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      Tinospora cordifolia protects against inflammation associated anemia by modulating inflammatory cytokines and hepcidin expression in male Wistar rats

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          Abstract

          Systemic iron homeostasis dysregulation is primarily associated with inflammation- associated anemia (AI) due to hepcidin up-regulation. Tinospora cordifolia (TC) has shown remarkable anti-inflammatory properties and has been found useful in the treatment of inflammatory disorders. However, the effects and mechanisms of TC on AI have not been studied yet. We conducted in vivo and in vitro studies to evaluate the effect of TC on AI. HPLC studies were also carried out to find out active constituents in TC extract. Model system exhibiting AI was developed by repeated injections of HKBA in Wistar rats. TC treated groups showed significantly higher levels of Hb and RBC count compared to the inflammatory control group. TC treatment showed reduction in the expression of the HAMP (hepcidin) gene in the rat liver. TC extract also inhibited gene expression of inflammatory cytokines (TNF-α, IL-1β) and decreased NO production in RAW 264.7 cells. The HPLC analysis revealed the presence of tinosporaside, which could have synergistically contributed to the above findings. Overall results indicate that TC therapy was able to maintain circulating iron through reduction of inflammatory cytokines and expression of hepcidin in rats.

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          Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi) – validation of the Ayurvedic pharmacology through experimental and clinical studies

          T. cordifolia (Guduchi) is a large, glabrous, perennial, deciduous, climbing shrub of weak and fleshy stem found throughout India. It is a widely used plant in folk and Ayurvedic systems of medicine. The chemical constituents reported from this shrub belong to different classes, such as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, phenolics, aliphatic compounds and polysaccharides. Various properties of T. cordifolia, described in ancient texts of Ayurveda, like Rasayana, Sangrahi, Balya, Agnideepana, Tridoshshamaka, Dahnashaka, Mehnashaka, Kasa-swasahara, Pandunashaka, Kamla-Kushta-Vataraktanashaka, Jwarhara, Krimihara, Prameha, Arshnashaka, Kricch-Hridroganashak, etc., are acquiring scientific validity through modern research adopting "reverse pharmacological" approach. Potential medicinal properties reported by scientific research include anti-diabetic, antipyretic, antispasmodic, anti-inflammatory, anti-arthritic, antioxidant, anti-allergic, anti-stress, anti-leprotic, antimalarial, hepato-protective, immuno-modulatory and anti-neoplastic activities. This review brings together various properties and medicinal uses of T. cordifolia described in Ayurveda, along with phytochemical and pharmacological reports.
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            Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia.

            Iron maldistribution has been implicated in multiple diseases, including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25-amino acid peptide. Hepcidin is induced by inflammation, causes iron to be sequestered, and thus, potentially contributes to AI. Human hepcidin (hHepc) overexpression in mice caused an iron-deficient phenotype, including stunted growth, hair loss, and iron-deficient erythropoiesis. It also caused resistance to supraphysiologic levels of erythropoiesis-stimulating agent, supporting the hypothesis that hepcidin may influence response to treatment in AI. To explore the role of hepcidin in inflammatory anemia, a mouse AI model was developed with heat-killed Brucella abortus treatment. Suppression of hepcidin mRNA was a successful anemia treatment in this model. High-affinity antibodies specific for hHepc were generated, and hHepc knock-in mice were produced to enable antibody testing. Antibody treatment neutralized hHepc in vitro and in vivo and facilitated anemia treatment in hHepc knock-in mice with AI. These data indicate that antihepcidin antibodies may be an effective treatment for patients with inflammatory anemia. The ability to manipulate iron metabolism in vivo may also allow investigation of the role of iron in a number of other pathologic conditions.
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              The liver: conductor of systemic iron balance.

              Iron is a micronutrient essential for almost all organisms: bacteria, plants, and animals. It is a metal that exists in multiple redox states, including the divalent ferrous (Fe(2+)) and the trivalent ferric (Fe(3+)) species. The multiple oxidation states of iron make it excellent for electron transfer, allowing iron to be selected during evolution as a cofactor for many proteins involved in central cellular processes including oxygen transport, mitochondrial respiration, and DNA synthesis. However, the redox cycling of ferrous and ferric iron in the presence of H2O2, which is physiologically present in the cells, also leads to the production of free radicals (Fenton reaction) that can attack and damage lipids, proteins, DNA, and other cellular components. To meet the physiological needs of the body, but to prevent cellular damage by iron, the amount of iron in the body must be tightly regulated. Here we review how the liver is the central conductor of systemic iron balance and show that this central role is related to the secretion of a peptide hormone hepcidin by hepatocytes. We then review how the liver receives and integrates the many signals that report the body's iron needs to orchestrate hepcidin production and maintain systemic iron homeostasis.
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                Author and article information

                Contributors
                ppkulkarni@aripune.org
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                29 July 2019
                29 July 2019
                2019
                : 9
                : 10969
                Affiliations
                [1 ]ISNI 0000 0001 0730 5817, GRID grid.417727.0, Bioprospecting Group, , Agharkar Research Institute, ; G. G. Agarkar Road, Pune, 411004 Maharashtra India
                [2 ]ISNI 0000 0001 2190 9326, GRID grid.32056.32, Savitribai Phule Pune University, ; Ganeshkhind, Pune, 411007 Maharashtra India
                [3 ]ISNI 0000 0001 0730 5817, GRID grid.417727.0, Animal House, Developmental Biology Group, , Agharkar Research Institute, ; G. G. Agarkar Road, Pune, 411004 Maharashtra India
                Author information
                http://orcid.org/0000-0002-3929-2990
                Article
                47458
                10.1038/s41598-019-47458-0
                6662690
                31358831
                c5a7a7a8-7038-4f57-9d79-54a45565e300
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 April 2019
                : 12 July 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001411, Indian Council of Medical Research (ICMR);
                Categories
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                © The Author(s) 2019

                Uncategorized
                anaemia,iron
                Uncategorized
                anaemia, iron

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