Drug Target in Neuroimmune Disorders - Springer | A Tale of Two Medicines | Scoop.it

Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-κB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson’s disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation.

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Krishan Maggon 's curator insight, November 13, 3:22 AM
Molecular NeurobiologyDecember 2014, Volume 50, Issue 3, pp 1059-1084Date: 22 Apr 2014The Glutathione System: A New Drug Target in Neuroimmune DisordersGerwyn Morris, George Anderson, Olivia Dean, Michael Berk, Piotr Galecki, Marta Martin-Subero,Michael Maes
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Hypoxia-induced IL-32β increases glycolysis in breast cancer cells

Hypoxia-induced IL-32β increases glycolysis in breast cancer cells | A Tale of Two Medicines | Scoop.it

IL-32β is highly expressed and increases the migration and invasion of gastric, lung, and breast cancer cells. Since IL-32 enhances VEGF production under hypoxic conditions, whether IL-32β is regulated by hypoxia was examined. Hypoxic conditions and a mimetic chemical CoCl2 enhanced IL-32β production. When cells were treated with various inhibitors of ROS generation to prevent hypoxia-induced ROS function, IL-32β production was suppressed by both NADPH oxidase and mitochondrial ROS inhibitors. IL-32β translocated to the mitochondria under hypoxic conditions, where it was associated with mitochondrial biogenesis. Thus, whether hypoxia-induced IL-32β is associated with oxidative phosphorylation (OXPHOS) or glycolysis was examined. Both of aerobic and anaerobic glycolysis impaired in IL-32β-depleted cells, and the hypoxia-induced IL-32β increased glycolysis through activation of lactate dehydrogenase. Src is also known to increase lactate dehydrogenase activity, and the hypoxia-induced IL-32β was found to stimulate Src activation by inhibiting the dephosphorylation of Src. These findings revealed that a hypoxia-ROS-IL-32β-Src-glycolysis pathway is associated with the regulation of cancer cell metabolism.

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The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer

The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer | A Tale of Two Medicines | Scoop.it

Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long-term adverse effects on prostate health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and restriction of dairy protein intake, especially during mTORC1-dependent phases of prostate development and differentiation, may offer protection from the most common dairy-promoted cancer in men of Western societies.

Jonathan Middleton's insight:

Researchers noted: "mTORC1 activation by leucine-rich dairy consumption may be attenuated by natural plant-derived inhibitors of mTORC1. Increasing studies have demonstrated that 3,3´-diindolylmethane (DIM), epigallocatechin gallate (EGCG), genistein, curcumin, resveratrol and caffeine, all inhibit mTORC1 signaling directly or indirectly and have been suggested to reduce the risk of PCa and other common cancers"

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Epigenetic impact of dietary polyphenols in cancer chemoprevention: lifelong remodeling of our epigenomes.

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Dietary regulation of PI3K/AKT/GSK-3ß pathway in Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles composed of phosphorylated Tau. Several findings suggest that correcting signal dysregulation for Tau phosphorylation in AD may offer a potential therapeutic approach. The PI3K/AKT/GSK-3β pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. This pathway appears to be crucial in AD because it promotes protein hyper-phosphorylation in Tau. Understanding those regulations may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances in the involvement of the PI3K/AKT/GSK-3β pathways in cell signaling of neuronal cells. We also review recent studies on the features of several diets and the signaling pathway involved in AD.
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Curcumin inhibits hypoxia-induced migration in K1 papillary thyroid cancer cells.

Curcumin, traditionally used as food and medicinal purposes, has recently been reported to have protective efficacy against hypoxia. Hypoxia is one of the important reactive factors in tumor metastasis, which is a key problem in clinical thyroid cancer therapy. In present study, we investigate the anti-metastatic effect of curcumin on the K1 papillary thyroid cancer cells as well as its potential mechanisms. The results show that curcumin effectively inhibits hypoxia-induced reactive oxygen species (ROS) upregulation and significantly decreases the mRNA and protein expression levels of hypoxia-inducible factor-1α (HIF-1α) in K1 cells. Curcumin also decreases the DNA binding ability of HIF-1α to hypoxia response element (HRE). Furthermore, curcumin enhances E-cadherin expression, inhibits metalloproteinase-9 (MMP-9) enzyme activity, and weakens K1 cells migration under hypoxic conditions. In summary, these results indicate that curcumin possesses a potent anti-metastatic effect and might be an effective tumoristatic agent for the treatment of aggressive papillary thyroid cancers.

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Vitamin Supplement Successfully Prevents Noise-Induced Hearing Loss In Mice.

Vitamin Supplement Successfully Prevents Noise-Induced Hearing Loss In Mice. | A Tale of Two Medicines | Scoop.it

Researchers from Weill Cornell Medical College and the Gladstone Institutes have found a way to prevent noise-induced hearing loss in a mouse using a simple chemical compound that is a precursor to vitamin B3. This discovery has important implications not only for preventing hearing loss, but also potentially for treating some aging-related conditions that are linked to the same protein.

 

Published today in Cell Metabolism, the researchers used the chemical nicotinamide riboside (NR) to protect the nerves that innervate the cochlea. The cochlea transmits sound information through these nerves to the spiral ganglion, which then passes along those messages to the brain. Exposure to loud noises damages the synapses connecting the nerves and the hair cells in the cochlea, resulting in noise-induced hearing loss.

 

The researchers set about trying to prevent this nerve damage by giving mice NR before or after exposing them to loud noises. NR was successful at preventing damage to the synaptic connections, avoiding both short-term and long-term hearing loss. What’s more, NR was equally effective regardless of whether it was given before or after the noise exposure.

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Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells.

Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF-α/IL-1β with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-α/IL-1β-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1β activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.

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Ursolic acid, a dietary phytochemical, decreases KRAS signaling and modulates cell death pathways in resistant CRC cells

KRAS mutations are frequent in colorectal cancer (CRC) and have the potential to activate proliferation and inhibit cell death through effects on MAPK/ERK and PI3K/Akt signaling pathways. Because diet is one of the most important determinants of CRC incidence and progression, we studied the effects of the dietary triterpenoid ursolic acid (UA) on proliferation and cell death induction in human CRC derived KRAS mutated cell lines.

 

Our results show that UA decreases cell proliferation and induces cell death while decreasing signaling through KRAS as indicated by a decrease in ERK and Akt phosphorylation (western blot). UA also induced cell death.

 

TP53 mutated cells are known to be resistant to the chemotherapeutic drug 5-FU. Caspase independent apoptosis (Tunel assay), was increased 6 fold by co-incubation of UA with 5-FU. However, apoptosis was only a small percentage of the total cell death induced by UA. In order to explain these observations, we looked into effects on autophagy. Autophagy is emerging as a promising therapeutic target for drug resistant tumors. UA modulated autophagy by inducing the accumulation of LC3 II and p62 levels an effect dependent on JNK activation.

 

In conclusion, this study shows UA’s anticancer potential as a modulator of KRAS signaling and cell death mechanisms increasing sensitivity to the chemotherapeutic drug 5-FU.

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Maybe Pauling was partly right – epigentic effects of Vitamin C

Maybe Pauling was partly right – epigentic effects of Vitamin C | A Tale of Two Medicines | Scoop.it

According to a paper just out in the Journal of Biological Chemistry, vitamin C, also known as ascorbic acid, may have a role in epigenetic regulation, specifically 5-hmC regulation. Gaofeng Wang at the University of Miami Miller School of Medicine and colleagues demonstrated that this critical dietary nutrient is involved in hydroxylation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in DNA, a reaction catalyzed by Tet methylcytosine dioxygenase.

 

This enzyme belongs to the Tet family proteins which, in turn, belong to the iron and 2-oxoglutarate-dependent dioxygenase superfamily. These enzymes catalyze the hydroxylation of many substrates, including methylated nucleic acids and proteins

 

The investigators found:

 

- The amount of 5-hmC was extremely low in mouse embryonic fibroblasts that were cultured in ascorbate-free medium. But when ascorbate was added in a dose- and time-dependent fashion, the amount of 5-hmC rose without affecting the expression of Tet genes.

 

- Treatment with the glutathione, a reducing agent, did not affect levels of 5-hmC

 

- Preventing the entry of ascorbate into cells and knocking down the expression of several Tet genes using short interference RNA technology inhibited the effect of ascorbate on 5-hmC.

 

Based on their data, the team concluded that ascorbate probably acts as a cofactor for Tet methylcytosine dioxygenase to hydroxylate 5-mC. Wang and colleagues say in the paper, “Our data support ascorbate as a critical mediator of the interface between the genome and environment.”

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Impacts of genetically engineered crops on pesticide use in the U.S. -- the first sixteen years

Genetically engineered, herbicide-resistant and insect-resistant crops have been remarkable commercial successes in the United States. Few independent studies have calculated their impacts on pesticide use per hectare or overall pesticide use, or taken into account the impact of rapidly spreading glyphosate-resistant weeds. A model was developed to quantify by crop and year the impacts of six major transgenic pest-management traits on pesticide use in the U.S. over the 16-year period, 1996–2011: herbicide-resistant corn, soybeans, and cotton; Bacillus thuringiensis (Bt) corn targeting the European corn borer; Bt corn for corn rootworms; and Bt cotton for Lepidopteron insects.

 

Herbicide-resistant crop technology has led to a 239 million kilogram (527 million pound) increase in herbicide use in the United States between 1996 and 2011, while Bt crops have reduced insecticide applications by 56 million kilograms (123 million pounds). Overall, pesticide use increased by an estimated 183 million kgs (404 million pounds), or about 7%.

 

Contrary to often-repeated claims that today’s genetically-engineered crops have, and are reducing pesticide use, the spread of glyphosate-resistant weeds in herbicide-resistant weed management systems has brought about substantial increases in the number and volume of herbicides applied. If new genetically engineered forms of corn and soybeans tolerant of 2,4-D are approved, the volume of 2,4-D sprayed could drive herbicide usage upward by another approximate 50%. The magnitude of increases in herbicide use on herbicide-resistant hectares has dwarfed the reduction in insecticide use on Bt crops over the past 16 years, and will continue to do so for the foreseeable future.

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Study Shows How Vitamin E Can Help Prevent Cancer

Study Shows How Vitamin E Can Help Prevent Cancer | A Tale of Two Medicines | Scoop.it

l studyResearchers Researchers have identified an elusive anti-cancer property of vitamin E that has long been presumed to exist, but difficult to find.

 

Many animal studies have suggested that vitamin E could prevent cancer, but human clinical trials following up on those findings have not shown the same benefits.

 

In this new work, researchers showed in prostate cancer cells that one form of vitamin E inhibits the activation of an enzyme that is essential for cancer cell survival. The loss of the enzyme, called Akt, led to tumor cell death. The vitamin had no negative effect on normal cells.

 

“This is the first demonstration of a unique mechanism of how vitamin E can have some benefit in terms of cancer prevention and treatment,” said lead author Ching-Shih Chen, professor of medicinal chemistry and pharmacognosy at The Ohio State University and an investigator in Ohio State’s Comprehensive Cancer Center.

 

The study appears in the March 19, 2013, issue of the journal Science Signaling.

 

 

Jonathan Middleton's insight:

Full study http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910367/

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Latest FDA Moves Could Stop Further Research on Supplements.

Latest FDA Moves Could Stop Further Research on Supplements. | A Tale of Two Medicines | Scoop.it

…and turn supplements into drugs. What is this agency thinking?

 

What the FDA does about supplements is usually complicated—we think intentionally so, in order to confuse Congress and critics. Bear with us as we try to disentangle the threads.

 

We need to get this story out now because the FDA has just opened a public comment period. It is vital to flood the agency and especially Congress with messages.

 

The FDA has a history of preventing scientific information about food and supplements from being disseminated. Now, if the agency gets its way, the FDA will be able to keep scientific research from being performed in the first place. In fact, our confidential sources tell us that studies on nutrients and dietary supplements are already coming to an abrupt halt. And it’s all because of the FDA’s guidance on INDs, or Investigational New Drug applications.

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Anti-HIV-1 Activity of Eight Monofloral Iranian Honey Types

Anti-HIV-1 Activity of Eight Monofloral Iranian Honey Types | A Tale of Two Medicines | Scoop.it

Monofloral Iranian honeys from eight floral sources were analyzed to determine their anti-HIV-1 activities as well as their effects on lymphocyte proliferation. The Peripheral Blood Mononuclear Cells (PBMCs) used in this study were prepared from five healthy volunteers who were seronegative for HIV, HCV, HBV and TB. The anti-HIV-1 activity of eight different honeys was performed by quantitative polymerase chain reaction (PCR) assay and high pure viral nucleic acid kit. The results demonstrated that monofloral honeys from Petro selinum sativum, Nigella sativa, Citrus sinensis, Zataria multiflora, Citrus aurantium and Zizyphus mauritiana flowers had potent anti-HIV-1 activity with half maximal effective concentration (EC50) values of 37.5, 88, 70, 88, 105 and 5 µg/ml respectively. However, monofloral Iranian honeys from Astragalus gummifer and Chamaemelum nobile flowers had weak anti-HIV-1 activity. The frequency and intensity of CD4 expression on PBMCs increased in the presence of all honey types. CD19 marker were also increased after the treatment with monofloral honeys from Z.multiflora and N. sativa. The anti-HIV-1 agent in monofloral honeys from P.sativum, N. sativa, Z. multiflora and Z. mauritiana flowers was detected by spectroscopic analysis as methylglyoxal. Time of drug addition studies demonstrated that the inhibitory effect of methylglyoxal is higher on the late stage of HIV-1 infection. The result demonstrated that methylglyoxal isolated from monofloral honey types is a good candidate for preclinical evaluation of anti-HIV-1 therapies.

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The Effects of Herbs and Fruits on Leukaemia

The Effects of Herbs and Fruits on Leukaemia | A Tale of Two Medicines | Scoop.it

There is an ocean of knowledge about medicinal plants, but still only a few pearls have been searched as therapeutic agents. This review article elaborated different species of plants and fruits used as traditional medicines against leukaemia. Studies suggested that herbal medicines have a great potential in combating leukaemia. These herbs and fruits could be the best candidate for future leukaemia therapy with minimal adverse effects, easier availability, and better acceptability as compared to chemotherapy and probably they will provide more potent antileukaemic agents in future.

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