Sanguisorba officinalis

Sanguisorba officinal
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Rosaceae

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Herb

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Great Burnet

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The Od Force of the whole of the plant is used as one of the components in the preparation of the remedy. It is a topoisomerase poison.

In the epithelial-mesenchymal transition (EMT), an important cellular process, epithelial cells become mesenchymal cells. . This process is also critically involved in cancer metastasis. In a rewinding process this Od Force cancels the imposed pharmacological activities employed to give the suffering human subject abatements, including anti-angiogenic activity. Transforming growth factor-beta 1 (TGF-β1) induces the EMT and promotes lung adenocarcinoma migration and invasion through the Smad2/3 signalling pathway. The chemical inhibitory effects on lung cancer migration and invasion, the Od Force in question here exhibits the inhibited TGF-β1-induced EMT in the A549 cell line as a result the focus of diversion that causes by the loss of the Od Force for which the said inhibition occurs. The significantly prevented the activation of Smad2/3 signalling pathway by TGF-β1 is hereby withdrawn. Additionally, this Od Force decreases the increased expression functions of the epithelial marker E-cadherin and withdraws the repression of the expression of Snail and the mesenchymal marker N-cadherin during TGF-β1-induced EMT. Moreover, it reverses the regulated expression of EMT-dependent genes induced by TGF-β1. Finally, it forces the wheel that caused inhibition of the migration and invasion of TGF-β1-stimulated A549 cells. It expresses the suppressed lung cancer migration and invasion by exhibiting the inhibiting TGF-β1 induction of the EMT to lift the focus from the nerve system.

The epithelial–mesenchymal transition (EMT) is important for generating multiple tissues during organismal development. This process is particularly essential for the gastrulation of metazoans and neural crest delamination of vertebrates. EMT is also involved in wound healing. However, EMT dysfunction leads to pathological conditions, including carcinogenesis and fibrosis. The most critical difference between embryonic and tumorigenic EMT is that genetically abnormal cells are employed during EMT for tumorigenesis, and these cells lose sensitivity to normal growth regulatory signals. During EMT, polarized epithelial cells are converted into mesenchymal cells. Therefore, epithelial cells lose characteristics that enable differentiation, including cell–cell adhesion, apical–basal polarity and motility dysfunction, and obtain mesenchymal properties, such as motility, invasiveness and apoptotic resistance. So EMT affects embryo formation, implantation, organ development and the generation of various cell types. EMT promotes wound healing, tissue regeneration and fibrosis, and participates in inflammation.  EMT is involved in cancer progression and metastasis.

Embryonic stem cells (ESCs) are acquired from the inner cell mass of early blastocysts. Accordingly, these cells differentiate into multiple cell types

Cadherins are calcium ion-dependent glycoproteins expressed on the cell surface. These proteins are involved in cell–cell adhesion and interaction. The cadherin family is divided into type 1 and type 2. E-cadherin is a cadherin family member that possesses a single-pass transmembrane domain, and this protein is primarily detected in epithelial cells. Although the region of E-cadherin that participates in cell–cell adhesion is unknown, the histidine-alanine-valine domain might have an important role in cell–cell interaction. E-cadherin has two preserved domains: the β-catenin-binding domain and p120-binding domain. The β-catenin-binding domain promotes the interaction between the actin cytoskeleton and E-cadherin. This interaction is achieved through the cytoplasmic cell adhesion complex, which comprises epithelial protein lost in neoplasm, β-catenin and α-catenin. As decreased E-cadherin expression on the cell surface might be involved in tumor progression and metastasis, E-cadherin is considered a repressor of tumor progression and metastasis. Decreased E-cadherin expression breaks down cell–cell contact and increases EMT induction, resulting in tumor motility. In colorectal carcinoma, which expresses STAT3, the expression of E-cadherin was decreased. However, the induction of small interfering RNA for STAT3 increased E-cadherin expression, thereby decreasing the invasive properties and expression of vimentin and N-cadherin in these cells. E-cadherin has also been associated with transcriptional repressive pathways through the E-box-binding proteins, Snail and Slug, and matrix metalloproteinase-7 (MMP-7) and MMP-13. For example, MMP-7 and MMP-13 can remove the extracellular E-cadherin domain, and the deleted soluble ectodomain might suppress E-cadherin activity in neighbouring cells.

A number of transcription factors, including Snail, ZEB and helix–loop–helix (HLH) family members, regulate EMT. In vertebrates, the Snail family comprises three members: Snail 1, Snail 2 and Snail 3. Snail 1 is also called ‘Snail,' and Snail 2 is also known as ‘Slug,' and these proteins suppress the expression of epithelial genes, such as E-cadherin and plakoglobin, and also activate the expression of mesenchymal proteins, including N-cadherin and fibronectin. The activation of the Snail family depends on a conserved zinc finger domain and an N-terminal snail/Gfi domain. In addition, the C-terminal region attaches to the E-box, represses the expression of target genes associated with epithelial cell markers and activates mesenchymal protein expression. Other transcription factors, including Ets-1 and specificity protein 1 are also involved in this process. The Snail family members are important factors for EMT regulation. In colon cancer (DLD1), cells transfected with Snail and Slug show increased β-catenin –T-cell factor-4 transcription complex formation. This complex increases the expression of transforming growth factor (TGF)-β3, resulting in the TGF-β3-induced upregulation of lymphoid enhancer factor-1 gene expression, which induces the EMT response. In addition, TGF-β1 and 2 stimulate EMT signalling pathways through Snail and Slug. Snail blocks epithelial markers, that is, cytokeratin-18, Muc-1, desmoplakin and E-cadherin, thereby increasing the expression of fibronectin and vimentin. It upregulates Rho-GTPase during gastrulation, resulting in cytoskeletal changes. In lung cancer, Slug acts as a metastasis-promoting gene, demonstrating that slug downregulates E-cadherin expression, upregulates MMP-2 and increases angiogenesis.

HLH family members also influence the EMT process. This protein family can be divided into seven groups. Class 1 HLH proteins include E12 and E47, class 2 HLH proteins include twist and class 5 HLH proteins include Ids. These three HLH groups, classes 1, 2, 5, are involved in EMT induction. E12 or E47 inhibit the expression of E-cadherin and plakoglobin and increase the production of vimentin and fibronectin. Ids repress transcription through different molecules, such as TGF-β, associated with the repression of E-cadherin expression. Ids do not bind DNA, but rather bind to E12 or E47, acting as negative inhibitors. The ectopic expression of twist represses the expression of E-cadherin, occludin and claudin-7 and facilitates the expression of vimentin and N-cadherin to enhance cancer cell migration and invasion. Twist forms a heterodimer with E12 and E47, and this dimer regulates transcription through DNA binding.

In vertebrates, the ZEB family includes ZEB1 (deltaEF1 or AREB6) and ZEB2 (smad-interacting protein 1, SIP1). ZEB family proteins possess a zinc finger cluster at each end, which interacts with DNA. A repressor motif in the central homeodomain and the recruitment of C-terminal-binding protein as a co-repressor mediate transcriptional repression through ZEB1 and ZEB2. However, the interaction between ZEB, PCAF and p300 converts ZEB1 from a repressor to an activator. These proteins reduce epithelial marker expression and increase mesenchymal marker expression during the induction of EMT. ZEB is activated through other signalling molecules, such as TGF-β, and growth factors that activate Ras/mitogen-activated protein kinase; in addition, this protein is repressed through microRNA 200 and microRNA 250 family members.

Several pathways regulate the EMT, including pathways involving TGF-β, Wnt, receptor tyrosine kinase (RTK), hedgehog, tumor necrosis factor-α and Notch. TGF-β is an important molecule for the induction of EMT during metastasis and embryogenesis. TGF-β was shown to have two actions: tumor suppression and tumor promotion. TGF-β acts as a tumor repressor during early tumor growth and induces cell growth arrest and apoptosis. During late tumor growth, TGF-β initiates cancer progression and metastasis through smad-dependent or smad-independent signalling pathways.  The Smad-dependent signalling pathway regulates EMT through the expression of snail, ZEB and twist. These transcriptional regulators repress the expression of epithelial markers, such as E-cadherin, plakoglobin and occludin, and also activate mesenchymal markers, including vimentin, fibronectin and N-cadherin. TGF-β signalling involves ligand binding to TGF receptors (TβR1 and TβR2). Smad2/3 is subsequently activated and forms a complex with smad4. Smad 2/3/4 complexes translocate to the nucleus and interact with other transcription factors to regulate the expression of target genes. Smad-independent pathways include phosphoinositide 3-kinase/Akt, Ras, mitogen-activated protein kinase and Rho-like GTPase pathways. These pathways upregulate the expression of snail, twist and ZEB. TGF-β also promotes EMT through interactions with Wnt and Notch.

The Notch pathway is initiated through interactions between the Notch receptor and ligands on adjacent cells. Four Notch receptors (1–4) and five ligands (Dll-1, Dll-3, Dll-4, Jagged-1 and Jagged-2) exist in mammals. Notch signalling is initiated through ligand binding to an adjacent receptor. Subsequently, γ-secretase cleaves the intramembrane Notch receptor. The released Notch intracellular domain translocates to the nucleus and interacts with C-protein-binding factor 1/Suppressor of Hairless/Lag-1 and acts as an activator of target genes, including Hes and Hey.  Notch signalling is insufficient to completely induce EMT and crosstalk with other signalling molecules might therefore be required, the Notch signalling pathway has been considered an important regulator for the induction of EMT. Notch activation morphologically, phenotypically and functionally converts epithelial cells into mesenchymal-type cells. This change has been associated with the downregulation of epithelial markers, including E-cadherin, Tei1, Tei2 and platelet–endothelial epithelial cell adhesion molecule-1, and the upregulation of mesenchymal markers, such as α-smooth muscle actin (SMA) and fibronectin.  Snail and slug are induced through Notch signalling to promote EMT, which has an important role during both embryonic development and tumor progression.

Wnt signalling is also important for diverse cell functions via canonical (β-catenin) or noncanonical pathways. The formation of the Wnt–Fz–LRP complex through the binding of ligands, that is, wnt1 and wnt3, to their receptors, Frizzled (Fz) and LRP 5/6, initiates the canonical pathway. Without the Wnt signalling pathway, cytoplasmic β-catenin forms a complex with Axin, adenomatous polyposis coli, glycogen synthase kinase-3β and Ck1. When the cell receives Wnt signals, a complex is formed between LRP5/6 and Fz. These structures affect β-catenin stabilization, nuclear translocation and protein accumulation. In the nucleus, β-catenin forms a complex with T-cell factor/lymphoid enhancer factor, thereby initiating the expression of Wnt target genes. During EMT, smad2 and smad 4 influence Wnt signaling to repress E-cadherin expression in medial-edge epithelial cells. Lymphoid enhancer factor-1 has also been associated with mesenchymal marker expression. Other studies have suggested that wnt3 promotes EMT through the increased expression of N-cadherin, twist and slug and the decreased expression of E-cadherin in the trastuzumab-insensitive cells, SKBR3/100-8 and BT474/100-2. The activation of Wnt signalling is important for the induction of EMT in breast and prostate cancers.

RTK signalling alone does not induce EMT. Therefore, interplay with other signalling molecules might be required. Growth factors, such as hepatocyte growth factor, epidermal growth factor and fibroblast growth factor, bind to their respective receptors and activate extensive crosstalk networks that affect EMT. These growth factors switch signals through the structural activation of RTK, which activates TGF-β and integrin signalling pathways to alter EMT. Three activities occurring downstream of Ras might be required for the induction of EMT: smad2 activation, phosphoinositide 3-kinase/Akt pathway initiation and Raf/mitogen-activated protein kinase signalling pathway.

 In most ESCs, the transformation of epithelial cells into mesenchymal cells might occur during ESC differentiation. Differentiation of human ESCs involves (1) the conversion from E-cadherin to N-cadherin, (2) increased vimentin expression, (3) the increase of repression molecules of E-cadherin, such as Snail and Slug, and (4) increased gelatinase activity and cellular motility. In undifferentiated human ESCs, the abrogation of E-cadherin-mediated cell–cell contact increases cellular motility and induces actin cytoskeleton rearrangement. The 5T4 antigen is expressed on the cell surface, generating a mesenchymal phenotype. The expression of the 5T4 oncofetal antigen is upregulated in colorectal, gastric and ovarian carcinomas. Overexpression of 5T4 antigen on mouse ESCs reduces cell–cell contact, downregulates E-cadherin expression and alters the actin cytoskeleton in epithelial cells. The lack of 5T4 antigen is involved in increase of the restoration of cell–cell contact, and the upregulation of E-cadherin production prevents the development of a mesenchymal morphology. This effect might reflect the stabilization of the cortical actin cytoskeleton rearrangement through E-cadherin, which blocks 5T4 antigen localization. Human ESC colonies, cultured under feeder-free conditions, undergo differentiation and develop a mesenchymal cell-like phenotype. The mesenchymal-like cells express more mesenchymal markers compared with a single upper layer of columnar (zone 1) cells. Human pluripotent stem cells resemble cells obtained from the epiblast. The occurrence of EMT in human pluripotent stem cells and embryoid bodies reflects the EMT observed during gastrulation in human development. Although ptk7-positive cells lose pluripotent marker and E-cadherin expression and acquire mesenchymal marker expression, ptk7 did not affect pluripotency or lineage marker changes.  EMT in ESCs might induce differentiation through several pathways.

MicroRNA acts as a regulator of EMT in many cell types. The microRNA 200 family members suppress EMT and the differentiation of ESCs at the epiblast stem cell stage. The mesenchymal–epithelial transition is important in reprogramming fibroblasts. OCT4, SOX2, Klf4 and c-Myc are imported into fibroblasts, and these proteins induce the rapid downregulation of microRNA-155 and microRNA-10b, associated with EMT, and the upregulation of microRNA-205 and -429 during the development of induced pluripotent stem cells.  EMT is associated with the differentiation of ESCs. Certain factors, that is, the microRNA family, which regulate EMT at various pluripotent stages exist. Naïve cells are thought to be more undifferentiated than primed cells; these regulating factors may have an influence on pluripotent stages of naïve and primed cells.

EMT is important for embryonic development, and this process affects metastasis and the invasion of various cancers. Several molecules, including TGF-β and other growth factors, induce EMT. These factors bind to their respective receptors and might also interact with each other. Various signalling pathways (for example, the TGF-β, Wnt/glycogen synthase kinase-3β, Notch and RTK signalling pathways) might be critical for the induction of EMT. ESCs are pluripotent. These cells can differentiate into many cell types.  ESCs might be controlled through EMT under various circumstances during differentiation. Transcriptional activators of EMT, such as snail and ZEB may also implicated in the differentiation of ESCs, and regulating factors, such as the microRNA family, specifically promoted or inhibited EMT at the pluripotent cell stage. Thus, ESCs remain at either the pluripotent stage or the more differentiated stage. EMT and regulating factors regulate the differentiation of ESCs. Because ESCs, rather than epiblast stem cells, are more undifferentiated, these cells undergo EMT differentiation, suggesting that this process contributes to naïve and primed cell types. So any chemical activity to control any suffering will be leaded to focus the further loss of the Od Force caused by this said chemical performances from the previous suffering zone to some other zone and naturally the loss here affects the cell to cell negatively charged electromagnetic circuit(s) are of the nerve system.

This Od Force exerts its exhibitory mechanism to lift the chemical inhibitory activities over the DNA topoisomerases. Catalytic strand-passing activities of topoisomerases I and II are inhibited. In cancelling this inhibition this Od Force in question overrules the mechanism that prevents the formation of covalent enzyme-DNA complexes intermediates. In its anti-poison it shows no stimulation withdrawal activities towards the formation of cleavable-complexes, with intracellular activity but without any marked selectivity.

The reorganized focusing on the nerve system due to chemical activities covering mainly four meridians of liver, lungs, kidneys and large intestine due to loss of the Od Force caused by the material treatment thereon is reversed herewith.

The Od Force in question exhibits the imposed chemical inhibition on the both CCR5 and CXCR4 tropic HIV-1 (ADA and HXB2). It also inhibits simian immunodeficiency. It erases the footprints left chemically in the human system reverse transcriptase inhibitor resistant viruses (K103N, Y188L, and K103N/Y188L/G190A) and a protease inhibitor resistant strain (PI-2840).

It withdraws the chemical diversion caused from the material treatment of the wound and ant-scar. Similarly it lifts the chemical shifts caused from the chemical activities imposed on the red blood cells causing anaemia or worse. It puts anti-irritant force on the irritation on the mucous membrane. It soothes the stimulated immune system. So in result it sweeps the foot prints dusts risk caused by the infection. The chemical hepatoprotective shifts which naturally focus on the nerve system are withdrawn herewith. The cell to cell negatively charged electromagnetic circuit(s) which has been deactivated materially for which the building of the cholesterol is disordered, is further hurt chemically to combat the said cholesterol build up. As a result a new focus appears on the nerve system. This diversion is withdrawn hare again. It exhibits the inhibited hepatic synthesis of cholesterol, activates the deactivated cell to cell electromagnetic circuit(s) the focus of which established after the chemical activity that decreases cholesterol absorption from the gut, increases cholesterol excretion.

The caused gastrointestinal distress is withdrawn by erasing the effective focus on the nerve system. In the same way the reflex expectorant effect is also rewind. In this respect the Od Force in question here interfere with the caused increase in the production of mucus in the lungs. On the contrary the respective chemical or material activity helps the patients of coughs of all sorts, but particularly for those with dry cough but with the diversion due to further loss of the Od Force caused as the chemical or material activity helps the patients of coughs or dry cough. It reverses the immune modulating and steps back the consistency of diversion of antineoplastic effects.

So this Od Force is anti-haemolytic. Anti-hypolipidemic, anti-immunomodulating and anti-cytotoxic and in the same way it erases the foot marks of the microbials. It cancels the diversions caused from the selected free radicals, antioxidant activities, reduced LDL cholesterol and inhibit the growth of cancerous.

In the way of taken charge of astringency and coagulant properties the human system further faces the additional loss of the Od Force here through a new focus preferably on the nerve is withdrawn herewith.In this way it plays the important role in withdrawing the diversion caused chemically in cases of prevented hemorrhages and internal bleeding. While the haemorrhages are being stopped the effective speed of blood circulation goes to a down status by the cost of mounted anti-circulating energy here and or this a new focus of imbalance will be viewed the erase of which is done herewith. The rearranged focus in treating hematochezia, bloody haemorrhoid with bright red colour chemically may come in force to exhibit even purging. Red profuse vaginal bleeding of metrorrhagia and metrostaxis due to blood heat accompanied by dry mouth and lips---the focusing zones of the nerve is a subject of withdrawing perfomance by this Od Force. It withdraws the diversion of materially treated blood lingering dysentery, actions of purging fire and relieving toxicities, empyrosis by lifting the diversions caused from cleared heat and cooled blood, relieved toxicity and eliminated swelling. It escorts the human system from suffering mostly burning from the externally medication to prevent toxic hepatitis due to lots of tannin absorption it contains. It adds up the lost Od Force resulted from the material treaments of abscess and carbuncle before and after pus is formed. The diversions from chemically treated various skin conditions are also under the surveillance of this Od Force for withdrawing the diversion herefrom. The constriction functioning on the blood vessel that stops bleeding of varicose veins, sweeling of the blood vessels on the surface of skin, eczema, burns, etc. are done reversed to salvage the additionally suffering human subjects. It also finds out the chemical shifts came from the diarrhea, leucorroea etc. like abnormal discharges to to counterbalance the Od Force that had been lost during the chemical process that keeps the sufferings behind the curtain as if the same has been cured. The chemical diversion of peptic ulcers and haematuria is also in the curing capability of thid Force selectively.